Database Query Results : , , ROS

ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2 inhibition: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α inhibition: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK activation: regulates energy metabolism and can increase ROS levels when activated.
• mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90 inhibition: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Mevalonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day, -Dipyridamole typically 200mg 2x/day Combined effect research
-Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2)

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy 
ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference
-generated from AI and Cancer database
ROS rating:  +++ strong | ++ moderate | + weak | ± mixed | 0 none
NRF2:        ↓ suppressed | ↑ activated | ± mixed | 0 none
Conditions:  [D] dose  [Fe] metal  [M] metabolic  [O₂] oxygen
             [L] light [F] formulation [T] tumor-type [C] combination




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



ROS">Piperlongumine
+++ ↓ [D][T] ROS-dominant






ROS">Shikonin
+++↓/±[D][T]ROS-dominant






ROS">Vitamin K3 (menadione)
+++↓[D]ROS-dominant






ROS">Copper (ionic / nano)
+++↓[Fe][F]ROS-dominant






ROS">Sodium Selenite
+++↓[D]ROS-dominant






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






ROS">Photodynamic Therapy (PDT)
+++0[L][O₂]ROS-dominant






ROS">Radiotherapy / Radiation
+++0[O₂]ROS-dominant






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






ROS">Salinomycin
++↓[D][T]ROS-dominant






ROS">Artemisinin / DHA
++↓[Fe][T]ROS-dominant






ROS">Sulfasalazine
++↓[C][T]ROS-dominant






ROS">FMD / fasting
++↓[M][C][O₂]ROS-dominant






ROS">Vitamin C (pharmacologic)
++↓[Fe][D]ROS-dominant






ROS">Silver nanoparticles
++±[F][D]ROS-dominant






ROS">Gambogic acid
++↓[D][T]ROS-dominant






ROS">Parthenolide
++↓[D][T]ROS-dominant






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






ROS">Ashwagandha (Withaferin A)
++↓[D][T]ROS-dominant






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






ROS">Methionine restriction
+↓[M][C][T]ROS-secondary






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






ROS">Galloflavin
+0[D]ROS-secondary






ROS">Piperine
+±[D][F]ROS-secondary






ROS">Propyl gallate
+↓[D]ROS-secondary






ROS">Scoulerine
+?[D][T]ROS-secondary






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






ROS">Alpha-lipoic acid (ALA)
±↑[D][M]NRF2-dominant






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






ROS">Quercetin
±↑/↓[D][Fe]NRF2-dominant






ROS">Resveratrol
±↑[D][M]NRF2-dominant






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
4384- ,    Silver nanoparticles: synthesis, properties, and therapeutic applications
- Review, Var, NA
AntiCan↑, AgNPs are employed in newly emerging applications as photosensitizers/radiosensitizers, antiviral and anticancer agents.
RadioS↑,
CellMemb↑, underlying anticancer mechanisms of AgNPs include (1) disruption of cell membranes, and (2) production of reactive oxygen species and Ag+ to damage protein or DNA.
ROS↑,
DNAdam↑,
PhotoS↑, photosensitizing mechanism of AgNPs is based on nonradiative decay converting photo energy to thermal energy.
eff↑, Smaller particles have a larger surface area and, therefore, have greater toxic potential

2327- 2DG,    2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents
- Review, Var, NA
Glycolysis↓, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death
HK2↓,
mt-ROS↑, 2-DG-mediated glucose deprivation stimulates reactive oxygen species (ROS) production in mitochondria, also leading to AMPK activation and autophagy stimulation.
AMPK↑,
PPP↓, 2-DG has been shown to block the pentose phosphate shunt
NADPH↓, Decreased levels of NADPH correlate with reduced glutathione levels, one of the major cellular antioxidants.
GSH↓,
Bax:Bcl2↑, Valera et al. also observed that in bladder cancer cells, 2-DG treatment modulates the Bcl-2/Bax protein ratio, driving apoptosis induction
Apoptosis↑,
RadioS↑, 2-DG radiosensitization results from its effect on thiol metabolism
eff↓, (NAC) treatment, downregulated glutamate cysteine ligase activity, or overexpression of ROS scavenging enzymes
Half-Life↓, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate
other↝, Adverse effects of 2-DG administration in humans include fatigue, sweating, dizziness, and nausea, mimicking the symptoms of hypoglycemia
eff↓, Moreover, 2-DG has to be used at relatively high concentrations (≥5 mmol/L) in order to compete with blood glucose

1336- 2DG,    2-deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells
- in-vitro, GBM, SK-N-SH
ROS↑, selectively enhancing metabolic oxidative stress.
GlucoseCon↓, mimic in vitro glucose deprivation that selectively kills cancer cells by oxidative stress.
other↓, Treatment with antioxidants protects neuroblastoma cells from 2DG-induced cell killing

1337- 2DG,  Rad,    2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer
- in-vivo, NA, NA
ChemoSen↑, combination of 2DG and ionizing radiation resulted in greater inhibition of tumor growth and increased survival, relative to either agent alone
GlucoseCon↓,
ROS↑,

1339- 2DG,  Cisplatin,    2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells
- in-vitro, HNSCC, FaDu
ChemoSen↑, combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone
ROS↑,
GSH↓,
other↓, Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin.

1341- 3BP,    The HK2 Dependent “Warburg Effect” and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate
- Review, NA, NA
Glycolysis↓, second-generation glycolysis inhibitor.
OXPHOS↓,
*toxicity↓, Normal cells remain unharmed
ROS↑, well known that this compound generates ROS
GSH↓,
eff↑, 3BP demonstrates synergistic activity with other compounds that reduce intracellular levels of GSH

5271- 3BP,    The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside
- Review, Var, NA
selectivity↑, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues.
selectivity↑, results obtained in cancer research with this small molecule have contradicted the just noted general fear. Indeed, a promising drug has been revealed with an effective mechanism of action and an outstanding selectivity towards cancer cells
ATP↓, once inside cancer cells 3BP can then inhibit both of their energy (ATP) producing systems, i.e., glycolysis, likely by inhibiting hexokinase-2 (hk-2) and mitochondrial oxidative phosphorylation
Glycolysis↓,
HK2↓,
mt-OXPHOS↓,
GAPDH↓, Different reports have shown that 3BP is able to inhibit GAPDH activity leading to the loss of the ATP-producing steps that occur downstream of this enzyme
mtDam↑, Mitochondria related cell death has also been reported following 3BP treatment.
GSH↓, Ehrke and co-workers have demonstrated that 3BP inhibits glycolysis and deplete the glutathione levels in primary rat astrocytes
ROS↑, Others have also observed an increase in ROS levels following 3BP treatment that induces endoplasmic reticulum stress
ER Stress↑,
TumAuto↑, Autophagy has been associated with 3BP activity in breast cancer cell lines (Zhang et al., 2014),
LC3‑Ⅱ/LC3‑Ⅰ↑, 3BP leads to aggressive autophagy involving a decrease in the ratio of LC3I/LC3II and the levels of p62 as well as dephosphorylation of Akt and p53.
p62↓,
Akt↓,
HDAC↓, 3BP’s, it has been reported to be involved in suppressing epigenetic events as it inhibits histone deacetylase (HDAC) isoforms 1 and 3 in MCF-7 breast cancer cells leading to apoptosis
TumCA↑, Proliferation inhibition by 3BP treatment has also been related with the induction of S-phase and G2/M- phase arrest (Liu et al. 2009)
Bcl-2↓, downregulation of the expression of Bcl-2, c-Myc and mutant p53, the upregulation of Bax, activation of caspase-3 and mitochondrial leakage of cytochrome c
cMyc↓,
Casp3↑,
Cyt‑c↑,
Mcl-1↓, mitochondria mediated apoptosis triggered by 3BP was found to be associated with the downregulation of Mcl-1 through the phosphoinositide-3-kinase/Akt pathway (Liu et al. 2014).
PARP↓, 3BP treatment decreases the levels of poly(ADP-ribose) polymerase (PARP) and cleaved PARP.
ChemoSen↑, it might be a good adjuvant for commonly used chemotherapy agents, or a replacement for such agents.

5277- 3BP,    3-Bromopyruvate inhibits pancreatic tumor growth by stalling glycolysis, and dismantling mitochondria in a syngeneic mouse model
- in-vivo, PC, Panc02
HK2↓, It exerts potent anticancer effects by inhibiting hexokinase II enzyme (HK2) of the glycolytic pathway in cancer cells while not affecting the normal cells.
selectivity↑, it doesn’t affect the normal cells but strongly toxic to cancer cells
ATP↓, 3-BP killed 95% of Panc-2 cells at 15 μM concentration and severely inhibited ATP production by disrupting the interaction between HK2 and mitochondrial Voltage Dependent Anion Channel-1 (VDAC1) protein.
mtDam↑, Electron microscopy data revealed that 3-BP severely damaged mitochondrial membrane in cancer cells.
Dose↝, We further examined therapeutic effect of 3-BP in syngeneic mouse pancreatic cancer model by treating animals with 10, 15 and 20 mg/kg dose. 3-BP at 15 & 20 mg/kg dose level significantly reduced tumor growth by approximately 75-80% in C57BL/6 female
TumCG↓, 3-BP inhibit in vivo pancreatic tumor growth in C57BL/6 mouse model
Casp3↑, observed enhanced expression of active caspase-3 in tumor tissues exhibited apoptotic death.
Glycolysis↓, Notably, metabolomic data also revealed severe inhibition in glycolysis, NADP, ATP and lactic acid production in cancer cells treated with 40 μM 3-BP.
NADPH↓,
ATP↓,
ROS↑, 3-BP treatment produces increased levels of reactive oxygen species (ROS), which causes DNA damage with reduction of free glutathione levels [11].
DNAdam↑,
GSH↓,
Bcl-2↓, Further, treatment with 40 µM of 3-BP suppressed BCL2L1 expression and causing activation of mitochondrial caspases
Casp↑,
lactateProd↓, Metabolic inhibition of glucose consumption and lactic acid production in cancer cells treated with 3-BP

5273- 3BP,    The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view
- Review, Var, NA
AntiCan↑, 3BP exhibited strong anticancer effects in both preclinical and human studies e.g. energy depletion, oxidative stress, anti-angiogenesis, anti-metastatic effects, targeting cancer stem cells and antagonizing the Warburg effect.
ROS↑,
angioG↓,
CSCs↓,
Warburg↓,
GSH↓, Reported decrease in endogenous cellular GSH content upon 3BP treatment was confirmed to be due to the formation of 3BP-GSH complex i
Thiols↓, Being a thiol blocker, 3BP may attack thiol groups in tissues and serum proteins e.g. albumin and GSH.

5272- 3BP,    The efficacy of the anticancer 3-bromopyruvate is potentiated by antimycin and menadione by unbalancing mitochondrial ROS production and disposal in U118 glioblastoma cells
- in-vitro, GBM, U87MG - in-vitro, Nor, HEK293
Glycolysis↓, We used the antiglycolytic 3-bromopyruvate (3BP) as a metabolic modifier to treat U118 glioblastoma cell
ROS↑, ROS generated in mitochondria were enhanced at 30 μM 3BP, possibly by unbalancing their generation and their disposal because of glutathione peroxidase inhibition.
GPx↓,
eff↓, Indeed, the scavenger of mitochondrial superoxide MitoTEMPO counteracted 3BP-induced cyt c release and weakened the potentiating effect of 3BP/
OXPHOS↓, (3BP) is a reactive non-specific drug that can act as a metabolic modifier by interfering with glycolysis and oxidative phosphorylation in cancer cells
HK2↓, The mitochondrial hexokinase-II is the main target since its activity is specifically blocked by the formation of a pyruvinyl adduct after reacting with 3BP at the surface of the outer mitochondrial membrane
ATP↓, In malignant tumour cell lines, 3BP inhibits ATPase activity, reduces ATP levels, and reverses chemoresistance by antagonizing drug efflux by acting on the ATP-binding cassette transporters (
ROS↑, Furthermore, 3BP increases the production of reactive oxygen species (ROS) (Ihrlund et al., 2008; Kim et al., 2008; Macchioni et al., 2011a), induces ER stress,
ER Stress↑,
BioAv↓, Unfortunately, prolonged treatment with the drug reduces ROS levels and confers resistance by inducing regulatory genes that act on antioxidant systems.
Cyt‑c↑, 3BP induces cytochrome c release without triggering an apoptotic cascade in U118 cells
eff↑, The ROS enhancers antimycin and menadione sensitize U118 cells to 3BP

5263- 3BP,  CET,    3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis
- in-vitro, CRC, DLD1 - NA, NA, HCT116
eff↑, Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines
Ferroptosis↓, co-treatment induced ferroptosis, autophagy, and apoptosis.
TumAuto↑,
Apoptosis↑,
FOXO3↑, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1
AMPKα↑,
p‑Beclin-1↑,
HK2↓, 3-Bromopyruvate (3-BP), also known as hexokinase II inhibitor II, has shown promise as an anticancer agent against various types of cancer
ATP↓, 3-BP exerts its anticancer effects by manipulating cell energy metabolism and regulating oxidative stress, as evidenced by the accumulation of reactive oxygen species (ROS) [13,14,15,16].
ROS↑,
Dose↝, Eight days postinoculation, xenografted mice were randomly divided into four groups and intraperitoneally injected with PBS, 3-BP, cetuximab, or a combination of 3-BP and cetuximab every four days for five injections.
TumVol↓, 3-BP alone or co-treatment with 3-BP and cetuximab significantly reduced the tumor volume and tumor weight on Day 28, but co-treatment showed a greater reduction than 3-BP alone
TumW↓,
xCT↑, The protein level of SLC7A11 was significantly upregulated in all three cell lines following co-treatment (Fig. 2B).
GSH↓, co-treatment with 3-BP and cetuximab led to glutathione (GSH) depletion (Fig. 2D), reactive oxygen species (ROS) production
eff↓, Knockdown of either ATG5 or Beclin1 attenuated the cell death and MDA production induced by co-treatment
MDA↑,

5257- 3BP,    Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment
- Review, Var, NA
Glycolysis↓, In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug.
mt-OXPHOS↓, Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells.
HK2↓, The direct inhibition of mitochondrial HK-II isolated from the rabbit liver implanted VX2 tumor via 3-BrPA was demonstrated by Ko et al. [17].
Cyt‑c↑, -BrPA treatment resulted in an increase of cytochrome c release [59,60], along with an elevated expression of active proapoptotic caspase-3 and a decrease of antiapoptotic Bcl-2 and Mcl-1 [59]
Casp3↓,
Bcl-2↓,
Mcl-1↓,
GAPDH↓, Additionally, GAPDH was found to be inhibited by 3-BrPA in several studies
LDH↓, Recent reports showed 3-BrPA had ability to inhibit post glycolysis targets and other metabolic pathways, such as LDH, PDH, TCA cycle, and glutaminolysis
PDH↓, 3-BrPA was proven to be an inhibitor of PDH [72,73,74],
TCA↓,
GlutaM↓, this inhibition of TCA cycle can lead to the impairment of glutaminolysis due to α-KG generated from glutamine is incorporated into the TCA cycle by IDH and αKD activities
GSH↓, Indeed, a remarkable decrease of reduced glutathione (GSH) level was observed after 3-BrPA treatment in both microorganisms and various tumor cells [53,61,65].
ATP↓, 3-BrPA successfully killed AS-30D hepatocellular carcinoma (HCC) cells via the inhibition of both ATP-producing glycolysis and mitochondrial respiration [17].
mitResp↓,
ROS↑, the increase of ROS and concomitant decrease of GSH were commonly found in 3-BrPA-mediated antitumor studies [53,59,61,64,65,76,77,86,89].
ChemoSen↑, When 3-BrPA was combined with cisplatin or oxaliplatin with non-toxic low-dose, 3-BrPA strikingly enhanced the antiproliferative effects of both platinum drugs in HCT116 cells and resistant p53-deficient HCT116 cells [89].
toxicity↝, Finally, two years after the first diagnosis, the patient died due to an overload of liver function rather than the tumor itself [118].

5270- 5-ALA,  PDT,    5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy
- Review, Var, NA
other↝, Since the use of ALA-based drugs for tumor diagnosis or therapy depends on preferential PpIX tumor accumulation, we begin this review with an overview of PpIX biosynthesis from ALA and end with the prospect of combining the diagnostic and therapeutic
ROS↑, These components individually are not harmful but become cytotoxic when combined due to the generation of reactive oxygen species (ROS) via type I and II photochemical reactions.
other↝, ALA was known to cause endogenous PpIX accumulation in human lymphocytes in the 1970s [15].
mtDam↑, which causes direct mitochondrial structural damage and Ca2+ release [24].
Ca+2↑,
ER Stress↑, ALA-PDT is known to damage the endoplasmic reticulum (ER) and cause Ca2+ release, triggering apoptosis through ER-stress signaling [25].
Apoptosis↑,
TumAuto↑, Lastly, ALA-PDT is also known to induce autophagy, the degradation of cellular components by lysosomes.
other↝, ALA administration exhibits red fluorescence and photosensitizing activity upon light activation.
Dose↝, Although blue and red light-emitting diode (LED) illuminators are commonly used as the light source to activate ALA and MAL for PDT of AK lesions, natural daylight is emerging as an attractive and convenient alternative.
Imm↑, ALA-PDT not only directly kills tumor cells but also elicits potent immune responses with important implications in the long-term therapeutic outcome.

3453- 5-ALA,    The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis
- in-vitro, Lung, A549
OXPHOS↑, A549 exposed to ALA exhibited enhanced oxidative phosphorylation, which was indicated by an increase in COX protein expression and oxygen consumption.
OCR↑,
Warburg↓, These data demonstrate that ALA inhibits the Warburg effect and induces cancer cell death.
ROS↑, ALA significantly increased O2-generation over 4 h
SOD2↑, ALA stimulates MnSOD, catalase and HO-1 protein expression.
Catalase↑,
HO-1↑,
Casp3↑, ALA induced an increase in the protein expression of activated (cleaved) caspase-3.
Apoptosis↑, these data demonstrate that ALA induced caspase- dependent apoptosis in A549 cells.

4774- 5-FU,  TQ,  CoQ10,    Exploring potential additive effects of 5-fluorouracil, thymoquinone, and coenzyme Q10 triple therapy on colon cancer cells in relation to glycolysis and redox status modulation
- in-vitro, CRC, NA
AntiCan↑, All treatments resulted in anticancer effects depicted by cell cycle arrest and apoptosis, with TQ demonstrating greater efficacy than CQ10, both with and without 5-FU.
TumCCA↑,
Apoptosis↑,
eff↑,
Bcl-2↓, However, 5-FU/TQ/CQ10 triple therapy exhibited the most potent pro-apoptotic activity in all cell lines, portrayed by the lowest levels of oncogenes (CCND1, CCND3, BCL2, and survivin)
survivin↓,
P21↑, and the highest upregulation of tumour suppressors (p21, p27, BAX, Cytochrome-C, and Cas- pase-3).
p27↑,
BAX↑,
Cyt‑c↑,
Casp3↑,
PI3K↓, The triple therapy also showed the strongest suppression of the PI3K/AKT/mTOR/HIF1α pathway, with a concurrent increase in its endogenous inhibitors (PTEN and AMPKα) in all cell lines used.
Akt↓,
mTOR↓,
Hif1a↓,
PTEN↑,
AMPKα↑,
PDH↑, triple therapy favoured glucose oxidation by upregulating PDH, while decreasing LDHA and PDHK1 enzymes.
LDHA↓,
antiOx↓, most significant decline in antioxidant levels and the highest increases in oxidative stress markers
ROS↑,
AntiCan↑, This study is the first to demonstrate the superior anticancer effects of TQ compared to CQ10, with and without 5-FU, in CRC treatment.

1900- AF,    Potential Anticancer Activity of Auranofin
- Review, Var, NA
TrxR↓, Auranofin inhibits the activity of thioredoxin reductase (TrxR
ROS↑, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis
Apoptosis↓,
TumCP↓, TrxR1 knockdown also inhibits cancer cell proliferation and DNA replication
eff↑, cytotoxicity of cisplatin is increased in cells expressing high levels of TrxR1 compared with cells expressing low levels

5459- AF,    Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells
- in-vitro, Ovarian, NA
ROS↑, AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer.
TrxR↓, The primary mechanism of action of auranofin is to act as a pro-oxidative agent, increasing the production of reactive oxygen species (ROS) as a consequence of inhibiting the thioredoxin reductase (TrxR) anti-oxidant system
MMP↓, triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis.
Apoptosis↑,
eff↓, Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC).
Casp3↑, lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage
Casp7↑,
DNAdam↑,
eff↑, Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH.
GSH↓,
angioG↓, Additionally, auranofin has been shown to inhibit angiogenesis
ChemoSen↑, In this study, we identified the mechanisms of cytotoxicity induced by auranofin in HGSOC cells that have different clinical sensitivities to platinum.
cl‑PARP↑, the cleavage of poly-ADP ribose polymerase (PARP), and the polyubiquitination of proteins
eff↑, synergistic lethal interaction between auranofin and a second pro-oxidant agent, the glutathione (GSH) inhibitor, L-buthionine sulfoximine (L-BSO);

5466- AF,    Auranofin Inhibition of Thioredoxin Reductase in a Preclinical Model of Small Cell Lung Cancer
- in-vivo, Lung, NA
TrxR↓, TrxR is viable target in clinical trials using the anti-rheumatic drug, auranofin (AF).
Dose↝, 4 mg/kg once daily resulting in 18 μM gold in the plasma and 50% inhibition of TrxR activity in DMS273 SCLC tumors.
RadioS↑, effective inhibitor of TrxR and suggest that AF could be used as an adjuvant in radio-chemotherapy protocols to enhance therapeutic efficacy.
ChemoSen↑,
ROS↑, We also demonstrated the suppressing TrxR with AF can sensitize breast cancer stem cells to ROS induced differentiation and cytotoxicity.16
Diff↑,
toxicity↓, These results suggest that this dosing regimen is nontoxic to kidneys, liver, and bone marrow as well as demonstrating a trend toward a survival advantage in tumor bearing animals.

5465- AF,    The Thioredoxin Reductase Inhibitor Auranofin Suppresses Pulmonary Metastasis of Osteosarcoma, But Not Local Progression
- in-vitro, OS, NA
TrxR↓, Auranofin (AUR), a thioredoxin reductase (TXNRD) inhibitor, shows anticancer activity against several cancers.
ROS↑, AUR induced apoptosis of OS cells via the oxidative stress-MAPK-Caspase 3 pathway, and suppressed the migration of OS cells.
TumCMig↓,

5464- AF,    Inhibition of Thioredoxin-Reductase by Auranofin as a Pro-Oxidant Anticancer Strategy for Glioblastoma: In Vitro and In Vivo Studies
- vitro+vivo, GBM, NA
TrxR↓, Gold derivatives are irreversible inhibitors of TrxR. Among them, auranofin (AF), a selective TrxR inhibitor, has proven its effectiveness as a drug for the treatment of rheumatoid arthritis
BioAv↓, further clinical application of AF could be challenging due to the low solubility and insufficient delivery to glioblastoma.
ROS↑, The inhibition of TrxR1, which leads to increased ROS levels, is currently recognized as the primary mechanism of AF cytotoxicity [106]. In vitro studies have also shown that AF inhibits other thioredoxin reductases, such as TrxR2 and TrxR3
eff↝, The literature indicates that not all cancer tumors exhibit the same level of TrxR expression, affecting their sensitivity to AF.
TET1?, AF was shown to inhibit TET1 in T-ALL models
BioAv↑, Encapsulating AF into nanoparticles or combining it with other pharmaceutical excipients can minimize its potential adverse effects, preserve its interaction with serum proteins, and result in greater stability.

5463- AF,    Will Auranofin Become a Golden New Treatment Against COVID-19?
- Review, Covid, NA
IL6↓, This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway.
NF-kB↓,
ATF2↓,
TrxR↓, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis.
ROS↑,
Apoptosis↑,
IL6↓, Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6.
Dose↑, After 14 days of treatment with 21 mg/day auranofin, plasma gold concentration reached 1.18 µM to 2.21 µM ‘auranofin equivalent’

5462- AF,    Repurposing Auranofin for Oncology and Beyond: A Brief Overview of Clinical Trials as Mono- and Combination Therapy
- Review, Var, NA
AntiTum↑, Over the last twenty years, AF has also been repurposed as an antitumor, antiviral, and antibacterial drug.
Bacteria↓,
TrxR↓, ability to inhibit thioredoxin reductase (TrxR) and disrupt redox homeostasis, leading to selective cytotoxicity in cancer cells.
ChemoSen↑, synergistic effects observed when AF is combined with chemotherapeutics, targeted therapies, or immune modulators.
Dose↝, Patients received AF orally twice daily on days 1–28. atients received AF orally, 6 mg in the morning and 6 mg in the evening.
ROS↑, AF induces oxidative stress and apoptosis in cancer cells by disrupting redox homeostasis, while sirolimus inhibits mTOR signaling.
Apoptosis↑,
mTOR↓,

5461- AF,    Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells
- in-vitro, BC, MDA-MB-231 - in-vitro, Nor, MCF10
Paraptosis↑, We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells.
ER Stress↑,
TrxR↓, covalent inhibition of thioredoxin reductase (TrxR)
selectivity↑, subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells
toxicity↝, whereas 4~5 μM AF killed both cancer and MCF10A cells
ROS↑, We found that treatment with 5 μM AF very weakly and transiently increased ROS levels at 2~4 h and then again at 24 h
mt-TrxR1↓, AF inhibits cytosolic and mitochondrial TrxR (TrxR1 and TrxR2), two selenoenzymes for the Trx pathway [3]
mt-TrxR2↓,

5460- AF,    Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species
- vitro+vivo, Var, 4T1
RadioS↑, AF at 3–10 μM is a potent radiosensitizer in vitro
ROS↑, . The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS)
eff↓, N-acetyl cysteine counteracted radiosensitization. (NAC)
mt-OCR↓, We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions.
DNAdam↑, Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis
Apoptosis↑,
TrxR↓, targeting thioredoxin reductase (TrxR)
eff↑, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse.

5472- AF,    Auranofin induces apoptosis and necrosis in HeLa cells via oxidative stress and glutathione depletion
- in-vitro, Cerv, HeLa
TrxR↓, Auranofin (Au), an inhibitor of thioredoxin reductase, is a known anti‑cancer drug
AntiCan↑,
TumCG↓, Au inhibited the growth of HeLa cells with an IC50 of ~2 µM at 24 h.
Apoptosis↑, This agent induced apoptosis and necrosis, accompanied by the cleavage of poly (ADP‑ribose) polymerase and loss of mitochondrial membrane potential.
necrosis↑,
cl‑PARP↑,
MMP↓,
ROS↑, With respect to the levels of ROS and GSH, Au increased intracellular O2•- in the HeLa cells and induced GSH depletion.
GSH↓,
eff↓, The antioxidant, N‑acetyl cysteine, not only attenuated apoptosis and necrosis in the Au‑treated HeLa cells, but also decreased the levels of O2•- and GSH depletion in the cells.

5471- AF,    Anti-Tumoral Treatment with Thioredoxin Reductase 1 Inhibitor Auranofin Fosters Regulatory T Cell and B16F10 Expansion in Mice
- vitro+vivo, Melanoma, B16-F10
TrxR1↓, Auranofin, an FDA-approved antirheumatic drug and thioredoxin reductase 1 (TXNRD1) inhibitor, has demonstrated anti-tumoral properties
AntiTum↑,
ROS↑, TXNRD1 Inhibitors Elevated ROS Levels, Activate NRF2, and Kill B16F10 Cells In Vitro
NRF2↑,
TumCD↑,

5470- AF,    Exploring a Therapeutic Gold Mine: The Antifungal Potential of the Gold-Based Antirheumatic Drug Auranofin
- Review, Var, NA
TrxR↓, mechanism of action of auranofin was correlated with thioredoxin reductase inhibition,
other↝, but other modes of action such as interference with mitochondrial protein import and NADH kinase were also described and discussed
IL6↑, Conversely, auranofin stimulated IL-6 and IL-8 secretion in monocytes,
IL8↑,
NK cell⇅, NK activation was only observed at low doses of auranofin, while high doses inhibited NK activity
COX2↓, suppression of pro-inflammatory factors such as COX-2 (cyclooxygenase-2), NOS (nitric oxide synthase), NF-κB (nuclear factor-κB), and TrxR, as well as on the activation of peroxyredoxin-1 and Nrf2 (nuclear factor erythroid 2-related factor 2) [19].
NOS2↓,
NRF2↑,
Prx↑,
Half-Life↑, plasma half-lives of 15–25 days [24]
Dose↝, To avoid frequently occurring diarrhea, oral doses of 3–6 mg per day, or below, should also be considered when repurposing auranofin for the treatment of other human diseases.
ROS↑, Imbalances in this system lead to the accumulation of cytotoxic ROS.
NF-kB↓, Auranofin can bind to IKK, which ultimately leads to NF-κB inhibition

5468- AF,    The gold complex auranofin: new perspectives for cancer therapy
- Review, Var, NA
TrxR↓, Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria.
ROS↑, Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise
eff↑, TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer.
Apoptosis↑, promotion of ASK-induced apoptosis, and blockage of cell growth, proliferation, and survival due to reduced AKT activity and NF-kB- and p53-mediated transcription.
TumCG↓,
TumCP↓,
Akt↓,
NF-kB↓,
DNAdam↑, DNA damage
eff↝, auranofin inhibits TrxR1 in a p53-independent manner
eff↓, Pre-treatment with NAC counteracted the cancer cell killing effects of auranofin,
PI3K↓, auranofin induces cytotoxicity in human pancreatic adenocarcinoma and non-small cell lung cancer via the inhibition of the PI3K/AKT/mTOR pathway
Akt↓,
mTOR↓,
Hif1a↓, auranofin inhibits the cancer cell response to hypoxia, demonstrated by a decrease in HIF-1 𝛼 expression and VEGF secretion upon auranofin treatment under hypoxic conditions
VEGF↓,
Casp3↑, auranofin was shown to induce caspase-3-mediated apoptosis in human ovarian carcinoma SKOV-3 cells
CSCs↓,
ATP↓, it was found that auranofin inhibits ABCG2 function by depleting cellular ATP via inhibition of glycolysis [96]
Glycolysis↓,
eff↑, auranofin synergizes with another Trx1 inhibitor, piperlongumine, in killing gastric cancer cells in association with ROS-mediated ER stress response and mitochondrial dysfunction.
eff↑, when the gold complex is combined with either selenite or tellurite [104]
MMP↓, Increased ROS induced by AUR causes decreased membrane potential in the mitochondrial membrane, resulting in a decrease in anti-apoptotic proteins, caspase-dependent cell death, and translocation of apoptosis-inducing factor (AIF)
AIF↑,
toxicity↓, Auranofin is considered safe for human use in treating rheumatoid arthritis; thus, this gold derivative can reach the clinic for other diseases relatively quickly and at a low cost

5434- AG,    Recent Advances in the Mechanisms and Applications of Astragalus Polysaccharides in Liver Cancer Treatment: An Overview
- Review, Liver, NA
AntiCan↑, Preclinical studies indicate that APS exerts significant anti-liver cancer effects through multiple biological actions, including the promotion of apoptosis, inhibition of proliferation, suppression of epithelial–mesenchymal transition, regulation of
Apoptosis↑,
TumCP↓,
EMT↓,
Imm↑, improving host immune response
ChemoSen↑, APS exhibits synergistic effects when combined with conventional chemotherapeutics and interventional treatments such as transarterial chemoembolisation, improving efficacy and reducing toxicity.
BioAv↓, limitations such as low bioavailability and a lack of large-scale clinical trials remain challenges for clinical translation.
TumCG↓, APS significantly inhibited tumour growth in H22-bearing mice with a dose-dependent effect (100, 200, 400 mg/kg), with the 400 mg/kg group achieving a tumour inhibition rate of 59.01%
IL2↑, APS enhance the thymus and spleen indices and elevates the key cytokines, including IL-2, IL-12, and TNF-α.
IL12↑,
TNF-α↑,
P-gp↓, APS reversed chemoresistance by downregulating P-glycoprotein and MDR1 mRNA expression
MDR1↓,
QoL↑, These effects contributed to improved treatment tolerance and enhanced quality of life [39].
Casp↑, APS can activate both the intrinsic and extrinsic apoptotic pathways, leading to caspase activation and DNA fragmentation
DNAdam↑,
Bcl-2↓, Mechanistically, APS downregulate antiapoptotic proteins such as Bcl-2 while upregulating proapoptotic proteins such as Bax and cleaved caspase-3.
BAX↑,
MMP↓, APS have been shown to disrupt the mitochondrial membrane potential and promote the release of cytochrome c, thereby enhancing apoptotic cascades in hepatocellular carcinoma models.
Cyt‑c↑,
NOTCH1↓, APS (0.1, 0.5, and 1.0 mg/mL) were shown to reduce both mRNA and protein levels of Notch1 in a concentration-dependent manner.
GSK‐3β↓, APS significantly inhibited the proliferation of HepG2 cells by downregulating the expression of glycogen synthase kinase-3β (GSK-3β), with 200 μg/mL being the most effective concentration.
TumCCA↑, APS exerted these effects by inducing cell cycle arrest at the G2/M and S phases, thereby impeding tumour cell proliferation [35].
GSH↓, HepG2 cells. APS also reduced intracellular glutathione (GSH) levels, increased reactive oxygen species (ROS) and lipid peroxidation levels, and elevated intracellular iron ion concentrations—all in a dose-dependent manner.
ROS↑,
lipid-P↑,
c-Iron↑,
GPx4↓, APS treatment led to the downregulation of GPX4 and upregulation of ACSL4, indicating that APS promotes ferroptosis in liver cancer cells.
ACSL4↑,
Ferroptosis↑,
Wnt↓, inhibit the expression of key proteins involved in the Wnt/β-catenin signalling pathway
β-catenin/ZEB1↓,
cycD1/CCND1↓, by downregulating the key oncogenic targets, including β-catenin, C-myc, and cyclin D1, which subsequently reduces Bcl-2 expression and activates the apoptotic cascade in HepG2 liver cancer cells.
Akt↓, It also inhibited the Akt/p-Akt signalling pathway.
PI3K↓, APS inhibit the PI3K/AKT/mTOR signalling pathway, which is a central negative regulator of autophagy.
mTOR↓,
CXCR4↓, PS upregulated the epithelial marker E-cadherin while downregulating the mesenchymal marker vimentin and the chemokine receptor CXCR4 at both mRNA and protein levels, suggesting that APS suppress liver cancer cell growth and metastasis by inhibiting
Vim↓,
PD-L1↓, APS interfere with immune checkpoint signalling by downregulating Programmed death-ligand 1 (PD-L1) expression on tumour cells.
eff↑, The preparation of polysaccharide–SeNP composites typically involves using sodium selenite (Na2SeO3) as the precursor and ascorbic acid (Vc) as the reducing agent, with synthesis carried out via a chemical reduction method in a polysaccharide solutio
eff↑, Mechanistic investigations revealed that AASP–SeNPs elevated intracellular ROS levels and reduced the mitochondrial membrane potential (∆Ψm).
ChemoSen↑, APS enhance doxorubicin-induced endoplasmic reticulum (ER) stress by reducing O-GlcNAcylation levels, thereby promoting apoptosis of liver cancer cells.
ChemoSen↑, APS inhibited BEL-7404 human liver cancer cell growth in a concentration-dependent manner and showed stronger cytotoxicity when combined with cisplatin.
chemoP↑, APS protects against chemotherapy-induced liver injury, particularly that caused by CTX, through antiapoptotic mechanisms

342- AgNPs,    Silver nanoparticles; a new hope in cancer therapy?
- Review, NA, NA
ROS↑,
DNAdam↑,
Apoptosis↑,
mtDam↑,

341- AgNPs,    Bioprospecting a native silver-resistant Bacillus safensis strain for green synthesis and subsequent antibacterial and anticancer activities of silver nanoparticles
- in-vitro, Liver, HepG2
TumCD↑, viability of the cancer HepG2 cell line was 84.42, 65.25, 48.76 and 36.25%, respectively, at 5, 10, 15 and 20 µg mL−1 AgNPs concentrations
ROS↑,

335- AgNPs,  PDT,    Biogenic Silver Nanoparticles for Targeted Cancer Therapy and Enhancing Photodynamic Therapy
- Review, NA, NA
ROS↑,
GSH↓,
GPx↑,
Catalase↓,
SOD↓,
p38↑,
BAX↑,
Bcl-2↓,

330- AgNPs,  Rad,    Reactive oxygen species acts as executor in radiation enhancement and autophagy inducing by AgNPs
- in-vitro, GBM, U251
TumAuto↑,
ROS↑,

375- AgNPs,  ALA,    Alpha-Lipoic Acid Prevents Side Effects of Therapeutic Nanosilver without Compromising Cytotoxicity in Experimental Pancreatic Cancer
- in-vitro, PC, Bxpc-3 - in-vitro, PC, PANC1 - in-vitro, PC, MIA PaCa-2 - in-vivo, NA, NA
mtDam↑, in cancer cells only. ALA protected normal cells
ROS↑, in cancer cells only. ALA protected normal cells
*toxicity↓, Nonmalignant CRL-4023 and LX-2 cells were treated with α-lipoic acid at concentrations of 0.5 mM, 1 mM, 2 mM and 3 mM, Both cell lines were largely resistant to any concentration
Dose∅, ALA dose: we used α-lipoic acid concentrations of 0.5 and 1 mM
selectivity↑, higher sensitivity of malignant cells to AgNPs.

327- AgNPs,  MS-275,    Combination Effect of Silver Nanoparticles and Histone Deacetylases Inhibitor in Human Alveolar Basal Epithelial Cells
- in-vitro, Lung, A549
Apoptosis↑,
ROS↑,
LDH↓, leakage of lactate dehydrogenase (LDH);
TNF-α↑,
mtDam↑,
TumAuto↑,
Casp3↑,
Casp9↑,
DNAdam↑, induced DNA-fragmentation

324- AgNPs,  CPT,    Silver Nanoparticles Potentiates Cytotoxicity and Apoptotic Potential of Camptothecin in Human Cervical Cancer Cells
- in-vitro, Cerv, HeLa
ROS↑,
Casp3↑,
Casp9↑,
Casp6↑,
GSH↓,
SOD↓,
GPx↓,
MMP↓, loss of
P53↑,
P21↑,
Cyt‑c↑,
BID↑,
BAX↑,
Bcl-2↓,
Bcl-xL↓,
Akt↓,
Raf↓,
ERK↓,
MAP2K1/MEK1↓,
JNK↑,
p38↑,

322- AgNPs,  Cisplatin,    Heterogeneous Responses of Ovarian Cancer Cells to Silver Nanoparticles as a Single Agent and in Combination with Cisplatin
- in-vitro, Ovarian, A2780S - in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, OVCAR-3
ROS↑,
DNAdam↑,
GSH/GSSG↓,

320- AgNPs,    Silver nanoparticles induce endoplasmatic reticulum stress response in zebrafish
- vitro+vivo, NA, HUH7
ROS↑,
ER Stress↑,
TNF-α↑,

316- AgNPs,    Endoplasmic reticulum stress: major player in size-dependent inhibition of P-glycoprotein by silver nanoparticles in multidrug-resistant breast cancer cells
- in-vitro, BC, MCF-7
GRP78/BiP↑, AgNP treatment induced the expression of ER chaperons Grp94 and Grp78/Bip,
ER Stress↑, depleted endoplasmic reticulum (ER) calcium stores, caused notable ER stress and decreased plasma membrane positioning of Pgp
ROS↑,
mtDam↑,

309- AgNPs,    Interference of silver, gold, and iron oxide nanoparticles on epidermal growth factor signal transduction in epithelial cells
- in-vitro, NA, A431
ROS↑,
Akt↓,
p‑ERK↓, Erk phosphorylation

306- AgNPs,    Cancer Therapy by Silver Nanoparticles: Fiction or Reality?
- Analysis, NA, NA
EPR↝, takes advantage of EPR
ROS↑, silver ions drive the formation of ROS, which triggers massive oxidative stress, thereby activating the cellular pathways leading to cell death
IL1↑, IL-1b
IL8↑, IL-8 mRNA levels
ER Stress↑,
MMP9↑, it has been shown that 20 nm AgNPs increase the MMP-9 secretion
MMP↓, loss of mitochondrial membrane potential and mitochondrial structural disorganization, were reported to accompany the AgNP-induced stres
Cyt‑c↑, cytochrome c release from the mitochondria into the cytoplasm and finally to apoptosis
Apoptosis↑,
Hif1a↑, AgNPs were shown to induce HiF-1α activation, thereby ultimately activating autophagy through the AMPK-mTOR pathway in PC-3 prostate cancer cells [89
BBB↑, AgNPs can affect the integrity of the blood–brain barrier and can cross this barrier in vitro through transcytosis
GutMicro↝, AgNP treatments might influence the composition of the gut microbiota,
eff↑, AgNPs are promising tools for targeted delivery
eff↑, the joint application of the nanoparticles and the HDAC inhibitor caused significantly increased ROS levels,
RadioS↑, idea to use AgNPs as radiosensitizers came along with the phenomenon that metals with high atomic numbers are capable of enhancing the effects of radiation

344- AgNPs,    Cytotoxicity and ROS production of manufactured silver nanoparticles of different sizes in hepatoma and leukemia cells
- in-vitro, Liver, HepG2
ROS↑,
GSH↓,

374- AgNPs,    Silver nanoparticles selectively treat triple‐negative breast cancer cells without affecting non‐malignant breast epithelial cells in vitro and in vivo
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
ER Stress↑,
DNAdam↑,
ROS↑,
Apoptosis↑,
GSH/GSSG↓, MDA‐MB‐231
NADPH/NADP+↓, MDA‐MB‐231
TumCG↓,
UPR↑, initiating UPR

373- AgNPs,    Cytotoxic Potential and Molecular Pathway Analysis of Silver Nanoparticles in Human Colon Cancer Cells HCT116
- in-vitro, Colon, HCT116
LDH↓, Increased lactate dehydrogenase leakage (LDH),
ROS↑,
MDA↑,
ATP↓,
GSH↓,
MMP↓, loss of

371- AgNPs,    Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549
- in-vitro, Lung, A549
ROS↑,
mtDam↑,

370- AgNPs,    Differential genotoxicity mechanisms of silver nanoparticles and silver ions
- in-vitro, lymphoma, TK6
ROS↑,

369- AgNPs,    Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis
- in-vitro, Liver, NA
ROS↑,
GSH↓,
DNAdam↑,
lipid-P↝, damage
Apoptosis↑,
BAX↑,
Bcl-2↓,
MMP↓, disruption
Casp9↑,
Casp3↑,
JNK↑,

367- AgNPs,    Presence of an Immune System Increases Anti-Tumor Effect of Ag Nanoparticle Treated Mice
- in-vivo, NA, NA
ROS↑,
mtDam↑,
TumCG↓,

365- AgNPs,    Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species
- in-vitro, Hepat, HepG2
ROS↑,
GlucoseCon↓,
TumCD↑,
NRF2↓, Decreased mRNA levels of Nrf2

363- AgNPs,    Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis
ROS↑,
lipid-P↑, lipid membrane peroxidation
Apoptosis↑,
BAX↑,
Bcl-2↓,
MMP↓, disruption
Cyt‑c↑, release from mitochondria
Casp3↑,
Casp9↑,
JNK↑,

359- AgNPs,    Anti-cancer & anti-metastasis properties of bioorganic-capped silver nanoparticles fabricated from Juniperus chinensis extract against lung cancer cells
- in-vitro, Lung, A549 - in-vitro, Nor, HEK293
Casp3↑,
Casp9↑,
P53↑,
ROS↑,
MMP2↓,
MMP9↓,
TumCCA↑, cessation in the G0/G1 phase
*toxicity↓, 9.87ug/ml(cancer cells) and 111.26 µg/ml(normal cells)
TumCMig↓,
TumCI↓,

346- AgNPs,  RSQ,    Investigating Silver Nanoparticles and Resiquimod as a Local Melanoma Treatment
- in-vivo, Melanoma, SK-MEL-28 - in-vivo, Melanoma, WM35
ROS↑,
Ca+2↝, disrupt mitochondrial homeostasis of Ca2+
Casp3↑, x2-4
Casp8↑, x2-4
Casp9↑, x4-14
CD4+↑,
CD8+↑,
tumCV↓,
eff↓, NAC, an ROS scavenger, could efficiently protect B16.F10 cells from the cytotoxic effects of Ag+ even when exposed to high concentrations of Ag+ (250 μg/ml)
*toxicity↓, non-toxic in mice as evidenced by: 1) no significant change in weights during the study period and 2) no significant increases in the levels of liver enzymes, (ALP), (AST), and ALT

347- AgNPs,    The Role of Silver Nanoparticles in the Diagnosis and Treatment of Cancer: Are There Any Perspectives for the Future?
- Review, NA, NA
ROS↑,
Apoptosis↑,
ER Stress↑,

348- AgNPs,    Induction of p53 mediated mitochondrial apoptosis and cell cycle arrest in human breast cancer cells by plant mediated synthesis of silver nanoparticles from Bergenia ligulata (Whole plant)
- in-vitro, BC, MCF-7
Apoptosis↑,
ROS↑,
MMP↓, loss of mitochondrial membrane potential (MMP)
P53↑,
BAX↑,
cl‑Casp3↑,

349- AgNPs,    Insight into the molecular mechanism, cytotoxic, and anticancer activities of phyto-reduced silver nanoparticles in MCF-7 breast cancer cell lines
- in-vitro, BC, MCF-7
Apoptosis↑,
ROS↑,
CellMemb↑, damage

350- AgNPs,    Cytotoxic and Apoptotic Effects of Green Synthesized Silver Nanoparticles via Reactive Oxygen Species-Mediated Mitochondrial Pathway in Human Breast Cancer Cells
- in-vitro, BC, MCF-7
ROS↑,
MMP↓,
P53↑,
BAX↑,
Casp3↑,
Casp9↑,
Bcl-2↓,

355- AgNPs,    Cytotoxicity and Genotoxicity of Biogenic Silver Nanoparticles in A549 and BEAS-2B Cell Lines
- in-vitro, Lung, A549 - in-vitro, NA, BEAS-2B
ROS↑,
DNAdam↑,
Apoptosis↑,

356- AgNPs,  MF,    Anticancer and antibacterial potentials induced post short-term exposure to electromagnetic field and silver nanoparticles and related pathological and genetic alterations: in vitro study
- in-vitro, BC, MCF-7 - in-vitro, Bladder, HTB-22
Apoptosis↑,
P53↑, Up-regulation in the expression level of p53, iNOS and NF-kB genes as well as down-regulation of Bcl-2 and miRNA-125b genes were detected post treatment.
iNOS↑,
NF-kB↑,
Bcl-2↓,
ROS↑, the present study evaluated the levels of ROS as well as the antioxidant enzymes (SOD and CAT)
SOD↑,
TumCCA↑, S phase arrest and accumulation of cells in G2/M phase was observed following exposure to AgNPs and EMF, respectively.
eff↑, Apoptosis induction was obvious following exposure to either ELF-EMF or AgNPs, however their apoptotic potential was intensified when applied in combination
Catalase↑, Catalase (CAT)
other↑, swollen cells, swollen nuclei with mixed euchromatin and heterochromatin, ruptured cell membranes

357- AgNPs,    Hypoxia-mediated autophagic flux inhibits silver nanoparticle-triggered apoptosis in human lung cancer cells
- in-vitro, Lung, A549 - in-vitro, Lung, L132
mtDam↑,
ROS↑,
Hif1a↑, HIF-1α expression was upregulated after AgNPs treatment under both hypoxic and normoxic conditions HIF-1α knockdown enhances hypoxia induced decrease in cell viability
LC3s↑,
p62↑,
eff↓, Hypoxia decreases the effects of anticancer drugs in solid tumor cells through the regulation of HIF-1α

358- AgNPs,    Preparation of triangular silver nanoparticles and their biological effects in the treatment of ovarian cancer
- vitro+vivo, Ovarian, SKOV3
TumCCA↑, arrested the cell cycle in G0/G1 phase
ROS↑,
Casp3↑,
TumCG↓,
cycD1/CCND1↓, and cyclinA2

353- AgNPs,    The mechanism of cell death induced by silver nanoparticles is distinct from silver cations
- in-vitro, BC, SUM159
lipid-P↑, caused by AgNPs not Ag+
H2O2↑, caused by Ag+
ROS↑,
Apoptosis↑,

377- AgNPs,    Anticancer Action of Silver Nanoparticles in SKBR3 Breast Cancer Cells through Promotion of Oxidative Stress and Apoptosis
- in-vitro, BC, SkBr3
ROS↑,
Apoptosis↑,
Bax:Bcl2↑,
VEGF↑, VEGF-A
Akt↓,
PI3K↓,
TAC↓,
TOS↑,
OSI↑,
MDA↑,
Casp3↑,
Casp7↑,

402- AgNPs,  MF,    Anticancer and antibacterial potentials induced post short-term exposure to electromagnetic field and silver nanoparticles and related pathological and genetic alterations: in vitro study
- in-vitro, BC, MCF-7
P53↑,
iNOS↑,
NF-kB↑,
Bcl-2↓,
miR-125b↓,
ROS↑, 2.9x for 2hr
SOD↑, 2.4x for 2hr

400- AgNPs,  MF,    Polyvinyl Alcohol Capped Silver Nanostructures for Fortified Apoptotic Potential Against Human Laryngeal Carcinoma Cells Hep-2 Using Extremely-Low Frequency Electromagnetic Field
- in-vitro, Laryn, HEp2
TumCP↓, especially in the G0/G1 and S phases.
Casp3↑,
P53↑,
Beclin-1↑,
TumAuto↑,
GSR↑, oxidative stress biomarker
ROS↑, oxidative stress biomarker
MDA↑, oxidative stress biomarker
ROS↑,
SIRT1↑,
Ca+2↑, induce apoptosis in osteoclasts by increasing intracellular and nucleus Ca2+ concentration
Endon↑, increases endonuclease activity
DNAdam↑,
Apoptosis↑,
NF-kB↓,

397- AgNPs,  GEM,    Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment
- in-vitro, Ovarian, A2780S
P53↑,
P21↑,
BAX↑,
Bak↑,
Cyt‑c↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
ROS↑,
MMP↓,

394- AgNPs,    Anticancer activity of Moringa oleifera mediated silver nanoparticles on human cervical carcinoma cells by apoptosis induction
- in-vitro, Cerv, HeLa
ROS↑,

393- AgNPs,    Green synthesized plant-based silver nanoparticles: therapeutic prospective for anticancer and antiviral activity
- in-vitro, NA, HCT116
mtDam↑,
ROS↑,
TumCCA↑,
Casp3↑,
BAX↑,
Bcl-2↓,
P53↑,

381- AgNPs,    Silver Nanoparticles Exert Apoptotic Activity in Bladder Cancer 5637 Cells Through Alteration of Bax/Bcl-2 Genes Expression
- in-vitro, Bladder, 5637
ROS↑,
BAX↑,
Bcl-2↓,
Casp3↑,
Casp7↑,
Apoptosis↑,

385- AgNPs,    Probiotic-derived silver nanoparticles target mTOR/MMP-9/BCL-2/dependent AMPK activation for hepatic cancer treatment
- in-vitro, Hepat, HepG2 - in-vitro, Hepat, WI38
TNF-α↑, AgNPs induce an upregulation in the synthesis of inflammation-associated cytokines, including (TNF-α and IL-33), within HepG2 cells.
IL33↑,
mTOR↓,
MMP9↓,
Bcl-2↓,
ROS↑,
Apoptosis↑,

388- AgNPs,    Apoptotic efficacy of multifaceted biosynthesized silver nanoparticles on human adenocarcinoma cells
- in-vitro, BC, MCF-7
ROS↑, ROS production
Casp3↑,
BAX↑,
P53↑,
Casp↑, Upregulation of caspases, apoptotic mediators, were observed after exposure of MCF-7 to the RAgNPs
Cyt‑c↑, The release of cytochrome c was determined after 24 h RAgNPs treatment.
MMP↓, The treated cells increased the depolarized mitochondrial membrane and decreased the polarized membranes.
DNAdam↑, Ag NPs perform well as cancer therapeutics because they can disrupt the mitochondrial respiratory chain, which induces the ROS generation, DNA damage and ATP synthesis
Bcl-2↓, Upon treatment with AgNPs or cisplatin, MCF-7 cells showed decreased Bcl-2 expression and increased Bax expression, representing the mitochondrial connection in cell death
BAX↑,

390- AgNPs,    Anti-cancerous effect of albumin coated silver nanoparticles on MDA-MB 231 human breast cancer cell line
- in-vitro, BC, MDA-MB-231 - in-vivo, BC, NA
ROS↑,
TumVol↓,

384- AgNPs,    Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy
- in-vitro, Testi, F9
LDH↓, When the cells were treated with AgNPs and AgNO3, the amount of LDH leaked into the media increased in a dose-dependent manner
ROS↑,
mtDam↑,
DNAdam↑,
P53↑,
P21↑,
BAX↑,
Casp3↑,
Bcl-2↓,
Casp9↑,
Nanog↓,
OCT4↓,

1406- AgNPs,    The antioxidant effects of silver, gold, and zinc oxide nanoparticles on male mice in in vivo condition
- in-vivo, Nor, NA
*ROS↓, (AuNP) as an antioxidant agent by inhibiting the formation of reaction oxygen species (ROS) and scavenging the free radicals.
*GPx↑,
*Catalase↑,
*ROS↑, AgNPs have toxic effect on the mitochondria of liver and result in the production of ROS and they decrease glutathione in the liver

1908- AgNPs,    Exposure to Silver Nanoparticles Inhibits Selenoprotein Synthesis and the Activity of Thioredoxin Reductase
- in-vitro, Lung, A549
TrxR↓, Exposure likewise inhibited TrxR activity in cultured cells, and Ag ions were potent inhibitors of purified rat TrxR isoform 1 (cytosolic) (TrxR1) enzyme.
TrxR1↓, Exposure to AgNPs leads to the inhibition of selenoprotein synthesis and inhibition of TrxR1
ROS↑, likely mechanism underlying increases in oxidative stress
ER Stress↑, increases endoplasmic reticulum stress,
TumCP↓, reduced cell proliferation during exposure to Ag.
selenoP↓, Exposure to AgNPs inhibits incorporation of selenium into selenoproteins.

1903- AgNPs,    Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Managemen
- in-vitro, Lung, U1285
TrxR↓, accumulate into cancer cells and to selectively target Thioredoxin (TrxR),
eff↝, 2 µM was able to decrease TrxR enzyme activity by about 68%, compared with auranofin, which at the same concentration
ROS↑, cellular production of reactive oxygen species (ROS)

5236- AgNPs,    Adaptive regulations of Nrf2 alleviates silver nanoparticles-induced oxidative stress-related liver cells injury
- in-vitro, Liver, HepG2 - in-vitro, Nor, L02
tumCV↓, AgNPs induced a concentration-dependent decline in HepG2 and L02 cells viability.
ROS↑, • AgNPs induced ROS increase and apoptosis in HepG2 and L02 cells.
*ROS↑,
DNAdam↑, AgNPs induced DNA damage, autophagy and cell cycle arrest in HepG2 and L02 cells.
*DNAdam↑,
eff↓, N-acetylcysteine (NAC)alleviated AgNPs-induced cytotoxicity in HepG2 and L02 cells.
selectivity↑, Interestingly, HepG2 cells were more sensitive to AgNPs than L02 cells, and this may be related to the different ROS generation and responses to AgNPs by cancer cells and normal cells.

5238- AgNPs,    β-Sitosterol-assisted silver nanoparticles activates Nrf2 and triggers mitochondrial apoptosis via oxidative stress in human hepatocellular cancer cell line
- in-vitro, HCC, HepG2
TumCP↓, BSS-SNPs significantly inhibited the proliferation and induced ROS and Nrf-2 expression in HepG2 cells.
ROS↑,
NRF2↑,
BAX↑, BSS-SNPs treatment caused apoptosis-related morphological changes and upregulated the pro-apoptotic markers such as bax, p53, cytochrome c, and caspases-9, -3 and downregulated bcl-2 expressions.
P53↑,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Bcl-2↓,

5239- AgNPs,    NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells
- in-vitro, Nor, HUVECs
*ROS↑, AgNP exposure significantly and dose-dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs.
*Apoptosis↑,
*NRF2↝, AgNPs could disrupt the inactivation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in HUVECs.

4403- AgNPs,    Silver Nanoparticles Decorated UiO-66-NH2 Metal-Organic Framework for Combination Therapy in Cancer Treatment
- in-vitro, GBM, U251 - in-vitro, GBM, U87MG - in-vitro, GBM, GL26 - in-vitro, Cerv, HeLa - in-vitro, CRC, RKO
AntiCan↑, Among the various NPs, silver nanoparticles (AgNPs) have garnered attention due to their cytotoxic and genotoxic properties in cancer cells.
eff↑, Our results demonstrate that UiO-66-NH2@AgNPs@Cis-Pt and its combinations exhibit enhanced cytotoxicity compared to individual components such as AgNPs and Cis-Pt.
EPR↑, Their nanometric structure allows them to easily penetrate and accumulate in tumour tissues either actively, via targeting systems [6,7,8], or passively, by taking advantage of tumour angiogenesis and the enhanced permeation and retention (EPR) effe
selectivity↑,
ROS↑, Once inside, AgNPs induce an increase in the production of reactive oxygen species (ROS) and cause mitochondrial dysfunctions, caspases activation, apoptosis, autophagy, and DNA damage
Casp↑,
Apoptosis↑,
DNAdam↑,
tumCV↓, figure 8
eff↑, One of the primary characteristics of AgNPs is their ability to release Ag+ ions from their surface in response to low pH or oxidation.

4404- AgNPs,  Rad,    Main Approaches to Enhance Radiosensitization in Cancer Cells by Nanoparticles: A Systematic Review
- Review, Var, NA
eff↑, Asharani et al compared the toxicity between 3–10 nm Pt, 5–35 nm Ag, and 15–35 nm Au NPs covered with PVA, and concluded that Ag NPs were the most toxic,
ROS↑, been suggested by different biological studies that they can produce ROS, and therefore can affect the concentration of intracellular calcium, activate transcription factors, and induce cytokine production

4400- AgNPs,  Rad,    Differential cytotoxic and radiosensitizing effects of silver nanoparticles on triple-negative breast cancer and non-triple-negative breast cells
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10 - in-vitro, BC, MDA-MB-231 - in-vitro, BC, BT549 - in-vivo, BC, MDA-MB-231
ROS↑, AgNPs is known to cause dose-dependent toxicities, including induction of oxidative stress and DNA damage, which can lead to cell death.
DNAdam↑,
selectivity↑, We show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages.
TumCG↓, reduce TNBC growth and improve radiation therapy.
RadioS↑,
Dose↝, s 23±14 nm: particles were diluted to 40 μg/mL. 25 μg/mL AgNP dilution for 24 hours. zeta potential of AgNPs in water at pH 7 was approximately −36 mV, indicating good colloidal stability.
selectivity↑, Depending on AgNP dose, all three TNBC cell lines were 5- to 10-fold more sensitive to AgNP exposure than the nontumorigenic breast cells.
other↝, this study demonstrate that the cytotoxicity was dependent on exposure of cells to intact AgNPs and not due to Ag+ ions
eff↓, toxicity of AgNPs was significantly reduced in MDA-MB-231, MCF-7, and MCF-10A cells following pretreatment with GSH
eff↑, Selective depletion of GSH by BSO resulted in increased AgNP toxicity in all cell lines.
γH2AX↑, AgNPs significantly increased γH2AX in these cells compared to radiation alone.
Dose↓, Strikingly, an AgNP dose of as little as 1 μg/mL resulted in a dose enhancement of IR treatment (approximately 2-fold at the 2 Gy dose) f
eff↑, Moreover, intratumoral injection of AgNPs with or without radiation treatment can inhibit the growth of TNBC xenografts in mice

4399- AgNPs,  Chit,    Silver nanoparticles impregnated alginate-chitosan-blended nanocarrier induces apoptosis in human glioblastoma cells
- in-vitro, GBM, U87MG
DNAdam↑, extensive DNA damage.
ROS↑, Elevation in reactive oxygen species level indicates induction of oxidative stress in treated cells.
MMP↓, Mitochondrial dysfunction in cell death is evident from the depolarization of mitochondrial membrane potential (ΔΨm ).
eff↑, induction of apoptosis at low concentration of Ag NPs present in Ag NPs-Alg-Chi NC in comparison with free Ag NPs makes it a promising tool for cancer therapy.

4398- AgNPs,    Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier
- in-vitro, Colon, HT29
Apoptosis↑, The involvement of mitochondrial pathway of cell death in the Ag-CS NCs induced apoptosis was evident from the depolarization of mitochondrial membrane potential (ΔΨ(m)).
MMP↓,
Casp3↑, up-regulation of caspase 3 expression
ROS↑, increased production of intracellular ROS due to Ag-CS NCs treatment indicated that the oxidative stress could augment the induction of apoptosis in HT 29 cells
eff↑, use of significantly low concentration of Ag NPs impregnated in chitosan nanocarrier is a much superior approach in comparison to the use of free Ag NPs in cancer therapy.

4389- AgNPs,    Graphene Oxide-Silver Nanocomposite Enhances Cytotoxic and Apoptotic Potential of Salinomycin in Human Ovarian Cancer Stem Cells (OvCSCs): A Novel Approach for Cancer Therapy
- in-vitro, Ovarian, NA
tumCV↓, Ag was toxic to OvCSCs and reduced cell viability by mediating the generation of reactive oxygen species, leakage of lactate dehydrogenase, reduced mitochondrial membrane potential
ROS↑,
LDH↓,
MMP↑,
CSCs↓, rGO–Ag may be a novel nano-therapeutic molecule for specific targeting of highly tumorigenic ALDH+CD133+ cells
AntiCan↑, Overall, these results suggest that the rGO–Ag is a promising material for inhibiting the cell viability of ovarian cancer cells and ovarian cancer stem cells.

4388- AgNPs,    Differential Cytotoxic Potential of Silver Nanoparticles in Human Ovarian Cancer Cells and Ovarian Cancer Stem Cells
- in-vitro, Cerv, NA
tumCV↓, the numbers of A2780 (bulk cells) and ALDH+/CD133+ colonies were significantly reduced
CSCs↓,
selectivity↑, induced apoptosis in pancreatic CSCs and cancer cell lines, but had no effect on human normal pancreatic epithelial cells
Apoptosis↑,
ROS↑, figure 5, AgNPs induces apoptosis by oxidative stress
LDH↓, figure 5 (leakage outside the cell increases)
Casp3↑, AgNPs treated cells shows up-regulation of caspase-3, bax, bak, and c-myc, genes
BAX↑,
Bak↑,
cMyc↑,
MMP↓, and loss of mitochondrial membrane potential.

4414- AgNPs,    Silver nanoparticles: Forging a new frontline in lung cancer therapy
- Review, Lung, NA
tumCV↑, AgNPs exhibit significant cytotoxic and apoptotic effects in lung cancer cell lines through mechanisms involving gene regulation, reactive oxygen species (ROS) production, and mitochondrial depolarization.
ROS↑,
MMP↓,
TumCCA↑, dose-dependent reductions in cell viability, cell cycle arrest, and apoptosis induction.
Apoptosis↑,
angioG↓, inhibit angiogenesis

4417- AgNPs,    Caffeine-boosted silver nanoparticles target breast cancer cells by triggering oxidative stress, inflammation, and apoptotic pathways
- in-vitro, BC, MDA-MB-231
ROS↑, Caf-AgNPs significantly increased ROS, malondialdehyde, COX-2, IL-1β, and TNF-α level in BC cells, which was accompanied by a decrease in glutathione levels.
MDA↑,
COX2↑,
IL1β↑,
TNF-α↑,
GSH↓,
Cyt‑c↑, increased levels of cytosolic cytochrome c, caspase-3, and Bax proteins, as well as a significant decrease in Bcl-2 expression and Bcl-2/Bax ratio
Casp3↑,
BAX↑,
Bcl-2↓,
LDH↓, Cancer cells subjected to Caf-AgNPs demonstrated elevated lactate dehydrogenase (LDH) membrane leakage
cycD1/CCND1↓, notable downregulation of cyclin D1 and cyclin-dependent kinase 2 (CDK2) mRNA expression
CDK2↓,
TumCCA↑, several mechanisms for cellular destruction, including cell cycle arrest, oxidative stress induction, modulation of the inflammatory response, and mitochondrial apoptosis
mt-Apoptosis↑,

4415- AgNPs,  SDT,  CUR,    Examining the Impact of Sonodynamic Therapy With Ultrasound Wave in the Presence of Curcumin-Coated Silver Nanoparticles on the Apoptosis of MCF7 Breast Cancer Cells
- in-vitro, BC, MCF-7
tumCV↓, Curcumin-coated silver nanoparticles (Cur@AgNPs) have shown potential as a sensitizer, demonstrating adverse effects on cancer cell survival.
BAX↑, proapoptotic genes, such as Bax and Caspase-3, increased, while the expression of the antiapoptotic gene Bcl-2 decreased in MCF7 cells treated with the SDT.
Casp3↑,
Bcl-2↓,
eff↑, effect of SDT in the presence of Cur@AgNPs decreases cell viability dependence on US mode
ROS↑, Combined treatment increased the amount of ROS induction
sonoS↑, Higher concentrations of AgNPs (100 μg/ml) acted as acoustic sensitizers and enhanced ROS production
eff↑, Using curcumin as a biological coating reduced the toxicity of AgNPs and improved their significant effects with SDT
MMP↓, reduction in mitochondrial membrane potential (MMP) and the opening of mitochondrial permeability transition pores (mPTPs)
Cyt‑c↑, ultimately facilitating the release of cytochrome c from the mitochondria into the cytosol.

4413- AgNPs,  Anzaroot,    Green synthesis of silver nanoparticles from plant Astragalus fasciculifolius Bioss and evaluating cytotoxic effects on MCF7 human breast cancer cells
- in-vitro, BC, MCF-7
chemoP↑, These compounds have been shown to effectively treat heart diseases and inhibit cancer cell growth while also alleviating chemotherapy side effects.
TumCG↓,
eff↑, anzroot plant can be effectively used as a reducing agent for AgNPs synthesis, and AgNPs have the potential to be used effectively in cancer therapy methods and to inhibit the growth of cancer cells.
CellMemb↑, As the AgNPs concentration increased, the permeability of the membrane increased
selectivity↑, Cancer cells exhibit higher permeability and retention, allowing for preferential interaction with SNPs due to their nanoscale size
ROS↑, AgNPs respond to intracellular signaling through ROS activation, and p53-mediated apoptosis is notably effective when using AgNPs
P53↑,

4410- AgNPs,    Green-synthesized silver nanoparticles: a sustainable nanoplatform for targeted colon cancer therapy
- Review, Colon, NA
AntiCan↑, AgNPs exert potent anticancer effects against colon cancer cell lines primarily by inducing cell death through mechanisms including reactive oxygen species (ROS) generation
ROS↑,
mtDam↑, mitochondrial dysfunction, and apoptosis modulation, leading to significant reductions in cell viability.
tumCV↓,
selectivity↑, effectively targeting cancer cells while sparing healthy counterparts, thereby emphasizing their safety profile and potential for minimizes ng systemic toxicity.

4405- AgNPs,    Silver nanoparticles defeat p53-positive and p53-negative osteosarcoma cells by triggering mitochondrial stress and apoptosis
- in-vitro, OS, NA
Apoptosis↑, According to our findings AgNPs are able to kill osteosarcoma cells independently from their actual p53 status and induce p53-independent cancer cell apoptosis.
other↑, AgNPs kill cells through a Trojan-horse type mechanism, suggesting that the intracellularly accumulated nanoparticles release toxic silver ions
ROS↑, Those ions induce the generation of reactive oxygen species (ROS)
eff↑, t has been reported that 5 nm AgNPs were more toxic compared to 20 nm and 50 nm particles in four different cell lines
P53↝, Nearly 50% of all human cancers have been characterised by impaired p53 function which attenuates therapeutic efficacy. The level of p53 protein increased markedly upon 20 μM of 5 nm and 85 μM of 35 nm sized AgNP treatments
Apoptosis↑, Induction of apoptosis was verified by immunostaining U2Os and Saos-2 cells with cleaved caspase 3 specific antibody after treatments with 20 μM of 5 nm and with 85 μM of 35 nm sized AgNPs for 24 h
cl‑Casp3↑,
survivin↓, as decreased survivin and elevated caspase 3 mRNA levels were measured
MMP↓, Decreased mitochondrial membrane potential was detected in 5 nm and 35 nm AgNPs treated U2Os (a) and Saos-2
Cyt‑c↑, Elevated levels of cytoplasmic cytochrome c was detected in 5 nm and 35 nm AgNP-treated U2Os and Saos-2 cells

4431- AgNPs,  doxoR,    Oxidative Stress-Induced Silver Nano-Carriers for Chemotherapy
- in-vitro, BC, 4T1 - in-vivo, BC, 4T1 - in-vitro, Nor, 3T3
AntiCan↑, AgNPs have been demonstrated to exhibit anti-tumor effects through cell apoptosis.
ROS↑, ox-carried PA-AgNPs generate reactive oxidation species intensively beside 4T1 cells.
TumVol↓, in vivo study confirms that PA-AgNPs with Dox successfully inhibit tumors, which are about four times smaller than the control group and have high biosafety that can be applied for chemotherapy.
EPR↑, While all normal cells need enough vitamins to survive, cancer cells require a considerable number of vitamins to proliferate rapidly. As a result, the receptors on the cancer cell surface are overexpressed to capture as many vitamins as possible.
selectivity↑, PA-AgNPs (without/with Dox) concentrations ranging from 0 to 100 μg mL−1 did not seem to impair 3T3 cell viability due to poor uptake by normal cells.
ChemoSen↑, These results suggested that Dox-carried PA-AgNPs were both safer and more effective for cancer prevention.

4362- AgNPs,    Enhancing Colorectal Cancer Radiation Therapy Efficacy using Silver Nanoprisms Decorated with Graphene as Radiosensitizers
- in-vitro, CRC, HCT116 - in-vitro, CRC, HT29 - in-vivo, NA, NA
eff↑, large surface area-to-volume ratio, which can be exploited in cancer radiotherapy to locally enhance the radiation dose deposition in tumors
TumCG↓, Treatment with nanoparticles and a single radiation dose of 10 Gy significantly reduces the growth of colorectal tumors
OS↑, increases the survival time as compared to treatment with radiation only
RadioS↑, combine standard-dose radiotherapy with radiosensitizers to enhance the radiation therapy efficacy locally within tumors while sparing adjacent healthy tissues
eff↑, suggested that graphene enhances the cellular uptake when combined with metals in nanocomposites
ROS↑, ROS, the most potent of these free radicals, can travel to and indirectly damage DNA
DNAdam↑,
eff↝, PEGylated GQD-decorated Silver Nanoprisms (pGAgNPs) show better intracellular uptake as compared to PEGylated Silver Nanoprisms (pAgNPs)

4428- AgNPs,    p38 MAPK Activation, DNA Damage, Cell Cycle Arrest and Apoptosis As Mechanisms of Toxicity of Silver Nanoparticles in Jurkat T Cells
- in-vitro, AML, Jurkat
toxicity↝, The effect of Ag ions was also investigated and compared with that of AgNPs, as it is anticipated that Ag ions will be released from AgNPs, which may be responsible for their toxicity.
tumCV↓, Cell viability tests indicated high sensitivity of Jurkat T cells when exposed to AgNPs compared to Ag ions
ROS↑, AgNPs and Ag ions induce similar levels of cellular reactive oxygen species during the initial exposure period and; after 24 h, they were increased on exposure to AgNPs compared to Ag ions, which suggest that oxidative stress may be an indirect caus
p38↑, AgNPs exposure activates p38 mitogen-activated protein kinase through nuclear factor-E2-related factor-2 and nuclear factor-kappaB signaling pathways, subsequently inducing DNA damage, cell cycle arrest and apoptosis.
NRF2↓,
NF-kB↝,
DNAdam↑,
Apoptosis↑,

4429- AgNPs,    Comparative proteomic analysis reveals the different hepatotoxic mechanisms of human hepatocytes exposed to silver nanoparticles
- in-vitro, Liver, HepG2
*toxicity↝, As the liver is one of the largest accumulation and deposition sites of circulatory AgNPs, it is important to evaluate the hepatotoxicity induced by AgNPs
selectivity↑, cancerous liver cells were generally more sensitive than the normal liver cells.
mt-ROS↑, mitochondrial ROS has been identified as one of the causes of AgNPs-induced hepatotoxicity

4430- AgNPs,    Evaluation of the Genotoxic and Oxidative Damage Potential of Silver Nanoparticles in Human NCM460 and HCT116 Cells
- in-vitro, Colon, HCT116 - in-vitro, Nor, NCM460
*Bacteria↓, Nano Ag has excellent antibacterial properties and is widely used in various antibacterial materials, such as antibacterial medicine and medical devices, food packaging materials and antibacterial textiles
ROS↑, intracellular reactive oxygen species (ROS) increased
p‑p38↑, Ag NPs can promote the increase in P38 protein phosphorylation levels in two colon cells and promote the expression of P53 and Bax.
BAX↑,
Bcl-2↓, Ag NPs can promote the down-regulation of Bcl-2, leading to an increased Bax/Bcl-2 ratio and activation of P21, further accelerating cell death
BAX↑,
P21↑,
TumCD↑,
toxicity↝, low concentration of nano Ag has no obvious toxic effect on colon cells, while nano Ag with concentrations higher than 15 μg/mL will cause oxidative damage to colon cells.

4363- AgNPs,    Immunomodulatory properties of silver nanoparticles contribute to anticancer strategy for murine fibrosarcoma
- in-vivo, fibroS, NA
TumVol↓, incidence and size of fibrosarcoma were reduced or delayed when murine fibrosarcoma groups were treated by AgNP-MSA
TNF-α↓, TNF-α, IL-6 and IL-1β these cytokines were found to be downregulated after treatment with AgNP-MSA
IL6↓,
IL1β↓,
*toxicity↝, liver sections were found to have normal architecture in all treated groups except those treated at the 9 and 10 mg/kg b.w. doses
TumCG↓, treatment with AgNPs, the logistic growth of the tumor incidence was significantly lower (
selectivity↑, MSA-AgNPs aggregated instantly in response to the acidic extracellular pH of solid tumors, leading to greatly enhanced uptake by cancer cells
selectivity↑, Because the particle size in the study was approximately 10 nm, any AgNP that escaped entry into the tumor microenvironment and entered the systemic circulation was effectively cleared from the body.
Weight↑, AgNP-MSA not only inhibited the tumor incidence but also helped to overcome the progressive body weight loss of tumor-bearing mice.
ROS↑, anticancer property demonstrated by AgNP can be attributed to this increase in oxidative stress in the tumor microenvironment.
NO↑, AgNPs significantly increased the oxygen free radical and NO levels in the tumor microenvironment, which oppose hypoxia.

4432- AgNPs,    Emerging nanostructure-based strategies for breast cancer therapy: innovations, challenges, and future directions
- Review, NA, NA
ROS↑, This review focus on the abilities of nanoparticles to induce oxidative stress, prevent proliferation, and trigger apoptosis in cancer cells.
TumCP↓,
Apoptosis↑,

4433- AgNPs,    Advancements in metal and metal oxide nanoparticles for targeted cancer therapy and imaging: Mechanisms, applications, and safety concerns
- in-vitro, Liver, HepG2 - in-vitro, Nor, L02
selectivity↑, we evaluated the cytotoxicity of different-sized AgNPs and found that the cancerous liver cells were generally more sensitive than the normal liver cells
selectivity↓, HepG2 cells respond to stresses by adapting energy metabolism, upregulating metallothionein expression and increasing the expression of antioxidants, while L02 cells protect themselves by increasing DNA repair and macro-autophagy.
mt-ROS↑, mitochondrial ROS has been identified as one of the causes of AgNPs-induced hepatotoxicity.

4435- AgNPs,  Gluc,    Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
selectivity↑, Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs’ uptake by cancer cells.
ROS↑, NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis.
mtDam↑,
TumCCA↑,
TumCP↓,
Apoptosis↑,
MMP↓, AgNPs were able to depolarize the cells’ mitochondria to 32.74% and 10.36%, respectively

4436- AgNPs,    Silver Nanoparticles (AgNPs) as Enhancers of Everolimus and Radiotherapy Sensitivity on Clear Cell Renal Cell Carcinoma
- in-vitro, Kidney, 786-O
ROS↑, AgNPs are cytotoxic to 786-O cells, a ccRCC cell line, entering through endocytosis, increasing ROS, depolarizing mitochondrial membrane, and blocking the cell cycle, leading to a reduction of proliferation capacity and apoptosis.
MMP↑,
TumCCA↑,
TumCP↓,
Apoptosis↑,
RadioS↑, 786-O is intrinsically resistant to radiation, but after AgNPs’ administration, radiation induces cytotoxicity through mitochondrial membrane depolarization and S phase blockage.

4439- AgNPs,    Anticancer Potential of Green Synthesized Silver Nanoparticles Using Extract of Nepeta deflersiana against Human Cervical Cancer Cells (HeLA)
- in-vitro, Cerv, HeLa
ROS↑, significant increase in ROS and lipid peroxidation (LPO), along with a decrease in MMP and glutathione (GSH) levels.
lipid-P↑,
MMP↓,
GSH↓,
TumCCA↑, significant increase in ROS and lipid peroxidation (LPO), along with a decrease in MMP and glutathione (GSH) levels.
Apoptosis↑,
Necroptosis↑,
TumCD↑, AgNPs-induced cell death in HeLA cells suggested the anticancer potential of ND-AgNPs.
Dose↝, ND-AgNPs at 10, 25, and 50 µg/ml concentration

4364- AgNPs,    Selective cytotoxicity of green synthesized silver nanoparticles against the MCF-7 tumor cell line and their enhanced antioxidant and antimicrobial properties
- in-vitro, BC, MCF-7
TumCD↑, AgNPs and the extract exhibited 70% and 40% cytotoxicity against MCF-7 cancerous cells, respectively, while CSN caused 56% cell death (at the concentration of 60 µg/mL)
selectivity↑, It was observed that AgNPs were much less cytotoxic when tested against a noncancerous cell line (L-929)
*antiOx↑, These include antioxidant, antifungal, anti-inflammatory, antiviral, anti-angiogenesis, and antimicrobial effects
*Inflam↓,
AntiTum↑, antitumor properties of AgNPs
ROS↑, AgNPs interact with mitochondria and disrupt the cellular electron transfer chain function leading to an increase in the ROS level. oxidative stress generated by ROS could be considered as a main toxicity mechanism of AgNPs against cells

4381- AgNPs,    Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells
- in-vitro, Liver, HepG2
eff↓, toxicity of AgNPs was prevented by use of the antioxidant N-acetylcysteine, and AgNP-induced DNA damage was also prevented by N-acetylcysteine.
ROS↑, AgNP cytotoxicity is primarily the result of oxidative stress and is independent of the toxicity of Ag+ ions.
other↑, Ag exposure is associated with specific clinical symptoms, such as argyria, which causes an irreversible gray coloration of the skin

4380- AgNPs,    Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways
- in-vitro, Lung, A549
ROS↑, AgNPs caused ROS formation in the cells
tumCV↓, reduction in their cell viability
MMP↓, and mitochondrial membrane potential (MMP)
TumCCA↑, increase in the proportion of cells in the sub-G1 (apoptosis) population, S phase arrest
PCNA↓, down-regulation of the cell cycle associated proliferating cell nuclear antigen (PCNA) protein
eff↓, Pretreatment of the A549 cells with N-acetyl-cysteine (NAC), an antioxidant, decreased the effects of AgNPs

4379- AgNPs,    Exposure to silver nanoparticles induces size- and dose-dependent oxidative stress and cytotoxicity in human colon carcinoma cells
- in-vitro, CRC, LoVo
eff↑, uptake of silver nanoparticles in cells of the human intestinal LoVo cell line was dependent on size.
TumCD↑, Silver nanoparticles in sizes of 10–100 nm induced cytotoxicity in a size- and dose-dependent manner via ROS generation.
ROS↑,
Bacteria↓, antimicrobial properties of silver nanoparticles (AgNPs)

4378- AgNPs,    Exploring silver nanoparticles for cancer therapy and diagnosis
- Review, Var, NA
AntiTum↑, AgNPs show great promise for cancer therapy due to their antitumoral effects demonstrated by several in vitro and in vivo studies (Table 1)
ROS↑, well known that their toxicity relies on the generation of reactive oxygen species (ROS)
eff↑, synergic combination of AgNPs and chemotherapy drugs
RadioS↑, in vitro studies have highlighted the ability of AgNPs to enhance cell/tissue sensitivity to radiotherapy (RT).

4375- AgNPs,    The cellular uptake and cytotoxic effect of silver nanoparticles on chronic myeloid leukemia cells
- in-vitro, AML, K562
eff↑, AgNPs were demonstrated to be able to enter K562 cells (a CML cell line) in a dose-dependent manner and locate in endosomes
ROS↑, Reactive oxygen species (ROS) could be generated upon AgNPs exposure and cause cytotoxicity and apoptosis.
Apoptosis↑,
eff↓, alterations caused by AgNPs exposure could be reversed by the addition of Vitamin C (an antioxidant).

4371- AgNPs,    Effects of Green Silver Nanoparticles on Apoptosis and Oxidative Stress in Normal and Cancerous Human Hepatic Cells in vitro
- in-vitro, Liver, HUH7
ROS↑, The gAgNPs induced more ROS in the HuH-7 cells than in the CHANG cells.
selectivity↑, HuH-7 cells showed an increased sensitivity to gAgNPs than the CHANG cells.
DNAdam↑, higher concentrations of gAgNPs may induce significant cytotoxicity and cause DNA damage and apoptosis.
Apoptosis↑,
GSH↓, The level of glutathione was decreased (Figure 4B) and lipid peroxide was increased in HuH-7 cells than CHANG cells (Figure 4A).
lipid-P↑,
MMP↓, indicating loss of MMP
DNAdam↑, higher DNA damage was seen in HuH-7 cells than CHANG cells

4370- AgNPs,    Effect of silver nanoparticles in the induction of apoptosis on human hepatocellular carcinoma (HepG2) cell line
- in-vitro, Liver, HepG2
tumCV↓, decreased cell viability in a concentration-dependent manner and the IC50 of 75 μg/mL for Ag NPs
ROS↑, Ag NPs cytotoxicity was associated with induction of ROS and cell apoptosis in HepG2 cell line
Apoptosis↑,

4369- AgNPs,    Silver nanoparticles induce p53-mediated apoptosis in human bronchial epithelial (BEAS-2B) cells
- in-vitro, Nor, BEAS-2B
*ROS↑, we observed oxidative stress in BEAS-2B cells exposed to Ag-NPs.

4365- AgNPs,    Biomedical Applications of Silver Nanoparticles: An Up-to-Date Overview
- Review, Var, NA
ROS↑, the most remarkable mechanistic mode of AgNP-based antimicrobial effects is represented by their adhesion to microbial cells, ROS and free-radical generation, microbial wall piercing and penetration inside cells, and modulation and modification of mi
*toxicity↓, high intrinsic antimicrobial efficiency and non-toxic nature
*Bacteria↓,
*Inf↓, silver-based compounds and materials were used for the unconventional and effective control of distinctive infections
*Diff↑, Previous studies reported that AgNPs naturally improve the differentiation process of MC3T3-1 pre-osteoblast cells and subsequent bone-like tissue mineralization,
*eff↑, studies showed that AgNP-implanted titanium displayed improved antibacterial ability,
RadioS↑, making them suitable candidates for detection and dose-enhancement purposes in X-ray irradiation applications
selectivity↑, selective uptake into cancerous cells, AgNP-derived scattered light can be used for imaging purposes, whereas absorbed light can be used for selective hyperthermia

4383- AgNPs,    Exploring the Potentials of Silver Nanoparticles in Overcoming Cisplatin Resistance in Lung Adenocarcinoma: Insights from Proteomic and Xenograft Mice Studies
- in-vitro, Lung, A549 - in-vivo, Lung, A549
Apoptosis↑, Silver nanoparticles (AgNPs) have shown great potential as therapeutic agents due to their ability to cause apoptotic cell death in cancer cells.
VEGF↓, suppressing the VEGF signaling pathway, repressing p53-mediated pathways, promoting cell cycle arrest,
P53↓,
TumCCA↑,
ROS↑, we found that AgNPs induced ROS generation
AntiTum↑, AgNPs exhibit similar antitumoral effects on both A549 and A549/DDP-bearing mice.
eff↑, AgNPs are internalized by cells far more effectively than free Ag+ under identical exposure conditions
ATP↓, AgNPs exposure also decreased basal respiration (52.3 ± 4.6 pmol/min/106 cells), maximal respiration (109.2 ± 12.2 pmol/min/106 cells), ATP production (
eff↑, These results explain why AgNPs remain effective against cisplatin-resistant A549 cells.
CTR1↑, recent studies have shown that AgNPs treatment significantly upregulates CTR1

4564- AgNPs,  GoldNP,  Cu,  Chemo,  PDT  Cytotoxicity and targeted drug delivery of green synthesized metallic nanoparticles against oral Cancer: A review
- Review, Var, NA
ROS↑, graphical abstract
DNAdam↑, inducing cell death through apoptotic signaling pathways, and inducing excess reactive oxygen species (ROS) in tumor cells, which leads to oxidative damage and increased production of proapoptotic enzymes
TumCCA↑,
eff↑, Metallic nanoparticles, especially those derived from metals, improve the effectiveness of anticancer agents by facilitating targeted delivery and sustained release at tumor sites.
Apoptosis↑,
eff↓, Au NPs are notable for their biocompatibility and are utilized in photothermal therapy to convert light into heat, effectively destroying cancer cells
ChemoSen↑, Magnesium oxide nanoparticles (MgO NPs) induce apoptosis through ROS production and enhance the impact of chemotherapy drugs, synthesized with plant extracts as reducing agents.

4563- AgNPs,  Rad,    Silver nanoparticles enhance neutron radiation sensitivity in cancer cells: An in vitro study
- in-vitro, BC, MCF-7 - in-vitro, Ovarian, SKOV3 - in-vitro, GBM, U87MG - in-vitro, Melanoma, A431
RadioS↑, Here, we, for the first time, present the results of the radiosensitizing properties of silver nanoparticles (AgNPs) (possessing low toxicity towards human body) against cancer cells under neutron irradiation.
ROS↑, The mechanism of AgNPs anticancer (intrinsic) effect includes oxidative stress, cell cycle arrest and apoptosis, activate endoplasmic reticulum stress, modulate various signaling pathways, etc
TumCCA↑,
Apoptosis↑,
ER Stress↑,

4561- AgNPs,  VitC,    Cellular Effects Nanosilver on Cancer and Non-cancer Cells: Potential Environmental and Human Health Impacts
- in-vitro, CRC, HCT116 - in-vitro, Nor, HEK293
NRF2↑, Nanosilver increased Nrf2 protein expression and disrupted the cell cycle at the G1 and G2/M phases.
TumCCA↑, AgNPs interact with DNA to stop the cell cycle and lead to apoptosis
ROS↑, Nanosilver induced significant mitochondrial oxidative stress in HCT116, whereas it did not in the non-cancer HIEC-6 and nanosilver/sodium ascorbate co-treatment was preferentially lethal to HCT116 cells,
selectivity↑,
*AntiViral↑, AgNPs are effective antiviral agents against various viruses such as human immunodeficiency virus, hepatitis B virus, and monkey pox virus through interaction with surface glycoproteins on the virus
*toxicity↝, Citrate and PVP-coated AgNPs have been found to be less toxic than non-coated AgNPs
ETC↓, AgNPs affects mitochondrial function through the disruption of the electron transport chain2,24,26,33,39–41
MMP↓, Studies have shown that exposure to AgNPs resulted in a decrease of mitochondrial membrane potential (MMP) in various in vitro and in vivo experiments
DNAdam↑, AgNPs has also been shown to interact with and induce damage to DNA, DNA strand breaks, DNA damage
Apoptosis↑, apoptosis induced by AgNPs were through membrane lipid peroxidation, ROS, and oxidative stress
lipid-P↑,
other↝, Several studies have showed AgNPs interact with various proteins such as haemoglobin, serum albumin, metallothioneins, copper transporters, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), malate dehydrogenase (MDH), and bacterial proteins.
UPR↑, Studies have shown exposure to AgNPs induces activation of the UPR
*GRP78/BiP↑, AgNPs induced increased levels of GRP78, phosphorylated PERK, phosphorylated eIF2-α, and phosphorylated IRE1α, spliced XBP1, cleaved ATF-6, CHOP, JNK and caspase 12
*p‑PERK↑,
*cl‑eIF2α↑,
*CHOP↑,
*JNK↑,
Hif1a↓, One study showed AgNPs inhibits HIF-1 accumulation and suppresses expression of HIF-1 target genes in breast cancer cells (MCF-7) and also found the protein levels of HIF-1α and HIF-1β decreased
AntiCan↑, Many studies have shown that ascorbic acid, on its own, has anti-cancer effects
*toxicity↓, However, when the rats were treated with both ascorbic acid and AgNPs, a decrease in toxic effects was observed in non-cancer parotid glands in rats
eff↑, Studies have shown both AgNPs and ascorbic acid have greater effects and toxicity in cancer cells relative to non-cancer cells

4559- AgNPs,    Anticancer activity of biogenerated silver nanoparticles: an integrated proteomic investigation
- in-vitro, BC, SkBr3 - in-vitro, CRC, HT-29 - in-vitro, CRC, HCT116 - in-vitro, Colon, Caco-2
MMP2↓, AgNPs-EPSaer induced a significant decrease of cell motility and MMP-2 and MMP-9 activity and a significant increase of ROS generation
MMP9↓,
ROS↑, remarkable ROS increase in a concentration-dependent manner. Compared to the control cells, a maximum of 2.25 and 1.75 fold increases in ROS generation was observed with 10 µg/ml concentration of AgNPs-EPSaer treatment
TumAuto↑, supported cell death mainly through autophagy and in a minor extend through apoptosis.
Apoptosis↑,
ER Stress↑, highlighted important pathways involved in AgNPs-EPSaer toxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment triggering cell death trough apoptosis and/or autophagy activation.

4558- AgNPs,    Role of Oxidative and Nitro-Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells
- in-vitro, PC, PANC1
ROS↑, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy.
selectivity↑, We found that the increase was lower in noncancer cells.
NO↑, PANC-1 cells with 0.5–5 μg/mL of 2.6 nm AgNPs or 5–100 μg/mL of 18 nm AgNPs caused an increase of NO level in a concentration-dependent manner
SOD↓, We observed a significant reduction in cytosolic and mitochondrial SOD and GPX-4 at protein level
GPx4↓,
Catalase↓, we showed that 2.6 nm AgNPs caused a higher decrease in SOD1, SOD2, and CAT at mRNA level after 24 h incubation than 18 nm AgNPs
TumCCA↑, 2.6 nm and 18 nm AgNPs, we noticed a decrease of G0/G1 phase cell population in a concentration-dependent manner compared with control
MMP↓, increase of the percentage of cells with low mitochondrial membrane potential (Δψm), compared to the untreated cells

4557- AgNPs,    The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells
- in-vitro, NA, NIH-3T3 - in-vitro, CRC, HCT116
Cyt‑c↑, Treatment with nanosilver induced the release of cytochrome c into the cytosol and translocation of Bax to mitochondria, indicating that nanosilver-mediated apoptosis is mitochondria-dependent.
ROS↑, Nanosilver-induced apoptosis was associated with the generation of reactive oxygen species (ROS) and JNK activation, and inhibition of either ROS or JNK attenuated nanosilver-induced apoptosis.
JNK↑,

4556- AgNPs,    Biofilm Impeding AgNPs Target Skin Carcinoma by Inducing Mitochondrial Membrane Depolarization Mediated through ROS Production
- in-vitro, Melanoma, A431
MMP↓, The depolarization of mitochondrial membrane potential ΔΨm through excess ROS production was deduced to be the triggering force behind the apoptotic cell death mechanism of the skin carcinoma
ROS↑,
*toxicity↓, AgNPs provides an economic, nontoxic, specific approach for targeting skin carcinoma with additional benefits of antibacterial activities.
Bacteria↓,

4555- AgNPs,    Silver nanoparticles from Dendropanax morbifera Léveille inhibit cell migration, induce apoptosis, and increase generation of reactive oxygen species in A549 lung cancer cells
- in-vitro, Lung, A549 - in-vitro, Liver, HepG2
*Bacteria↓, silver nanoparticles synthesized from Dendropanax morbifera Léveille leaves (D-AgNPs) exhibit antimicrobial activity and reduce the viability of cancer cells without affecting the viability of RAW 264.7 macrophage-like cells
tumCV↓,
selectivity↑,
ROS↑, enhanced the production of ROS in both cell lines.
Apoptosis↑, An increase in cell apoptosis and a reduction in cell migration in A549 cells were also observed after D-AgNP treatment.
TumCMig↓,
AntiCan↑, potential of D-AgNPs as a possible anticancer agent, particularly for the treatment of non-small cell lung carcinoma.

4549- AgNPs,    Silver nanoparticles: Synthesis, medical applications and biosafety
- Review, Var, NA - Review, Diabetic, NA
ROS↑, action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag+), generation of reactive oxygen species (ROS), destruction of membrane structure.
eff↑, briefly introduce a new type of Ag particles smaller than AgNPs, silver Ångstrom (Å, 1 Å = 0.1 nm) particles (AgÅPs), which exhibit better biological activity and lower toxicity compared with AgNPs.
other↝, This method involves reducing silver ions to silver atoms 9, and the process can be divided into two steps, nucleation and growth
DNAdam↑, antimicrobial mechanisms of AgNPs includes destructing bacterial cell walls, producing reactive oxygen species (ROS) and damaging DNA structure
EPR↑, Due to the enhanced permeability and retention (EPR) effect, tumor cells preferentially absorb NPs-sized bodies than normal tissues
eff↑, Large surface area may lead to increased silver ions (Ag+) released from AgNPs, which may enhance the toxicity of nanoparticles.
eff↑, Our team prepared Ångstrom silver particles, capped with fructose as stabilizer, can be stable for a long time
TumMeta↓, AgNPs can induce tumor cell apoptosis through inactivating proteins and regulating signaling pathways, or blocking tumor cell metastasis by inhibiting angiogenesis
angioG↓, Various studies support that AgNPs can deprive cancer cells of both nutrients and oxygen via inhibiting angiogenesis
*Bacteria↓, Rather than Gram-positive bacteria, AgNPs show a stronger effect on the Gram-negative ones. This may be due to the different thickness of cell wall between two kinds of bacteria
*eff↑, In general, as particle size decreases, the antibacterial effect of AgNPs increases significantly
*AntiViral↑, AgNPs with less than 10 nm size exhibit good antiviral activity 185, 186, which may be due to their large reaction area and strong adhesion to the virus surface.
*AntiFungal↑, Some studies confirm that AgNPs exhibit good antifungal properties against Colletotrichum coccodes, Monilinia sp. 178, Candida spp.
eff↑, The greater cytotoxicity and more ROS production are observed in tumor cells exposed to high positive charged AgNPs
eff↑, Nanoparticles exposed to a protein-containing medium are covered with a layer of mixed protein called protein corona. formation of protein coronas around AgNPs can be a prerequisite for their cytotoxicity
TumCP↓, Numerous experiments in vitro and in vivo have proved that AgNPs can decrease the proliferation and viability of cancer cells.
tumCV↓,
P53↝, gNPs can promote apoptosis by up- or down-regulating expression of key genes, such as p53 242, and regulating essential signaling pathways, such as hypoxia-inducible factor (HIF) pathway
HIF-1↓, Yang et al. found that AgNPs could disrupt the HIF signaling pathway by attenuating HIF-1 protein accumulation and downstream target genes expression
TumCCA↑, Cancer cells treated with AgNPs may also show cell cycle arrest 160, 244
lipid-P↑, Ag+ released by AgNPs induces oxidation of glutathione, and increases lipid peroxidation in cellular membranes, resulting in cytoplasmic constituents leaking from damaged cells
ATP↓, mitochondrial function can be inhibited by AgNPs via disrupting mitochondrial respiratory chain, suppressing ATP production
Cyt‑c↑, and the release of Cyt c, destroy the electron transport chain, and impair mitochondrial function
MMPs↓, AgNPs can also inhibit the progression of tumors by inhibiting MMPs activity.
PI3K↓, Various studies support that AgNPs can deprive cancer cells of both nutrients and oxygen via inhibiting angiogenesis
Akt↓,
*Wound Healing↑, AgNPs exhibit good properties in promoting wound repair and bone healing, as well as inhibition of inflammation.
*Inflam↓,
*Bone Healing↑,
*glucose↓, blood glucose level of diabetic rats decreased when treated with AgNPs for 14 days and 21 days without significant acute toxicity.
*AntiDiabetic↑,
*BBB↑, The small-sized AgNPs are easy to penetrate the body and cross biological barriers like the blood-brain barrier and the blood-testis barrier

4584- AgNPs,    Silver Nanoparticles Synthesized Using Carica papaya Leaf Extract (AgNPs-PLE) Causes Cell Cycle Arrest and Apoptosis in Human Prostate (DU145) Cancer Cells
- in-vitro, Pca, DU145
selectivity↑, AgNPs-PLE when compared with AgNPs-citric acid or PLE showed better efficacy against cancer cells and was also relatively less toxic to normal cells.
ROS↑, ROS production was observed at earlier time points in presence of AgNPs-PLE, suggesting its role behind apoptosis in DU145 cells.
BAX↑, induction of Bax, cleaved caspase-3, and cleaved PARP proteins. G1-S phase cell cycle check point marker, cyclin D1 was down-regulated along with an increase in cip1/p21 and kip1/p27 tumor suppressor proteins by AgNPs-PLE.
cl‑Casp3↑,
p‑PARP↑,
TumCCA↑,
cycD1/CCND1↓,
p27↑,
P21↑,
AntiCan↑, These findings suggest the anti-cancer properties of AgNPs-PLE.

4583- AgNPs,    Metal-Based Nanoparticles for Cardiovascular Diseases
- Review, NA, NA
RadioS↑, enhancing radiation-based anticancer therapy
*ROS↑, Silver nanoparticles (AgNPs) produce a pro-oxidant environment, though it is still unclear exactly how they increase reactive oxygen species (ROS).
*BBB↝, research contends that these particles mainly spare the blood–brain barrier (BBB) from toxicity, other reports found that administering AgNP altered the BBB’s permeability, providing a fascinating potential avenue for future applications

5147- AgNPs,    Size dependent anti-invasiveness of silver nanoparticles in lung cancer cells
- in-vitro, Lung, A549
TumCMig↓, 13 nm AgNPs significantly inhibit the migration and invasiveness of lung adenocarcinoma A549 cells, induce elevated reactive oxygen species and lead to NF-κB directed cellular apoptosis
TumCI↓,
ROS↑,
p‑NF-kB↑, 13 nm AgNPs was able to significantly upregulate the phosphorylation of NF-κB (p-NF-κB) in A549 cells
selectivity↑, we speculate that, AgNPs, which are pointed out that have a sustained release of Ag+ in an environment with lower pH (such as cancer cells)
eff↝, and this inhibitive effect is most pronounced treated with 13 nm AgNPs, while the effect starts decreasing with the size of 45 nm and completely vanishes for 92 nm AgNPs.

5143- AgNPs,    Thermal Co-reduction engineered silver nanoparticles induce oxidative cell damage in human colon cancer cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis
- in-vitro, CRC, HCT116
ROS↑, AgNP induces oxidative stress on HCT116 by increased levels of lipid peroxidation and reduced levels of glutathione.
lipid-P↑,
GSH↓,
MMP↓, Mitochondrial membrane depolarization was also analysed and Western blot analysis confirms the increased level of Bcl and Caspase-3 which indicates the mitochondrial -mediated apoptosis.
Casp3↑,
Apoptosis↑,
TumCCA↑, Mitochondrial membrane depolarization was also analysed and Western blot analysis confirms the increased level of Bcl and Caspase-3 which indicates the mitochondrial -mediated apoptosis.

5142- AgNPs,    Biosynthesized Protein-Capped Silver Nanoparticles Induce ROS-Dependent Proapoptotic Signals and Prosurvival Autophagy in Cancer Cells
- in-vitro, CRC, HUH7
ROS↑, Elucidation of the molecular mechanism revealed that bAgNPs induce cytotoxicity through elevation of reactive oxygen species (ROS) levels and induction of apoptosis.
Apoptosis↑,
eff↑, Interestingly, inhibition of autophagy increased the production of ROS, resulting in enhanced cell death
ChemoSen↑, bAgNPs Enhance Cytotoxicity of Chemotherapeutic Drug Cisplatin (CDDP)
EPR↑, The AgNPs were selected over free metal silver for exploration of their anticancerous effects because of the enhanced permeability of NPs into tumors, attributable to the EPR effect.
Casp↑, Induction of Apoptotic Cell Death by bAgNPs through Activation of Caspases
MAPK↑, Our results provide strong evidence for selective activation of MAPK pathways following AgNP exposure

2288- AgNPs,    Silver Nanoparticle-Mediated Cellular Responses in Various Cell Lines: An in Vitro Model
- Review, Var, NA
*ROS↑, Several studies have reported that AgNPs induce genotoxicity and cytotoxicity in both cancer and normal cell lines
Akt↓, high ROS levels, and reduced Akt and ERK signaling.
ERK↓,
DNAdam↑, increased ROS production, leading to oxidative DNA damage and apoptosis
Ca+2↑, The damage caused to the cell membrane is due to intracellular calcium overload, and further causes ROS overproduction and mitochondrial membrane potential variation
ROS↑,
MMP↓,
Cyt‑c↑, AgNPs induce apoptosis through release of cytochrome c into the cytosol and translocation of Bax to the mitochondria, and also cause cell cycle arrest in the G1 and S phases
TumCCA↑,
DNAdam↑, main result of AgNP toxicity is direct and oxidative DNA damage, ultimately causing apoptosis
Apoptosis↑,
P53↑, AgNPs induce apoptosis in spermatogonial stem cells through increased levels of ROS; mitochondrial dysfunction; upregulation of p53 expression; pErk1/2;
p‑ERK↑,
ER Stress↑, endoplasmic reticulum (ER) stress-induced apoptosis caused by AgNPs has attracted much research interest
cl‑ATF6↑, cleavage of activating transcription factor 6 (ATF6), and upregulation of glucose-regulated protein-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153)
GRP78/BiP↑,
CHOP↑,
UPR↑, In order to protect the cells against nanoparticle-mediated toxicity, the ER rapidly responds with the unfolded protein response (UPR), an important cellular self-protection mechanism

2287- AgNPs,    Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: The protective role of N-acetylcysteine
- in-vitro, Nor, HUVECs
*TumCP↓, AgNPs affects the morphology and function of endothelial cells which manifests as decreased cell proliferation, migration, and angiogenesis ability
*ROS↑, AgNPs can induce excessive cellular production of reactive oxygen species (ROS), leading to damage to cellular sub-organs such as mitochondria and lysosomes
*eff↓, treatment with ROS scavenger-NAC can effectively suppress AgNP-induced endothelial damage.
*MDA↑, exposure to AgNPs increased MDA levels and decreased GSH levels.
*GSH↓,
*MMP↓, significantly reduced both MMP and ATP levels (Fig. 7) in HUVECs,
*ATP↓,
*LC3II↑, expression levels of LC3-II and p62 were significantly increase
*p62↑,
*Bcl-2↓, the anti-apoptotic protein expression level of Bcl-2 in HUVECs decreased, while the pro-apoptotic protein expression levels of Bax and Caspase-3 increased significantly.
*BAX↑,
*Casp3↑,

2286- AgNPs,    ROS_localization_after_the_silver_nanoparticles_exposure_depending_on_particle_size">Short-term changes in intracellular ROS localisation after the silver nanoparticles exposure depending on particle size
- in-vitro, Nor, 3T3
*eff↑, These results indicate that the smaller silver particles were more cytotoxic and are consistent with the tentative theory that smaller AgNPs are more cytotoxi
*mt-ROS↑, increased mitochondrial ROS production in the presence of smaller AgNPs
*eff↑, smaller AgNPs particles induced higher levels of mitochondrial ROS

2836- AgNPs,  Gluc,    Glucose capped silver nanoparticles induce cell cycle arrest in HeLa cells
- in-vitro, Cerv, HeLa
eff↝, AgNPs synthesized are stable up to 10 days without silver and glucose dissolution.
TumCCA↑, AgNPs block the cells in S and G2/M phases, and increase the subG1 cell population.
eff↑, HeLa cells take up abundantly and rapidly AgNPs-G resulting toxic to cells in amount and incubation time dependent manner.
eff↑, The dissolution experiments demonstrated that the observed effects were due only to AgNPs-G since glucose capping prevents Ag+ release.
ROS↑, AgNPs cause toxic responses via induction of oxidative stress as consequence of the generation of intracellular (ROS), depletion of glutathione (GSH), reduction of the superoxide dismutase (SOD) enzyme activity, and increased lipid peroxidation
GSH↓,
SOD↓,
lipid-P↑,
LDH↑, significant LDH levels increase with the highest amount of AgNPs-G and maximum of toxicity was seen at 12 h.

2835- AgNPs,  Gluc,    Carbohydrate functionalization of silver nanoparticles modulates cytotoxicity and cellular uptake
- in-vitro, Liver, HepG2
Dose↝, Values found were between 3.2 and 3.9 molecules sugar/nm2.
eff↑, glucose and citrate coated nanoparticles show a similar toxicity, galactose and mannose functionalized nanoparticles were significant less toxic towards both cell lines.
ROS↑, suggesting that the toxicity is mainly caused by oxidative stress related to ROS formation
eff↝, Many authors have argued that in fact the toxicity of nanosilver is only caused by the ionic form [24]
eff↑, Trojan-horse mechanism has been often discussed in literature as a responsible for toxicity of silver nanoparticles.
eff↝, although mannose and glucose-functionalized nanoparticles present similar cellular uptakes, observed toxicities were considerably different.
eff↑, Actually, in this study, glucose-capped nanoparticles present the highest toxicity as well as protein carbonylation, despite their moderate cellular uptake, compared with other nanoparticles.
eff↝, Observed toxicity was strongly correlated with intracellular oxidative stress, measured as protein carbonylation, but not to cellular uptake.

2538- AgNPs,  SDT,  Z,    Dual-functional silver nanoparticle-enhanced ZnO nanorods for improved reactive oxygen species generation and cancer treatment
- Study, Var, NA - vitro+vivo, NA, NA
ROS↑, This study introduces zinc oxide (ZnO) nanorods (NRs) in situ loaded with silver nanoparticles (ZnO@Ag NRs), designed to optimize ROS production under ultrasound irradiation and offer significant advantages in tumor specificity and biosafety
eff↑, In conclusion, our findings confirmed that the ROS production ability of ZnO@Ag exceeded that of ZnO and is highly depended on the duration of US treatment in this study.
eff↑, The ZnO@Ag group had the most effective cell-killing effects under ultrasound (1.5 W/cm2, 50% duty cycle, 1 MHz, 5 min) than any of the other five groups
TumCP↓, ZnO@Ag significantly inhibited tumor cell proliferation, consistent with earlier tumor growth curve findings
toxicity↓, None of the intervention groups showed significant organ toxicity

252- Ajoene,    Ajoene, a Compound of Garlic, Induces Apoptosis in Human Promyeloleukemic Cells, Accompanied by Generation of Reactive Oxygen Species and Activation of Nuclear Factor κB
- in-vitro, AML, HL-60
H2O2↑,
NF-kB↑, Activation of Nuclear Factor κB
ROS↑,

1069- AL,    Allicin promotes autophagy and ferroptosis in esophageal squamous cell carcinoma by activating AMPK/mTOR signaling
- vitro+vivo, ESCC, TE1 - vitro+vivo, ESCC, KYSE-510 - in-vitro, Nor, Het-1A
TumCP↓,
LC3‑Ⅱ/LC3‑Ⅰ↑,
p62↓,
p‑AMPK↑,
mTOR↓,
TumAuto↑,
NCOA4↑,
MDA↑,
Iron↑, elevated malondialdehyde and Fe2+ production levels
TumW↓,
TumVol↓,
ATG5↑,
ATG7↑,
TfR1/CD71↓,
FTH1↓, suppressed the expression of ferritin heavy chain 1 (the major intracellular iron-storage protein)
ROS↑,
Iron↑,
Ferroptosis↑,
*toxicity↓, 80 μg/mL allicin for 24 h did not change the viability of Het-1A cells. A slight reduction in cell viability was observed when Het-1A cells were treated with 160 μg/mL allicin for 24 h

248- AL,    Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway
- in-vitro, GBM, U87MG
Bcl-2↓,
BAX↑,
MAPK↑,
ERK↑,
ROS↑, antioxidant prevented inhibitory effect
p38↑,
JNK↑,

254- AL,    Allicin and Cancer Hallmarks
- Review, Var, NA
NRF2⇅, 40 nM
BAX↑,
Bcl-2↓,
Fas↑,
MMP↓,
Bax:Bcl2↑,
Cyt‑c↑,
Casp3↑,
Casp12↑,
GSH↓, Allicin can easily penetrate the cell membrane and react with the cellular thiol to transiently deplete the intracellular GSH level, inducing the inhibition of cell cycle progression and growth arrest [98].
TumCCA↑,
ROS↑, An in vitro study indicated that allicin encourages oxidative stress and autophagy in Saos-2 and U2OS (osteosarcoma cells) by modulating the MALATI-miR-376a-Wnt and β-catenin pathway [99].
antiOx↓, As an antioxidant phytochemical, it scavenges reactive oxygen species (ROS) and protects cells from oxidative DNA damage [34].

257- AL,  Cisplatin,    Allicin Overcomes Hypoxia Mediated Cisplatin Resistance in Lung Cancer Cells through ROS Mediated Cell Death Pathway and by Suppressing Hypoxia Inducible Factors
- in-vitro, NSCLC, A549
ROS↑, apoptosis and autophagy pathway in A549 cells by ROS accumulation and facilitating S/G2-M phase arrest in both normoxia as well as hypoxia
HIF-1↓,
E-cadherin↑,
N-cadherin↓,
antiOx↓, ROS trigger cell death when its generation reached toxic threshold level by overcoming the antioxidant capacity of the cell and inducing irreversible oxidative modifications of lipid, protein or DNA [30, 48]
Dose↝, 10μg/ml (LD) and 40μg/ml (HD) allicin for 24hr

239- AL,    Allicin induces apoptosis in gastric cancer cells through activation of both extrinsic and intrinsic pathways
- in-vitro, GC, SGC-7901
Apoptosis↑,
Cyt‑c↑, induced cytochrome c release from the mitochondria
Casp3↑,
Casp8↑,
Casp9↑,
BAX↑,
Fas↑,
tumCV↓, 30ug/ml allicin treatment for 48 h reduced tumor cell viability by 70%
DNAdam↑, such as DNA damage, oxidative stress and heat shock proteins
ROS↑,
Telomerase↓, Allicin was shown to induce apoptosis in gastric cancer cells, partly by decreased telomerase activity (21).

236- AL,    Allicin: Chemistry and Biological Properties
- Analysis, NA, NA
GSH↓, allicin reacts with GSH
Bacteria↓, Antimicrobial
LDL↓, reduction without altering HDL
ROS↑, antioxidant at low doses
NRF2↑,
cognitive↑, by activating the Nrf2-system
memory↑, by activating the Nrf2-system
BP↓, via H2S generation
RNS↓,

235- AL,    Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway
- in-vitro, GBM, U87MG
Apoptosis↑,
Bcl-2↓,
BAX↑,
MAPK↑, mechanisms involved in apoptosis include the mitochondrial pathway, activation of mitogen-activated protein kinases (MAPKs), and caspase cascade and oxidant enzyme system.
p‑ERK↑, In the present study, the level of ERK phosphorylation was increased
ROS↑, ROS are related to allicin-induced apoptosis in the U87MG cells.
eff↓, This study demonstrated that allicin-induced apoptosis was down-regulated by the antioxidant enzyme system

234- AL,    Allicin Induces Anti-human Liver Cancer Cells through the p53 Gene Modulating Apoptosis and Autophagy
- in-vitro, HCC, Hep3B
ROS↑, increased the production of ROS levels at 1, 3, 6 h. I
*toxicity∅, In other study, allicin treatment did not increase the leakage of lactate-dehydrogenase (LDH) of primary rat hepatocytes until 1 mM allicin treated with rat hepatocytes24. For this reason, allicin could be inferred as safe to normal liver cells
MMP↓, Allicin decreased mitochondrial membrane potential
BAX↑,
Bcl-2↓,
AIF↑,
Casp3↑, protein expression levels of caspase-3, -8, -9 increased after allicin treatment
Casp8↑,
Casp9↑,
eff↓, Allicin significantly induced ROS overproduction, whereas NAC pretreatment decreased the ROS induction by allicin exposure in Hep 3B cells
γH2AX↑, significant increase in the expression of γ-H2AX was observed at the initial stages (3, 6 h), but not at the later stages of 12, 24, 48 h
selectivity↑, data suggested that allicin induced apoptosis in p53-deficiency human liver carcinoma cells but caused autophagy in p53-normal function human liver carcinoma cells.
DNA-PK↑, increases production of ROS, triggers DNA damage

233- AL,  5-FU,    Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway
- in-vivo, Liver, NA
ROS↑,
MMP↓,
Casp3↑, activated
PARP↑, increase of activated caspase-3 and PARP
Bcl-2↓,

231- AL,    Molecular Docking Studies with Garlic Phytochemical Constituents to Inhibit the Human EGFR Protein for Lung Cancer Therapy
- Analysis, Lung, NA
EGFR↓,
ROS↑, pro-oxidants in inflammatory conditions

2646- AL,    Anti-Cancer Potential of Homemade Fresh Garlic Extract Is Related to Increased Endoplasmic Reticulum Stress
- in-vitro, Pca, DU145 - in-vitro, Melanoma, RPMI-8226
AntiCan↑, simple homemade ethanol-based garlic extract (GE). We show that GE inhibits growth of several different cancer cells in vitro
eff↓, These activities were lost during freeze or vacuum drying, suggesting that the main anti-cancer compounds in GE are volatile.
ChemoSen↑, We found that GE enhanced the activities of chemotherapeutics
ER Stress↑, Our data indicate that the reduced proliferation of the cancer cells treated by GE is at least partly mediated by increased endoplasmic reticulum (ER) stress.
tumCV↓, homemade GE was found to reduce the viability of the two multiple myeloma (MM) cell lines, RPMI-8226 and JJN3, as well as the prostate cancer cell line DU145 in a dose-dependent manner,
DNAdam↑, GE alone slightly increased the percentage of tail DNA (% Tail) (representing cumulative levels of abasic sites, as well as single- and double-strand DNA breaks) measured at day one, compared to untreated cells
GSH∅, We could not detect any changes in cellular GSH levels after treatments with GE
HSP70/HSPA5↓, ; however, in support of increased ER stress after GE treatment, we detected an increased pulldown of HSPA5 (BIP), a member of the Hsp70 family
UPR↑, s leading to the accumulation of unfolded proteins in the ER (also known as GRP78)
β-catenin/ZEB1↓, we also found a reduction in the β-catenin leve
ROS↑, In further support for increased ER stress induced by GE, which will lead to elevated ROS-levels and oxidative stress
HO-2↑, we found a significant increase in proteins activated by and important for regulating cellular ROS levels, e.g., OXR1, Txnl1, Hmox2, and Sirt1
SIRT1↑,
GlucoseCon∅, glucose consumption, as well as lactate secretion, were not changed.
lactateProd∅,
chemoP↑, Garlic is reported to reduce cisplatin-induced nephrotoxicity and oxidative stress

2648- AL,    Allicin Inhibits Osteosarcoma Growth by Promoting Oxidative Stress and Autophagy via the Inactivation of the lncRNA MALAT1-miR-376a-Wnt/β-Catenin Signaling Pathway
- in-vitro, OS, SaOS2 - in-vivo, OS, NA
ROS↑, Allicin inhibited osteosarcoma growth and promoted oxidative stress and autophagy via MALATI-miR-376a
TumCG↓,
TumAuto↑,
Wnt↓, allicin promotes oxidative stress and autophagy to inhibit osteosarcoma growth by inhibiting the Wnt/β-catenin pathway in vivo and in vitro.
β-catenin/ZEB1↓,
MALAT1↓, Allicin Inhibited OS Growth by Promoting Oxidative Stress and Autophagy via Inactivation of the MALAT1-miR-376a-Wnt/β-Catenin Signal Pathway Axis In Vitro and In Vivo

2655- AL,    Allicin and Digestive System Cancers: From Chemical Structure to Its Therapeutic Opportunities
- Review, GC, NA
TGF-β↓, Allicin can reduce the expression of TGF-2 and its receptor after entering directly into gastric cancer cell
cycD1/CCND1↓, followed by not only downexpression of cyclinD1, cyclinE, and cyclin-dependent kinase (CDK),
cycE/CCNE↓,
CDK1↓, cyclin-dependent kinase (CDK)
DNAdam↑, but also causing DNA damage and generating ROS
ROS↑,
BAX↑, Allicin increases the levels of Bax (proapoptotic protein), Bcl-2 (antiapoptotic protein), and JNK
JNK↑,
MMP↓, through reduction in outer mitochondrial membrane potential
p38↑, allicin induces p38 mitogen that could induce the protein kinase (MAPK) and then increase the expression of Fas binding to Fas ligand (Fas L) and finally activate death pathway through activation of cyt C and caspase-8.
MAPK↑,
Fas↑,
Cyt‑c↑,
Casp8↑,
PARP↑, allicin makes caspase-dependent apoptosis through elevating PARP, caspase-3 and caspase-9, which are mediated by enhanced discharging of mitochondria cyt C to the cytosol.
Casp3↑,
Casp9↑,
Ca+2↑, allicin induces apoptosis via increasing the amounts of free Ca2+, ER stress.
ER Stress↑,
P21↑, generating ROS to produce p21 and phospho-p53 (Ser15).
CDK2↓, Then p21 suppressed the CDK-4/6/cyclinD complex, P21-PCNA, P21-CDK2, and subsequently reduced cdk1/cyclinB1 complex for G2/M phase cell cycle arrest
CDK6↑,
TumCCA↑,
CDK4↓, Then p21 suppressed the CDK-4/6/cyclinD complex

2658- AL,    The Toxic Effect Ways of Allicin on Different Cell Lines
- Review, Var, NA
*antiOx↑, The significant functional act of garlic is its anticancer, antimicrobial, antioxidant, antidiabetic, antifibrinolytic, immune enhancing, antiplatelet collected effect and its possible act in prohibiting cardiovascular illnesses
*AntiAg↑,
*cardioP↑,
Ca+2↑, Sultan et al.[34] stated that allicin is cytotoxic to monocytic leukemia cells (THP-1 cells) and stimulates calcium-linked hemolysis and eryptosis in human red blood cells. Allicin advances calcium grades in cells, reasons to oxidative stress and al
ROS↑, Allicin advances calcium grades in cells, reasons to oxidative stress and also induces CK1a, caspase, p38, mitogen-activated protein kinase
Casp↑,
p38↑,
MAPK↑,
hepatoP↑, Wu et al.[42] clarified that allicin applies hepaprotective action counter to hepatic toxicity of cells
chemoP↑, Throughout with other garlic preparations, aged garlic extract (AGE) has been indicated to have hepatoprotective, immune, improving, anticancer, and chemoprotective actions.

2663- AL,    Therapeutic Effect of Allicin on Glioblastoma
- in-vitro, GBM, U251 - in-vitro, GBM, U87MG
BioAv↝, After processing, such as cutting, crushing, chewing, or dehydration, alliinase rapidly breaks down alliin to form allicin. Allicin is immediately decomposed to other organosulfur compounds such as diallyl sulphide (DAS), diallyl disulfide(DADS), and
TumCCA↑, The results show DATS can reduce tumor growth by inhibits cell cycle progression and promotes p53-mediated tumor suppression pathways
P53↑,
HDAC↓, The findings demonstrate that DATS can inhibit U87MG cell growth in vivo by inhibiting HDAC [10].
CSCs↓, Inhibition of cancer stem cells(CSC)
ROS↑, DATS can induce apoptosis by ROS through regulation of Bcl-2 and have anticancer effect on human glioblastoma (U87MG) and neuroblastoma (SH-SY5Y) cells
ChemoSen↑, The most interesting thing is allicin can enhance the sensitivity of TMZ-resistant cells to TMZ by inhibiting MGMT expression.
MGMT↓,

2660- AL,    Allicin: A review of its important pharmacological activities
- Review, AD, NA - Review, Var, NA - Review, Park, NA - Review, Stroke, NA
*Inflam↓, It showed neuroprotective effects, exhibited anti-inflammatory properties, demonstrated anticancer activity, acted as an antioxidant, provided cardioprotection, exerted antidiabetic effects, and offered hepatoprotection.
AntiCan↑,
*antiOx↑,
*cardioP↑, This vasodilatory effect helps protect against cardiovascular diseases by reducing the risk of hypertension and atherosclerosis.
*hepatoP↑,
*BBB↑, This allows allicin to easily traverse phospholipid bilayers and the blood-brain barrier
*Half-Life↝, biological half-life of allicin is estimated to be approximately one year at 4°C. However, it should be noted that its half-life may differ when it is dissolved in different solvents, such as vegetable oil
*H2S↑, allicin undergoes metabolism in the body, leading to the release of hydrogen sulfide (H2S)
*BP↓, H2S acts as a vasodilator, meaning it relaxes and widens blood vessels, promoting blood flow and reducing blood pressure.
*neuroP↑, It acts as a neuromodulator, regulating synaptic transmission and neuronal excitability.
*cognitive↑, Studies have suggested that H2S may enhance cognitive function and protect against neurodegenerative diseases like Alzheimer's and Parkinson's by promoting neuronal survival and reducing oxidative stress.
*neuroP↑, various research studies suggest that the neuroprotective mechanisms of allicin can be attributed to its antioxidant and anti-inflammatory properties
*ROS↓,
*GutMicro↑, may contribute to the overall health of the gut microbiota.
*LDH↓, Liu et al. found that allicin treatment led to a significant decrease in the release of lactate dehydrogenase (LDH),
*ROS↓, allicin's capacity to lower the production of reactive oxygen species (ROS), decrease lipid peroxidation, and maintain the activities of antioxidant enzymes
*lipid-P↓,
*antiOx↑,
*other↑, allicin was found to enhance the expression of sphingosine kinases 2 (Sphk2), which is considered a neuroprotective mechanism in ischemic stroke
*PI3K↓, allicin downregulated the PI3K/Akt/nuclear factor-kappa B (NF-κB) pathway, inhibiting the overproduction of NO, iNOS, prostaglandin E2, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha induced by interleukin-1 (IL-1)
*Akt↓,
*NF-kB↓,
*NO↓,
*iNOS↓,
*PGE2↓,
*COX2↓,
*IL6↓,
*TNF-α↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
*MPO↓, Furthermore, allicin significantly decreased tumor necrosis factor-alpha (TNF-α) levels and myeloperoxidase (MPO) activity, indicating its neuroprotective effect against brain ischemia via an anti-inflammatory pathway
*eff↑, Allicin, in combination with melatonin, demonstrated a marked reduction in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), Kelch-like ECH-associated protein 1 (Keap-1), and NF-κB genes in rats with brain damage induced by acryl
*NRF2↑, Allicin treatment decreased oxidative stress by upregulating Nrf2 protein and downregulating Keap-1 expression.
*Keap1↓,
*TBARS↓, It significantly reduced myeloperoxidase (MPO) and thiobarbituric acid reactive substances (TBARS) levels,
*creat↓, and decreased blood urea nitrogen (BUN), creatinine, LDH, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels.
*LDH↓,
*AST↓,
*ALAT↓,
*MDA↓,
*SOD↑, Allicin also increased the activity of superoxide dismutase (SOD) as well as the levels of glutathione S-transferase (GST) and glutathione (GSH) in the liver, kidneys, and brain
*GSH↑,
*GSTs↑,
*memory↑, Allicin has demonstrated its ability to improve learning and memory deficits caused by lead acetate injury by promoting hippocampal astrocyte differentiation.
chemoP↑, Allicin safeguards mitochondria from damage, prevents the release of cytochrome c, and decreases the expression of pro-apoptotic factors (Bax, cleaved caspase-9, cleaved caspase-3, and p53) typically activated by cisplatin
IL8↓, Allicin has been found to regulate the immune system and reduce the levels of TNF-α and IL-8.
Cyt‑c↑, In addition, allicin was reported to induce cytochrome c, increase expression of caspase 3 [86], caspase 8, 9 [82,87], caspase 12 [80] along with enhanced p38 protein expression levels [81], Fas expression levels [82].
Casp3↑,
Casp8↑,
Casp9↑,
Casp12↑,
p38↑,
Fas↑,
P53↑, Also, significantly increased p53, p21, and CHK1 expression levels decreased cyclin B after allicin treatment.
P21↑,
CHK1↓,
CycB/CCNB1↓,
GSH↓, Depletion of GSH and alterations in intracellular redox status have been found to trigger activation of the mitochondrial apoptotic pathway was the antiproliferative function of allicin
ROS↑, Hepatocellular carcinoma (HCC) cells were sensitised by allicin to the mitochondrial ROS-mediated apoptosis induced by 5-fluorouracil
TumCCA↑, According to research findings, allicin has been shown to decrease the percentage of cells in the G0/G1 and S phases [87], while causing cell cycle arrest at the G2/M phase
Hif1a↓, Allicin treatment was found to effectively reduce HIF-1α protein levels, leading to decreased expression of Bcl-2 and VEGF, and suppressing the colony formation capacity and cell migration rate of cancer cells
Bcl-2↓,
VEGF↓,
TumCMig↓,
STAT3↓, antitumor properties of allicin have been attributed to various mechanisms, including promotion of apoptosis, inhibition of STAT3 signaling
VEGFR2↓, suppression of VEGFR2 and FAK phosphorylation
p‑FAK↓,

2666- AL,    Targeting the Interplay of Autophagy and ROS for Cancer Therapy: An Updated Overview on Phytochemicals
- Review, Var, NA
Inflam↓, , anti-inflammatory, anti-cancer, and immune-modulatory activities
AntiCan↑,
ROS↑, allicin treatment led to the accumulation of ROS
MAPK↑, activation of MAPK/JNK
JNK↑,
TumAuto↑, of autophagy in non small cell lung cancer (NSCLC) cells.
other↑, autophagy at a low dose of allicin is cytoprotective
Dose↝, whereas a high dose of allicin leads to autophagic cell death.
MALAT1↓, allicin could considerably induce oxidative stress and autophagy to suppress osteosarcoma growth via inactivating the MALAT1-miR-376a-Wnt/β-catenin axis,
Wnt↓,
β-catenin/ZEB1↓,

2000- AL,    Exploring the ROS-mediated anti-cancer potential in human triple-negative breast cancer by garlic bulb extract: A source of therapeutically active compounds
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, NA
selectivity↑, The inhibitory effect of ASEE was more pronounced in MDA-MB-231 cells than in MCF-7 cells, however, no substantial cytotoxicity was seen in normal Vero cells.
TumCG?,
*toxicity∅, no substantial cytotoxicity was seen in normal Vero cells
ROS↑, TNBC cells treated with high concentrations of ASEE were found in the late apoptotic stage and exhibited an increase in ROS level and a reduction in MMP
MMP↓,
TumCCA↑, increased the percentage of cells in the G2/M phase
P53↑, ASEE upregulated the p53 and Bax proteins while downregulated the Bcl-2, p-Akt, and p-p38 proteins.
Bcl-2↓,
p‑Akt↓,
p‑p38↓,
*ROS∅, Vero normal cells did not display the unusual morphological alteration and reduction in cell viability. ROS production revealed a 1.21 % ROS level only in control cells that is typically seen in healthy cells.

5356- AL,    Therapeutic role of allicin in gastrointestinal cancers: mechanisms and safety aspects
- Review, GC, NA
Apoptosis↑, induction of apoptosis, inhibition of proliferation, and disruption of cancer cell signaling pathways, including the MAPK, PI3K/AKT, and NF-κB pathways.
TumCP↓,
MAPK↓,
PI3K↓,
Akt↓,
NF-kB↓,
AntiCan↑, Allicin and its other derivatives, such as diallyl disulfide (DADS) and ajoene, have been found to have strong anticancer potential both in vitro and in vivo.
ChemoSen↑, effectiveness of allicin in augmenting conventional chemotherapy and retarding tumor growth proves that allicin is one of the most efficient complementary therapies.
TumCCA↑, In liver cancer, allicin has been shown to mediate cell cycle arrest and apoptosis
Apoptosis↑,
BioAv↑, Allicin (diallyl thiosulfinate) is a compound that is generated when a garlic clove is crushed
selectivity↑, Furthermore, it has no influence on the growth of healthy intestinal cells when it causes stomach cancer cells to undergo apoptosis
TGF-β↓, Allicin can reduce the production of TGF-β2 and its receptor after directly entering gastric cancer cells.
ROS↑, It induces oxidative stress by generating reactive oxygen species (ROS), leading to DNA damage and activation of key apoptotic mediators such as phospho-p53 and p21 [81].
DNAdam↑,
p‑P53↑,
P21↑,
cycD1/CCND1↓, Additionally, cyclin D1, cyclin E, and cyclin-dependent kinases (CDKs) can all be inhibited by allicin.
cycE/CCNE↓,
CDK4↓, suppressing the CDK-4/6/cyclin D complex
CDK6↓,
MMP↓, By lowering the outer mitochondrial membrane potential (MMP), allicin raises levels of nuclear factor kappa B (NF-κB), the proapoptotic protein Bax, while decreasing the antiapoptotic protein Bcl-2, which leads to apoptosis.
NF-kB↑,
BAX↑,
Bcl-2↓,
ER Stress↑, cellular effects of allicin, including its role in inducing ER stress
Casp↑, enhancing caspase activation and apoptosis-inducing factor (AIF)-mediated cell death.
AIF↑,
Fas↑, increasing Fas receptor expression and its binding to Fas ligand (FasL), leading to apoptosis through caspase-8 and cytochrome c activation.
Casp8↑,
Cyt‑c↑,
cl‑PARP↑, leading to poly (ADP-ribose) polymerase (PARP) cleavage and DNA fragmentation.
Ca+2↑, allicin elevates intracellular free Ca2⁺ levels, causing endoplasmic reticulum (ER) stress, which plays a critical role in apoptosis induction
*NRF2↑, by activating the Nrf2 pathway via KLF9, allicin protects against arsenic trioxide-induced liver damage,
*chemoP↑, Additionally, allicin has shown promise in reducing hepatotoxicity caused by tamoxifen (TAM), a commonly used treatment for hormone-dependent breast cancer
*GutMicro↑, Shi et al. [85] found that allicin can ameliorate high-fat diet-induced obesity in mice by altering their gut microbiome.
CycB/CCNB1↑, DATS impaired cell survival in the G2 phase by significantly upregulating cyclins A2 and B1.
H2S↑, DATS can also react with the cellular thiol glutathione to create H2S gas, which can control several other cellular functions [79].
HIF-1↓, allicin treatment (40 µg/ml) for NSCLC lowers the expression of HIF-1 and HIF-2 in hypoxic cells [73]
RadioS↑, Allicin has been shown to increase the sensitivity of X-ray radiation therapy in colorectal cancer, presumably by suppressing the levels of NF-κB, IKKβ mRNA, p-NF-κB, and p-IKKβ protein expression in vitro and in vivo

5167- AL,    The Effects of Allicin, a Reactive Sulfur Species from Garlic, on a Selection of Mammalian Cell Lines
- in-vitro, Nor, 3T3 - in-vitro, BC, MCF-7 - in-vitro, Lung, A549 - in-vitro, CRC, HT-29
Thiols↓, Garlic produces the thiol-reactive defence substance, allicin, upon wounding.
tumCV↓, Allicin reduced cell viability and cell proliferation in a concentration dependent manner.
TumCP↓, Allicin Inhibits Cell Proliferation
GSH↓, allicin reacts with and depletes the GSH pool.
GSSG↑, Allicin is a thiol-reagent and reacts easily with glutathione, forming S-allylmercaptoglutathione (GSSA) and leading to an increased production of GSSG
ROS↑, Allicin oxidizes thiols and causes oxidative stress in its own right.

277- ALA,    α-lipoic acid modulates prostate cancer cell growth and bone cell differentiation
- in-vitro, Pca, 22Rv1 - in-vitro, Pca, C4-2B
ROS↑, α-LA supplementation dramatically increased reactive oxygen species (ROS) levels and HIF-1α expression, which started the downstream molecular cascade and activated JNK/caspase-3 signaling pathway.
Hif1a↑, HIF-1α, is a key regulator in response to cellular stressors, and excessive ROS levels can influence its expression. (HIF-1α) is essential for the physiological response to hypoxia(resulting from elevated intracellular ROS levels)
JNK↑,
Casp3↑,
P21↑,
BAX↑,
Bcl-xL↓,
cFos↓,

278- ALA,    The Multifaceted Role of Alpha-Lipoic Acid in Cancer Prevention, Occurrence, and Treatment
- Review, NA, NA
ROS↑, direct anticancer effect of the antioxidant ALA is manifested as an increase in intracellular ROS levels in cancer cells
NRF2↑, enhance the activity of the anti-inflammatory protein nuclear factor erythroid 2–related factor 2 (Nrf2), thereby reducing tissue damage
Inflam↓,
frataxin↑,
*BioAv↓, Oral ALA has a bioavailability of approximately 30% due to issues such as poor stability in the stomach, low solubility, and hepatic degradation.
ChemoSen↑, ALA can enhance the functionality of various other anticancer drugs, including 5-fluorouracil in colon cancer cells and cisplatin in MCF-7 breast cancer cells
Hif1a↓, it is inferred that lipoic acid may inhibit the expression of HIF-1α
eff↑, act as a synergistic agent with natural polyphenolic substances such as apigenin and genistein
FAK↓, ALA inhibits FAK activation by downregulating β1-integrin expression and reduces the levels of MMP-9 and MMP-2
ITGB1↓,
MMP2↓,
MMP9↓,
EMT↓, ALA inhibits the expression of EMT markers, including Snail, vimentin, and Zeb1
Snail↓,
Vim↓,
Zeb1↓,
P53↑, ALA also stimulates the mutant p53 protein and depletes MGMT
MGMT↓, depletes MGMT by inhibiting NF-κB signalling, thereby inducing apoptosis
Mcl-1↓,
Bcl-xL↓,
Bcl-2↓,
survivin↓,
Casp3↑,
Casp9↑,
BAX↑,
p‑Akt↓, ALA inhibits the activation of tumour stem cells by reducing Akt phosphorylation.
GSK‐3β↓, phosphorylation and inactivation of GSK3β
*antiOx↑, indirect antioxidant protection through metal chelation (ALA primarily binds Cu2+ and Zn2+, while DHLA can bind Cu2+, Zn2+, Pb2+, Hg2+, and Fe3+) and the regeneration of certain endogenous antioxidants, such as vitamin E, vitamin C, and glutathione
*ROS↓, ALA can directly quench various reactive species, including ROS, reactive nitrogen species, hydroxyl radicals (HO•), hypochlorous acid (HclO), and singlet oxygen (1O2);
selectivity↑, In normal cells, ALA acts as an antioxidant by clearing ROS. However, in cancer cells, it can exert pro-oxidative effects, inducing pathways that restrict cancer progression.
angioG↓, Combining these two hypotheses, it can be hypothesized that ALA may regulate copper and HIF-2α to limit tumor angiogenesis.
MMPs↓, ALA was shown to inhibit invasion by decreasing the mRNA levels of key matrix metalloproteinases (MMPs), specifically MMP2 and MMP9, which are crucial for the metastatic process
NF-kB↓, ALA has been shown to enhance the efficacy of the chemotherapeutic drug paclitaxel in breast and lung cancer cells by inhibiting the NF-κB signalling pathway and the functions of integrin β1/β3 [138,139]
ITGB3↓,
NADPH↓, ALA has been shown to inhibit NADPH oxidase, a key enzyme closely associated with NP, including NOX4

279- ALA,    Lipoic acid-induced oxidative stress abrogates IGF-1R maturation by inhibiting the CREB/furin axis in breast cancer cell lines
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
Furin↓,
IGF-1R↓,
ROS↑, LA (0.5 and 1 mM) exerts its anticancer effects in the context of ovarian cancer by inducing the generation of reactive oxygen species (ROS)
CREB↓, we then demonstrated that this oxidative stress induced by LA is essential to inhibit CREB expression
Furin↓, reduction of furin expression is the consequence of the downregulation of CREB
IGF-1R↓, All of these events contribute to an inhibition of IGF-1R maturation

281- ALA,    Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation
- in-vitro, Lung, H460
mt-ROS↑, mitochondria are the primary source of ROS production induced by LA and that these ROS are involved in the apoptotic process.
Apoptosis↑,
Casp9↑,
Bcl-2↓,
eff↓, that all the tested antioxidants were able to inhibit apoptosis induced by LA or DHLA indicating that multiple ROS are involved in the apoptotic process.
eff↑, The pro-oxidant role of LA is generally observed under nonoxidative stress conditions, which is also supported by this study
H2O2↑, LA also induced peroxide generation in these cells
Dose↑, 100uM was enough to generate mitochondrial ROS in lung cancer cells

297- ALA,    Insights on the Use of α-Lipoic Acid for Therapeutic Purposes
- Review, BC, SkBr3 - Review, neuroblastoma, SK-N-SH - Review, AD, NA
PDH↑, ALA is capable of activating pyruvate dehydrogenase in tumor cells.
TumCG↓, ALA also significantly inhibited tumor growth in mouse xenograft model using BCPAP and FTC-133 cells
ROS↑, ALA is able to generate ROS, which promote ALA-dependent cell death in lung cancer [75], breast cancer [76] and colon cancer
AMPK↑,
EGR4↓,
Half-Life↓, Data suggests that ALA has a short half-life and bioavailability (about 30%)
BioAv↝,
*GSH↑, Moreover, it is able to increase the glutathione levels inside the cells, that chelate and excrete a wide variety of toxins, especially toxic metals from the body
*IronCh↑, The existence of thiol groups in ALA is responsible for its metal chelating abilities [14,35].
*ROS↓, ALA exerts a direct impact in oxidative stress reduction
*antiOx↑, ALA is being referred as the universal antioxidant
*neuroP↑, ALA has neuroprotective effects on Aβ-mediated cytotoxicity
*Ach↑, ALA show anti-dementia or anti-AD properties by increasing acetylcholine (ACh) production through activation of choline acetyltransferase, which increases glucose absorption
*lipid-P↓, ALA has multiple and complex effects in this way, namely scavenging ROS, transition metal ions, increasing the levels of reduced glutathione [59,63], scavenging of lipid peroxidation products
*IL1β↓, ALA downregulated the levels of the inflammatory cytokines IL-1B and IL-6 in SK-N-BE human neuroblastoma cells
*IL6↓,
TumCP↓, ALA inhibited cell proliferation, [18F]-FDG uptake and lactate formation and increased apoptosis in neuroblastoma cell lines Kelly, SK-N-SH, Neuro-2a and in the breast cancer cell line SkBr3.
FDG↓,
Apoptosis↑,
AMPK↑, ALA suppressed thyroid cancer cell proliferation and growth through activation of AMPK and subsequent down-regulation of mTOR-S6 signaling pathway in BCPAP, HTH-83, CAL-62 and FTC-133 cells lines.
mTOR↓,
EGFR↓, ALA inhibited cell proliferation through Grb2-mediated EGFR down-regulation
TumCI↓, ALA inhibited metastatic breast cancer cells migration and invasion, partly through ERK1/2 and AKT signaling
TumCMig↓,
*memory↑, Alzheimer’s Disease: ALA led to a marked improvement in learning and memory retention
*BioAv↑, Since ALA is poorly soluble, lecithin has been used as an amphiphilic matrix to enhance its bioavailability.
*BioAv↝, ALA were found to be considerably higher in adults with mean age greater than 75 years as compared to young adults between the ages of 18 and 45 years.
*other↓, ALA treatment has been recently studied by some clinical trials to explain its efficacy in preventing miscarriage
*other↝, 1800 mg of ALA or placebo were administrated orally every day, except during the period 2 days before to 4 days after administration of each dose of platinum to avoid potential interference with platinum’s antitumor effects
*Half-Life↓, Data shows a short half-life and bioavailability of about 30% of ALA due to mechanisms involving hepatic degradation, reduced ALA solubility as well as instability in the stomach.
*BioAv↑, ALA bioavailability is greatly reduced after food intake and it has been recommended that ALA should be admitted at least 2 h after eating or if taken before; meal should be taken at least 30 min after ALA administration
*ChAT↑, ALA show anti-dementia or anti-AD properties by increasing acetylcholine (ACh) production through activation of choline acetyltransferase, which increases glucose absorption
*GlucoseCon↑,

304- ALA,    alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation
- in-vitro, Colon, HT-29
mt-ROS↑, DHLA but not ALA was able to scavenge cytosolic o2- in HT-29 cells whereas both compounds increased O2 -generation inside mitochondria
Apoptosis↑,
Casp3↑, increased caspase-3-like activity (start after 300uM, figure 2A)
DNAdam↑, and was associated with DNA-fragmentation
Bcl-xL↓, down-regulation of the anti-apoptotic protein bcl-X
Dose↝, The margin between these apparent opposing effects of ROS-production and ROS-scavenging seems to be above 100 uM since at lower concentrations of DHLA no apoptosis-induction was observed.

266- ALA,    Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to cell death
- in-vitro, Ovarian, IGROV1
Mcl-1↓,
Bcl-xL↓,
BIM↑, strong induction
ROS↑,

259- ALA,    Increased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells
- in-vitro, Liver, HepG2 - in-vitro, Liver, FaO
Cyc↓, cyclin A
P21↑,
ROS↑, α-LA treatment at a concentration that induces apoptosis (500 µM) caused increased ROS generation in FaO cells, as early as 1 h after treatment with a further increase at 3 and 6 h.
p‑P53↑,
BAX↑, 500 µM α-LA produced an increase in Bax levels as early as 24 h
Cyt‑c↑, release from mitochondria
Casp↑, Treatment of HepG2 cells with 500 µM α-LA caused a time-dependent activation of caspase-3, as indicated by a progressive decrease of levels of pro-caspase-3
survivin↓,
JNK↑,
Akt↓,

264- ALA,    α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells
- in-vitro, HCC, FaO
ROS↑,
P53↑,
ER Stress↑,
UPR↑,
CHOP↑,
PDI↑,
GRP78/BiP↑,
GRP58↓,

265- ALA,    Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ROS↓, ALA decreased ROS production, SOD1 and GSTP1 protein expression
SOD↓, SOD1, DU145
GSTP1/GSTπ↓,
NRF2↓, significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2
p62↓, du145
p62↑, LNCaP
SOD↑, LNCaP
p‑mTOR↑, revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3.
Beclin-1↓,
ROS↑, Interestingly, in LNCaP cells, we observed an almost significant increase in ROS content (p = 0.06) after ALA compared to the control, concomitantly with a significant upregulation of the antioxidant enzyme SOD1 after 48 h.
SOD1↑,

267- ALA,    α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells
- vitro+vivo, Lung, A549 - vitro+vivo, Lung, PC9
Apoptosis↑,
ROS↑, mitochondrial ROS(remarkably increased)
PDK1↓,
NRF2↓,
PDK1↓,
Bcl-2↓,
Casp9↑,
Dose∅, 1.5 mM LA for 24 h

3434- ALA,    Alpha lipoic acid modulates metabolic reprogramming in breast cancer stem cells enriched 3D spheroids by targeting phosphoinositide 3-kinase: In silico and in vitro insights
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
tumCV↓, significant dose-dependent reduction in cell viability, with the half-maximal inhibitory concentration (IC50) of LA to be 3.2 mM for MCF-7 cells and 2.9 mM for MDA-MB-231 cells
PI3K↓, LA significantly inhibited PI3K, p-AKT, p-p70S6K and p-mTOR levels
p‑Akt↓,
p‑P70S6K↓,
mTOR↓,
ATP↓, LA markedly reduced both ATP levels and glucose uptake (Fig. 4A and 4B). LA also induced ROS generation in both MCF-7 and MDA-MB231 spheroids
GlucoseCon↓,
ROS↑,
PKM2↓, LA downregulated the expression of PKM2 and LDHA in the spheroids, indicating an inhibition of glycolysis in BCSCs
LDHA↓,
Glycolysis↓,
ChemoSen↑, LA enhances chemosensitivity of spheroids to Dox treatment

3436- ALA,    Alpha lipoic acid modulates metabolic reprogramming in breast cancer stem cells enriched 3D spheroids by targeting phosphoinositide 3-kinase: In silico and in vitro insights Author links open overlay panel
- in-vitro, BC, MCF-7
ChemoSen↑, LA also enhanced the sensitivity of breast cancer spheroids to doxorubicin (Dox), demonstrating a synergistic effect.
PI3K↓, LA inhibits PI3K/AKT signaling in breast cancer spheroids
Akt↓,
ATP↓, found that LA markedly reduced both ATP levels and glucose uptake
GlucoseCon↓,
ROS↑, LA also induced ROS generation in both MCF-7 and MDA-MB231 spheroids
PKM2↓, LA downregulated the expression of PKM2 and LDHA in the spheroids, indicating an inhibition of glycolysis in BCSCs
Glycolysis↓,
CSCs↓,
IGF-1R↓, LA inhibits IGF-1R via furin downregulation, synergizes with other anticancer drugs like paclitaxel and cisplatin, and enhances radiosensitivity in breast cancer
Furin↓,
RadioS↑,

3438- ALA,    The Potent Antioxidant Alpha Lipoic Acid
- Review, NA, NA - Review, AD, NA
*antiOx↑, Both of alpha lipoic acid and its reduced form have been shown to possess anti-oxidant, cardiovascular, cognitive, anti-ageing, detoxifying, anti-inflammatory, anti-cancer, and neuroprotective pharmacological properties
*cardioP↑,
*cognitive↑, Alpha lipoic acid has the ability to decrease cognitive impairment and may be a successful therapy for Alzheimer’s disease and any disease related dementias
*AntiAge↑,
*Inflam↓,
*AntiCan↑,
*neuroP↑, ALA has neuroprotective effects in experimental brain injury caused by trauma and subarachnoid hemorrhage
*IronCh↑, Also, the ability of ALA to chelate metals can produce an antioxidant effect
*ROS↑, DHLA can exert a pro-oxidant effect of donating its electrons for the reduction of iron, which can then break down peroxide to the prooxidant hydroxyl radical via the Fenton reaction [10]. So, ALA and its reduced form DHLA, can promote antioxidant pr
*Weight↓, α-lipoic acid supplementation at a dose of 300 mg/day might help to could help to promote weight loss and fat mass reduction in healthy overweight/obese women following an energy-restricted balanced diet
*Ach↑, Alpha lipoic acid increases the production of Acetylcholine (Ach) via activating choline acetyl transferase and increases glucose uptake, hence, supplying more acetyl-CoA for the production of Ach of each
*ROS↓, also scavenges reactive oxygen species, thereby increasing the concentration levels of reduced Glutathione (GSH).
*GSH↑,
*lipid-P↓, Alpha lipoic acid can scavenge lipid peroxidation products as hydroxynonenal and acrolein.
*memory↑, learning and memory in the passive avoidance test partially through its antioxidant activity.
*NRF2↑, α-LA treatment has been shown to increase Nrf2 nuclear localization
*ChAT↑, Alpha lipoic acid increases the production of Acetylcholine (Ach) via activating choline acetyl transferase and increases glucose uptake, hence, supplying more acetyl-CoA for the production of Ach of each
*GlucoseCon↑,
*Acetyl-CoA↑,

3442- ALA,    α‑lipoic acid modulates prostate cancer cell growth and bone cell differentiation
- in-vitro, Pca, 22Rv1 - in-vitro, Pca, C4-2B - in-vitro, Nor, 3T3
tumCV↓, Notably, α‑LA treatment significantly reduced the cell viability, migration, and invasion of PCa cell lines in a dose‑dependent manner.
TumCMig↓,
TumCI↓,
ROS↑, α‑LA supplementation dramatically increased reactive oxygen species (ROS) levels and HIF‑1α expression, which started the downstream molecular cascade and activated JNK/caspase‑3 signaling pathway
Hif1a↑, The expression of HIF-1α significantly increased following α-LA treatment and was comparable with the changes in ROS.
JNK↑,
Casp↑,
TumCCA↑, arrest of the cell cycle in the S‑phase, which has led to apoptosis of PCa cells
Apoptosis↑,
selectivity↑, Also, the treatment of α‑LA improved bone health by reducing PCa‑mediated bone cell modulation.

3443- ALA,    Molecular and Therapeutic Insights of Alpha-Lipoic Acid as a Potential Molecule for Disease Prevention
- Review, Var, NA - Review, AD, NA
*antiOx↑, antioxidant potential and free radical scavenging activity.
*ROS↓,
*IronCh↑, Lipoic acid acts as a chelating agent for metal ions, a quenching agent for reactive oxygen species, and a reducing agent for the oxidized form of glutathione and vitamins C and E.
*cognitive↑, α-Lipoic acid enantiomers and its reduced form have antioxidant, cognitive, cardiovascular, detoxifying, anti-aging, dietary supplement, anti-cancer, neuroprotective, antimicrobial, and anti-inflammatory properties.
*cardioP↓,
AntiCan↑,
*neuroP↑,
*Inflam↓, α-Lipoic acid can reduce inflammatory markers in patients with heart disease
*BioAv↓, bioavailability in its pure form is low (approximately 30%).
*AntiAge↑, As a dietary supplements α-lipoic acid has become a common ingredient in regular products like anti-aging supplements and multivitamin formulations
*Half-Life↓, it has a half-life (t1/2) of 30 min to 1 h.
*BioAv↝, It should be stored in a cool, dark, and dry environment, at 0 °C for short-term storage (few days to weeks) and at − 20 °C for long-term storage (few months to years).
other↝, Remarkably, neither α-lipoic acid nor dihydrolipoic acid can scavenge hydrogen peroxide, possibly the most abundant second messenger ROS, in the absence of enzymatic catalysis.
EGFR↓, α-Lipoic acid inhibits cell proliferation via the epidermal growth factor receptor (EGFR) and the protein kinase B (PKB), also known as the Akt signaling, and induces apoptosis in human breast cancer cells
Akt↓,
ROS↓, α-Lipoic acid tramps the ROS followed by arrest in the G1 phase of the cell cycle and activates p27 (kip1)-dependent cell cycle arrest via changing of the ratio of the apoptotic-related protein Bax/Bcl-2
TumCCA↑,
p27↑,
PDH↑, α-Lipoic acid drives pyruvate dehydrogenase by downregulating aerobic glycolysis and activation of apoptosis in breast cancer cells, lactate production
Glycolysis↓,
ROS↑, HT-29 human colon cancer cells; It was concluded that α-lipoic acid induces apoptosis by a pro-oxidant mechanism triggered by an escalated uptake of mitochondrial substrates in oxidizable form
*eff↑, Several studies have found that combining α-lipoic acid and omega-3 fatty acids has a synergistic effect in slowing functional and cognitive decline in Alzheimer’s disease
*memory↑, α-lipoic acid inhibits brain weight loss, downregulates oxidative tissue damage resulting in neuronal cell loss, repairs memory and motor function,
*motorD↑,
*GutMicro↑, modulates the gut microbiota without reducing the microbial diversity (

3454- ALA,    Lipoic acid blocks autophagic flux and impairs cellular bioenergetics in breast cancer and reduces stemness
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
TumCG↑, Lipoic acid inhibits breast cancer cell growth via accumulation of autophagosomes.
Glycolysis↓, Lipoic acid inhibits glycolysis in breast cancer cells.
ROS↑, Lipoic acid induces ROS production in breast cancer cells/BCSC.
CSCs↓, Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs
selectivity↑, In contrast, LA at similar doses. had no significant effect on the cell viability of the human embryonic kidney cell line (HEK-293)
LC3B-II↑, LA treatment (0.5 mM and 1.0 mM) increased the expression level of LC3B-I to LC3B-II in both MCF-7 and MDA-MB231cells at 48 h
MMP↓, LA induced mitochondrial ROS levels, decreased mitochondria complex I activity, and MMP in both MCF-7 and MDA-MB231 cells
mitResp↓, In MCF-7 cells, we found a substantial reduction in maximal respiration and ATP production at 0.5 mM and 1 mM of LA treatment after 48 h
ATP↓,
OCR↓, LA at 2.5 mM decreased OCR
NAD↓, we found that LA (0.5 mM and 1 mM) significantly reduced ATP production and NAD levels in MCF-7 and MDA-MB231 cells
p‑AMPK↑, LA treatment (0.5 mM and 1.0 mM) increased p-AMPK levels;
GlucoseCon↓, LA (0.5 mM and 1 mM) significantly decreased glucose uptake and lactate production in MCF-7, whereas LA at 1 mM significantly reduced glucose uptake and lactate production in MDA-MB231 cells but it had no effect at 0.5 mM
lactateProd↓,
HK2↓, LA reduced hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) expression in MCF-7 and MDA-MB231 cells
PFK↓,
LDHA↓,
eff↓, Moreover, we found that LA-mediated inhibition of cellular bioenergetics including OCR (maximal respiration and ATP production) and glycolysis were restored by NAC treatment (Fig. 6E and F) which indicates that LA-induced ROS production is responsibl
mTOR↓, LA inhibits mTOR signaling and thereby decreased the p-TFEB levels in breast cancer cells
ECAR↓, LA also inhibits glycolysis as evidenced by decreased glucose uptake, lactate production, and ECAR.
ALDH↓, LA decreased ALDH1 activity, CD44+/CD24-subpopulation, and increased accumulation of autophagosomes possibly due to inhibition of autophagic flux of breast cancer.
CD44↓,
CD24↓,

3541- ALA,    Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology
- Review, Var, NA
*antiOx↑, α-LA has been widely used as an antioxidant compound in many multivitamin formulations, food supplements, anti-aging formulas, and even in human and pet food recipes
*IronCh↑, potential role in the chelation of metals and in restoring normal levels of intracellular glutathione (GSH) after depletion caused by toxicants,
*GSH↑,
*BBB↑, ALA, which can pass through the blood-brain barrier (BBB
Apoptosis↑, increased level of apoptosis, mitochondrial membrane depolarization, ROS production, lipid peroxidation, poly-(ADP)-ribose polymerase 1 (PARP1), caspase 3 and 9 expression levels in simultaneous ALA (0.05 mM) and cisplatin(0.025 mM)-treated MCF7
MMP↓,
ROS↑,
lipid-P↑,
PARP1↑,
Casp3↑,
Casp9↑,
*NRF2↑, ALA's ability to activate Nfr2 in GSH production
*GSH↑,
*ROS↓, administration of ALA has been shown to reduce oxidative stress
RenoP↑, ALA also reduced lipid peroxidation in the kidneys caused by the anticancer drug cisplatin,
ChemoSen↑, ALA enhances the functions of various anticancer drugs such as 5-fluorouracil in CRC [146] and cisplatin in MCF-7 cells
*BG↓, ALA was shown to lower the blood glucose levels in patients with type 2 diabetes

1235- ALA,  Cisplatin,    α-Lipoic acid prevents against cisplatin cytotoxicity via activation of the NRF2/HO-1 antioxidant pathway
- in-vitro, Nor, HEI-OC1 - ex-vivo, NA, NA
ROS↑, production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity
HO-1↓, due to Cisplatin only
*toxicity↓, LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells (normal)
chemoP↑, had a protective effect against cisplatin-induced cytotoxicity
*ROS↓, Intracellular ROS production in HEI-OC1(normal) cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS
*HO-1↑, and increased the expression of the antioxidant proteins HO-1 and SOD1
*SOD1↑,
*NRF2↑, antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway

1352- And,    Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy
- in-vitro, AML, K562
Apoptosis↑, induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine
ROS↑,
HSP90↓, involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins

1354- And,    Andrographolide induces protective autophagy and targeting DJ-1 triggers reactive oxygen species-induced cell death in pancreatic cancer
- in-vitro, PC, NA - in-vivo, PC, NA
Apoptosis↑,
DJ-1↓, reduction in DJ-1 expression caused by Andro led to ROS accumulation
ROS↑,
TumAuto↑,
TumCCA↑, G2/M phase
TumCP↓,
TumW↓,
eff↓, pro-apoptotic effect of Andro was attenuated when NAC was co-administered

1351- And,  MEL,    Impact of Andrographolide and Melatonin Combinatorial Drug Therapy on Metastatic Colon Cancer Cells and Organoids
- in-vitro, CRC, T84 - in-vitro, CRC, COLO205 - in-vitro, CRC, HT-29 - in-vitro, CRC, DLD1
eff↑, dual therapy significantly promotes CRC cell death
Ki-67↓,
Casp3↑,
ER Stress↑,
ROS↑,
BAX↑,
XBP-1↑,
CHOP↑, Apoptosis signaling molecules BAX, XBP-1, and CHOP were significantly increased
eff↑, combinatorial treatment increased reactive oxygen species (ROS) levels

1350- And,  Cisplatin,    Synergistic antitumor effect of Andrographolide and cisplatin through ROS-mediated ER stress and STAT3 inhibition in colon cancer
- in-vitro, Colon, NA
ChemoSen↑, AP synergizes with cisplatin in exerting anticancer activity in colon cancer cells.
ER Stress↑,
STAT3↓,
ROS↑, pre-treatment of NAC, a ROS scavenger, reversed apoptosis induced by combined treatment of AP and cisplatin

1349- And,    Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction
- in-vitro, Lung, H460 - in-vitro, Lung, H1650
TumCG↓,
TumMeta↓,
Ferroptosis↑,
ROS↑,
MDA↑,
Iron↑,
GSH↓, lipid ROS reduced glutathione (GSH) accumulation
GPx4↓,
xCT↓, SLC7A11
MMP↓,
ATP↓,

1348- And,    Andrographolide Inhibits ER-Positive Breast Cancer Growth and Enhances Fulvestrant Efficacy via ROS-FOXM1-ER-α Axis
- in-vitro, BC, MCF-7 - in-vitro, BC, T47D - in-vivo, NA, NA
ERα/ESR1↓,
TumCG↓,
ROS↑,
FOXM1↓,
eff↑, In addition, AD in combination with fulvestrant (FUL) synergistically down-regulated ER-α expression to inhibit ER-positive breast cancer both in vitro and in vivo.

1999- Api,  doxoR,    Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation
- in-vitro, Nor, NRK52E - in-vitro, Nor, MPC5 - in-vitro, BC, 4T1 - in-vivo, NA, NA
neuroP↑, APG has a protective role against DOX-induced nephrotoxicity
ChemoSen∅, without weakening DOX cytotoxicity in malignant tumors.
RenoP↑, potential protective agent against renal injury. attenuate renal toxicity in cancer patients treated with DOX.
selectivity↑, APG maintained the cytotoxicity of DOX to tumor cells but not to renal cells. APG alone exhibited a prominent cytotoxic effect on 4T1 cells (Fig. 9E), but not on normal renal cells, at the same concentration
chemoP↑, Furthermore, APG revealed a dose-dependent improvement in normal renal cells against DOX-induced injury (Fig. 9E), with an exacerbation observed in 4T1 cells
ROS↑, Our in vivo study revealed that DOX caused a severe reduction in SOD activity and GSH levels, accompanied by an increase in MDA, leading to the overproduction of ROS and induction of oxidative injuries.
*ROS∅, Noteworthily, these changes were suppressed by APG(meaning on normal cells), consistent with several previous reports
*antiOx↑, APG has a similar antioxidative role as NAC and scavenges DOX-induced oxygen radicals and inhibits apoptosis significantly, implying that antioxidative stress is one of the main mechanisms through which APG protects renal tubular cells against DOX cy
*toxicity↓, We confirmed that APG mitigated the toxicity of DOX on normal renal cells by inhibiting oxidative stress, inflammation, and apoptosis.

1547- Api,    Apigenin: Molecular Mechanisms and Therapeutic Potential against Cancer Spreading
- Review, NA, NA
angioG↓,
EMT↓,
CSCs↓,
TumCCA↑,
Dose∅, Dried parsley 45,035ug/g: Dried chamomille flower 3000–5000ug/g: Parsley 2154.6ug/g:
ROS↑, activity of Apigenin has been linked to the induction of oxidative stress in cancer cells
MMP↓, triggering intracellular ROS accumulation and loss of mitochondrial integrity
Catalase↓, catalase and glutathione (GSH), molecules involved in alleviating oxidative stress, were downregulated after Apigenin
GSH↓,
PI3K↓, suppression of the PI3K/Akt and NF-κB
Akt↓,
NF-kB↓,
OCT4↓, glycosylated form of Apigenin (i.e., Vitexin) was able to suppress stemness features of human endometrial cancer, as documented by the downregulation of Oct4 and Nanog
Nanog↓,
SIRT3↓, inhibition of sirtuin-3 (SIRT3) and sirtuin-6 (SIRT6) protein levels
SIRT6↓,
eff↑, ability of Apigenin to interfere with CSC features is often enhanced by the co-administration of other flavonoids, such as chrysin
eff↑, Apigenin combined with a chemotherapy agent, temozolomide (TMZ), was used on glioblastoma cells and showed better performance in cell arrest at the G2 phase compared with Apigenin or TMZ alone,
Cyt‑c↑, release of cytochrome c (Cyt c)
Bax:Bcl2↑, Apigenin has been shown to induce the apoptosis death pathway by increasing the Bax/Bcl-2 ratio
p‑GSK‐3β↓, Apigenin has been shown to prevent activation of phosphorylation of glycogen synthase kinase-3 beta (GSK-3β)
FOXO3↑, Apigenin administration increased the expression of forkhead box O3 (FOXO3)
p‑STAT3↓, Apigenin can induce apoptosis via inhibition of STAT3 phosphorylation
MMP2↓, downregulation of the expression of MMP-2 and MMP-9
MMP9↓,
COX2↓, downregulation of PI3K/Akt in leukemia HL60 cells [156,157] and of COX2, iNOS, and reactive oxygen species (ROS) accumulation in breast cancer cells
MMPs↓, triggering intracellular ROS accumulation and loss of mitochondrial integrity, as proved by low MMP in Apigenin-treated cells
NRF2↓, suppressed the nuclear factor erythroid 2-related factor 2 (Nrf2)
HDAC↓, inhibition of histone deacetylases (HDACs) is the mechanism through which Apigenin induces apoptosis in prostate cancer cells
Telomerase↓, Apigenin has been shown to downregulate telomerase activity
eff↑, Indeed, co-administration with 5-fluorouracil (5-FU) increased the efficacy of Apigenin in human colon cancer through p53 upregulation and ROS accumulation
eff↑, Apigenin synergistically enhances the cytotoxic effects of Sorafenib
eff↑, pretreatment of pancreatic BxPC-3 cells for 24 h with a low concentration of Apigenin and gemcitabine caused the inhibition of the GSK-3β/NF-κB signaling pathway, leading to the induction of apoptosis
eff↑, In NSCLC cells, compared to monotherapy, co-treatment with Apigenin and naringenin increased the apoptotic rate through ROS accumulation, Bax/Bcl-2 increase, caspase-3 activation, and mitochondrial dysfunction
eff↑, Several studies have shown that Apigenin-induced autophagy may play a pro-survival role in cancer therapy; in fact, inhibition of autophagy has been shown to exacerbate the toxicity of Apigenin
XIAP↓,
survivin↓,
CK2↓,
HSP90↓,
Hif1a↓,
FAK↓,
EMT↓,

1565- Api,    Apigenin-7-glucoside induces apoptosis and ROS accumulation in lung cancer cells, and inhibits PI3K/Akt/mTOR pathway
- in-vitro, Lung, A549 - in-vitro, Nor, BEAS-2B - in-vitro, Lung, H1975
TumCP↓, AGL significantly reduced proliferation, promoted cell apoptosis, and attenuated the migration and invasion of A549 or H1975 cell
Apoptosis↑,
TumCMig↓,
TumCI↓,
Cyt‑c↑, elevated the levels of cytochrome C and MDA
MDA↑,
GSH↓, but reduced the production of GSH in A549 and H1975 cells.
ROS↑, AGL enhanced the accumulation of ROS
PI3K↓, induces ROS accumulation in lung cancer cells by repressing PI3K/Akt/mTOR pathway
Akt↓,
mTOR↓,

1537- Api,    Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer
- Review, PC, NA
TumCP↓,
TumCCA↑,
Apoptosis↑,
MMPs↓,
Akt↓,
*BioAv↑, delivery systems (nanosuspension, polymeric micelles, liposomes).
*BioAv↓, low solubility of apigenin in water (1.35 μg/mL) and its high permeability
Half-Life∅, (appearing in blood circulation after 3.9 h)
Hif1a↓, (HIF-1α) is targeted by apigenin in several cancers such as, ovarian cancer, prostate cancer, and lung cancer
GLUT1↓, GLUT-1 is blocked by apigenin (0–100 μM) under normoxic conditions
VEGF↓,
ChemoSen↑, apigenin can be applied as a chemosensitizer
ROS↑, accumulation of ROS produced were stimulated
Bcl-2↓, down-regulation of anti-apoptotic factors Bcl-2 and Bcl-xl as well as the up-regulation of apoptotic factors Bax and Bim.
Bcl-xL↓,
BAX↑,
BIM↑,

1536- Api,    Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells
- in-vitro, MM, MSTO-211H - in-vitro, MM, H2452
tumCV↓,
ROS↑, increase in intracellular reactive oxygen species (ROS)
MMP↓, caused the loss of mitochondrial membrane potential (ΔΨm)
ATP↓, ATP depletion
Apoptosis↑,
Necroptosis↑,
DNAdam↑,
TumCCA↑, delay at the G2/M phase of cell cycle
Casp3↑,
cl‑PARP↑,
MLKL↑,
p‑RIP3↑,
Bax:Bcl2↑,
eff↓, ATP supplementation restored cell viability and levels of DNA damage-, apoptosis- and necroptosis-related proteins that apigenin caused.
eff↓, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin.

1564- Api,    Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
- in-vitro, Pca, 22Rv1 - in-vivo, NA, NA
MDM2↓, downregulation of MDM2 protein
NF-kB↓, Exposure of 22Rv1 cells to 20 μM apigenin caused a decrease in NF-κB/p65 transcriptional activity by 24% at 12 h, which was further decreased to 41% at 24 h
p65↓,
P21↑,
ROS↑, Apigenin at these doses resulted in ROS generation
GSH↓, which was accompanied by rapid glutathione depletion
MMP↓, disruption of mitochondrial membrane potential
Cyt‑c↑, cytosolic release of cytochrome c
Apoptosis↑,
P53↑, accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment
eff↓, All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine
Bcl-xL↓,
Bcl-2↓,
BAX↑,
Casp↑, triggering caspase activation
TumCG↓, in vivo mice
TumVol↓, tumor volume was inhibited by 44 and 59%
TumW↓, wet weight of tumor was decreased by 41 and 53%

1563- Api,  MET,    Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
- in-vitro, Nor, HDFa - in-vitro, PC, AsPC-1 - in-vitro, PC, MIA PaCa-2 - in-vitro, Pca, DU145 - in-vitro, Pca, LNCaP - in-vivo, NA, NA
selectivity↑, Metformin increased cellular ROS levels in AsPC-1 pancreatic cancer cells, with minimal effect in HDF, human primary dermal fibroblasts.
selectivity↑, Metformin reduced cellular ATP levels in HDF, but not in AsPC-1 cells
selectivity↓, Metformin increased AMPK, p-AMPK (Thr172), FOXO3a, p-FOXO3a (Ser413), and MnSOD levels in HDF, but not in AsPC-1 cells
ROS↑,
eff↑, Metformin combined with apigenin increased ROS levels dramatically and decreased cell viability in various cancer cells including AsPC-1 cells, with each drug used singly having a minimal effect.
tumCV↓,
MMP↓, Metformin/apigenin combination synergistically decreased mitochondrial membrane potential in AsPC-1 cells but to a lesser extent in HDF cells
Dose∅, co-treatment with metformin (0.05, 0.5 or 5 mM) and apigenin (20 µM) dramatically increased cellular ROS levels in AsPC-1 cells
eff↓, NAC blocked the metformin/apigenin co-treatment-induced cell death in AsPC-1 cells
DNAdam↑, Combination of metformin and apigenin leads to DNA damage-induced apoptosis, autophagy and necroptosis in AsPC-1 cells but not in HDF cells
Apoptosis↑,
TumAuto↑,
Necroptosis↑,
p‑P53↑, p-p53, Bim, Bid, Bax, cleaved PARP, caspase 3, caspase 8, and caspase 9 were also significantly increased by combination of metformin and apigenin in AsPC-1
BIM↑,
BAX↑,
p‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
Cyt‑c↑, Cytochrome C was also released from mitochondria in AsPC-1 cell
Bcl-2↓,
AIF↑, Interestingly, autophagy-related proteins (AIF, P62 and LC3B) and necroptosis-related proteins (MLKL, p-MLKL, RIP3 and p-RIP3) were also increased by combination of metformin and apigenin
p62↑,
LC3B↑,
MLKL↑,
p‑MLKL↓,
RIP3↑,
p‑RIP3↑,
TumCG↑, in vivo
TumW↓, metformin (125 mg/kg) or apigenin (40 mg/kg) caused a reduction of tumor size compared to the control group (Fig. 7D). However, oral administration of combination of metformin and apigenin decreased tumor weight profoundly

2631- Api,    Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells
- in-vivo, GC, NA - in-vitro, GC, AGS
ER Stress↑, We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia.
Hif1a↓, APG Inhibits HIF-1α and Induces Cell Death under Hypoxia in GC Cells
EZH2↓,
HDAC↓, Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines.
TumAuto↑, APG Induces Autophagic Cell Death in GC Cells
p‑mTOR↓, APG decreased the phosphorylation of mTOR and increased the activation of AMPKα and ULK1
AMPKα↑,
GRP78/BiP↑, APG mediates the up-regulation of GRP78 through exosomes, and that this effect causes ER stress-induced cell death in APG-treated GC cells.
ROS↑, APG generates intracellular ROS release in colorectal cancer cells, and it causes various cell death types, including cell cycle arrest, chromatin condensation, MMP loss, intracellular Ca2+, annexin-v-positive cells, and ER stress-related cell death
MMP↓,
Ca+2↑, we found that APG exerts intracellular Ca2+ release in a dose- and time-dependent manner
ATF4↑, APG also increased ATF4 and CHOP in a time-dependent manner
CHOP↑,

2632- Api,    Apigenin inhibits migration and induces apoptosis of human endometrial carcinoma Ishikawa cells via PI3K-AKT-GSK-3β pathway and endoplasmic reticulum stress
- in-vitro, EC, NA
TumCP↓, We found that API could inhibit the proliferation of Ishikawa cells at IC50 of 45.55 μM, arrest the cell cycle at G2/M phase, induce apoptosis by inhibiting Bcl-xl and increasing Bax, Bak and Caspases.
TumCCA↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
Bak↑,
Casp↑,
ER Stress↑, Further, API could induce apoptosis by activating the endoplasmic reticulum (ER) stress pathway by increasing the Ca2+, ATF4, and CHOP.
Ca+2↑, after API treatment for 48 h, the intracellular Ca2+ concentration increased in cells in a dose-dependent manner.
ATF4↑,
CHOP↑,
ROS↑, the level of intracellular ROS increased gradually with the increase of API concentration.
MMP↓, mitochondrial membrane potential of 30 μM, 50 μM, and 70 μM groups decreased by 2.19%, 11.32%, and 14.91%, respectively.
TumCMig↓, API inhibits the migration and invasion of Ishikawa cells and the migration and invasion related gene and protein.
TumCI↓,
eff↑, In our study, API restrained the viability of Ishikawa cells, and the inhibition effect of API on Ishikawa cells was better than that of 5-FU.
P53↑, API induces p53 tumor suppressor proteins at the translational level and the induces p21
P21↑,
Cyt‑c↑, After the mitochondria release the Cyto-c, the Caspase-9 is activated, resulting in increased activity of Caspases
Casp9↑, In our study, the expression levels of Bad, Bax, Cyto-c, Caspase-9 and Caspase-3 proteins were up-regulated,
Casp3↑,
Bcl-xL↓, while the expression level of Bcl-xl was down-regulated

2633- Api,    Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells
- in-vitro, EC, NA
TumCP↓, Apigenin reduced proliferation and induced cell cycle arrest and apoptosis in the both endometriosis cell lines
TumCCA↑,
MMP↓, In addition, it disrupted mitochondrial membrane potential (MMP) which was accompanied by an increase in concentration of calcium ions in the cytosol and in pro-apoptotic proteins including Bax and cytochrome c in the VK2/E6E7 and End1/E6E7 cells
Ca+2↑,
BAX↑,
Cyt‑c↑,
ROS↑, Moreover, apigenin treated cells accumulated excessive reactive oxygen species (ROS), and experienced lipid peroxidation and endoplasmic reticulum (ER) stress with activation of the unfolded protein response (UPR) regulatory proteins.
lipid-P↑,
ER Stress↑,
UPR↑,
p‑ERK↓, Apigenin inhibited the phosphorylation of ERK1/2
ERK↓, Similar to previous studies, apigenin-induced apoptosis was also mediated by inactivation of ERK1/2 and JNK proteins and regulation of AKT protein in human endometriosis cells.
JNK↑,

2634- Api,    Apigenin induces both intrinsic and extrinsic pathways of apoptosis in human colon carcinoma HCT-116 cells
- in-vitro, CRC, HCT116
TumCG↓, Apigenin exerted cytotoxic effect on the cells via inhibiting cell growth in a dose-time-dependent manner and causing morphological changes, arrested cell cycle progression at G0/G1 phase
TumCCA↑,
MMP↓, decreased mitochondrial membrane potential of the treated cells
ROS↑, Apigenin increased respective ROS generation and Ca2+ release and thereby, caused ER stress in the treated cells.
Ca+2↑,
ER Stress↑,
mtDam↑, together with damaged mitochondrial membrane, and upregulated protein expression of CHOP, DR5, cleaved BID, Bax, cytochrome c, cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9, which triggered apoptosis of the cells.
CHOP↑,
DR5↑,
cl‑BID↑,
BAX↑,
Cyt‑c↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
Apoptosis↑,

2639- Api,    Plant flavone apigenin: An emerging anticancer agent
- Review, Var, NA
*antiOx↑, Apigenin (4′, 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties
*Inflam↓,
AntiCan↑,
ChemoSen↑, Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers.
BioEnh↑, Apigenin’s anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies.
chemoPv↑, apigenin highlighting its potential activity as a chemopreventive and therapeutic agent.
IL6↓, In taxol-resistant ovarian cancer cells, apigenin caused down regulation of TAM family of tyrosine kinase receptors and also caused inhibition of IL-6/STAT3 axis, thereby attenuating proliferation.
STAT3↓,
NF-kB↓, apigenin treatment effectively inhibited NF-κB activation, scavenged free radicals, and stimulated MUC-2 secretion
IL8↓, interleukin (IL)-6, and IL-8
eff↝, The anti-proliferative effects of apigenin was significantly higher in breast cancer cells over-expressing HER2/neu but was much less efficacious in restricting the growth of cell lines expressing HER2/neu at basal levels
Akt↓, Apigenin interferes in the cell survival pathway by inhibiting Akt function by directly blocking PI3K activity
PI3K↓,
HER2/EBBR2↓, apigenin administration led to the depletion of HER2/neu protein in vivo
cycD1/CCND1↓, Apigenin treatment in breast cancer cells also results in decreased expression of cyclin D1, D3, and cdk4 and increased quantities of p27 protein
CycD3↓,
p27↑,
FOXO3↑, In triple-negative breast cancer cells, apigenin induces apoptosis by inhibiting the PI3K/Akt pathway thereby increasing FOXO3a expression
STAT3↓, In addition, apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion of breast cancer cells [
MMP2↓,
MMP9↓,
VEGF↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
Twist↓,
MMP↓, Apigenin treatment of HGC-27 and SGC-7901 gastric cancer cells resulted in the inhibition of proliferation followed by mitochondrial depolarization resulting in apoptosis
ROS↑, Further studies revealed apigenin-induced apoptosis in hepatoma tumor cells by utilizing ROS generated through the activation of the NADPH oxidase
NADPH↑,
NRF2↓, Apigenin significantly sensitized doxorubicin-resistant BEL-7402 (BEL-7402/ADM) cells to doxorubicin (ADM) and increased the intracellular concentration of ADM by reducing Nrf2-
SOD↓, In human cervical epithelial carcinoma HeLa cells combination of apigenin and paclitaxel significantly increased inhibition of cell proliferation, suppressing the activity of SOD, inducing ROS accumulation leading to apoptosis by activation of caspas
COX2↓, melanoma skin cancer model where apigenin inhibited COX-2 that promotes proliferation and tumorigenesis
p38↑, Additionally, it was shown that apigenin treatment in a late phase involves the activation of p38 and PKCδ to modulate Hsp27, thus leading to apoptosis
Telomerase↓, apigenin inhibits cell growth and diminishes telomerase activity in human-derived leukemia cells
HDAC↓, demonstrated the role of apigenin as a histone deacetylase inhibitor. As such, apigenin acts on HDAC1 and HDAC3
HDAC1↓,
HDAC3↓,
Hif1a↓, Apigenin acts on the HIF-1 binding site, which decreases HIF-1α, but not the HIF-1β subunit, thereby inhibiting VEGF.
angioG↓, Moreover, apigenin was found to inhibit angiogenesis, as suggested by decreased HIF-1α and VEGF expression in cancer cells
uPA↓, Furthermore, apigenin intake resulted in marked inhibition of p-Akt, p-ERK1/2, VEGF, uPA, MMP-2 and MMP-9, corresponding with tumor growth and metastasis inhibition in TRAMP mice
Ca+2↑, Neuroblastoma SH-SY5Y cells treated with apigenin led to induction of apoptosis, accompanied by higher levels of intracellular free [Ca(2+)] and shift in Bax:Bcl-2 ratio in favor of apoptosis, cytochrome c release, followed by activation casp-9, 12
Bax:Bcl2↑,
Cyt‑c↑,
Casp9↑,
Casp12↑,
Casp3↑, Apigenin also augmented caspase-3 activity and PARP cleavage
cl‑PARP↑,
E-cadherin↑, Apigenin treatment resulted in higher levels of E-cadherin and reduced levels of nuclear β-catenin, c-Myc, and cyclin D1 in the prostates of TRAMP mice.
β-catenin/ZEB1↓,
cMyc↓,
CDK4↓, apigenin exposure led to decreased levels of cell cycle regulatory proteins including cyclin D1, D2 and E and their regulatory partners CDK2, 4, and 6
CDK2↓,
CDK6↓,
IGF-1↓, A reduction in the IGF-1 and increase in IGFBP-3 levels in the serum and the dorsolateral prostate was observed in apigenin-treated mice.
CK2↓, benefits of apigenin as a CK2 inhibitor in the treatment of human cervical cancer by targeting cancer stem cells
CSCs↓,
FAK↓, Apigenin inhibited the tobacco-derived carcinogen-mediated cell proliferation and migration involving the β-AR and its downstream signals FAK and ERK activation
Gli↓, Apigenin inhibited the self-renewal capacity of SKOV3 sphere-forming cells (SFC) by downregulating Gli1 regulated by CK2α
GLUT1↓, Apigenin induces apoptosis and slows cell growth through metabolic and oxidative stress as a consequence of the down-regulation of glucose transporter 1 (GLUT1).

2640- Api,    Apigenin: A Promising Molecule for Cancer Prevention
- Review, Var, NA
chemoPv↑, considerable potential for apigenin to be developed as a cancer chemopreventive agent.
ITGB4↓, apigenin inhibits hepatocyte growth factor-induced MDA-MB-231 cells invasiveness and metastasis by blocking Akt, ERK, and JNK phosphorylation and also inhibits clustering of β-4-integrin function at actin rich adhesive site
TumCI↓,
TumMeta↓,
Akt↓,
ERK↓,
p‑JNK↓,
*Inflam↓, The anti-inflammatory properties of apigenin are evident in studies that have shown suppression of LPS-induced cyclooxygenase-2 and nitric oxide synthase-2 activity and expression in mouse macrophages
*PKCδ↓, Apigenin has been reported to inhibit protein kinase C activity, mitogen activated protein kinase (MAPK), transformation of C3HI mouse embryonic fibroblasts and the downstream oncogenes in v-Ha-ras-transformed NIH3T3 cells (43, 44).
*MAPK↓,
EGFR↓, Apigenin treatment has been shown to decrease the levels of phosphorylated EGFR tyrosine kinase and of other MAPK and their nuclear substrate c-myc, which causes apoptosis in anaplastic thyroid cancer cells
CK2↓, apigenin has been shown to inhibit the expression of casein kinase (CK)-2 in both human prostate and breast cancer cells
TumCCA↑, apigenin induces a reversible G2/M and G0/G1 arrest by inhibiting p34 (cdc2) kinase activity, accompanied by increased p53 protein stability
CDK1↓, inhibiting p34 (cdc2) kinase activity
P53↓,
P21↑, Apigenin has also been shown to induce WAF1/p21 levels resulting in cell cycle arrest and apoptosis in androgen-responsive human prostate cancer
Bax:Bcl2↑, Apigenin treatment has been shown to alter the Bax/Bcl-2 ratio in favor of apoptosis, associated with release of cytochrome c and induction of Apaf-1, which leads to caspase activation and PARP-cleavage
Cyt‑c↑,
APAF1↑,
Casp↑,
cl‑PARP↑,
VEGF↓, xposure of endothelial cells to apigenin results in suppression of the expression of VEGF, an important factor in angiogenesis via degradation of HIF-1α protein
Hif1a↓,
IGF-1↓, oral administration of apigenin suppresses the levels of IGF-I in prostate tumor xenografts and increases levels of IGFBP-3, a binding protein that sequesters IGF-I in vascular circulation
IGFBP3↑,
E-cadherin↑, apigenin exposure to human prostate carcinoma DU145 cells caused increase in protein levels of E-cadherin and inhibited nuclear translocation of β-catenin and its retention to the cytoplasm
β-catenin/ZEB1↓,
HSPs↓, targets of apigenin include heat shock proteins (61), telomerase (68), fatty acid synthase (69), matrix metalloproteinases (70), and aryl hydrocarbon receptor activity (71) HER2/neu (72), casein kinase 2 alpha
Telomerase↓,
FASN↓,
MMPs↓,
HER2/EBBR2↓,
CK2↓,
eff↑, The combination of sulforaphane and apigenin resulted in a synergistic induction of UGT1A1
AntiAg↑, Apigenin inhibit platelet function through several mechanisms including blockade of TxA
eff↑, ex vivo anti-platelet effect of aspirin in the presence of apigenin, which encourages the idea of the combined use of aspirin and apigenin in patients in which aspirin fails to properly suppress the TxA
FAK↓, Apigenin inhibits expression of focal adhesion kinase (FAK), migration and invasion of human ovarian cancer A2780 cells.
ROS↑, Apigenin generates reactive oxygen species, causes loss of mitochondrial Bcl-2 expression, increases mitochondrial permeability, causes cytochrome C release, and induces cleavage of caspase 3, 7, 8, and 9 and the concomitant cleavage of the inhibitor
Bcl-2↓,
Cyt‑c↑,
cl‑Casp3↑,
cl‑Casp7↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑IAP2↑,
AR↓, significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. Apigenin treatment of LNCaP cells
PSA↓,
p‑pRB↓, apigenin inhibited hyperphosphorylation of the pRb protein
p‑GSK‐3β↓, Inhibition of p-Akt by apigenin resulted in decreased phosphorylation of GSK-3beta.
CDK4↓, both flavonoids exhibited cell growth inhibitory effects which were due to cell cycle arrest and downregulation of the expression of CDK4
ChemoSen↑, Combination therapy of gemcitabine and apigenin enhanced anti-tumor efficacy in pancreatic cancer cells (MiaPaca-2, AsPC-1)
Ca+2↑, apigenin in neuroblastoma SH-SY5Y cells resulted in increased apoptosis, which was associated with increases in intracellular free [Ca(2+)] and Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and activation of caspase-9, calpain, caspase-3,12
cal2↑,

2593- Api,    Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo
- in-vivo, BC, 4T1
TumCP↓, API suppresses 4T1 cells proliferation
TumCMig↓, API restraints 4T1 cells migration and invasion
TumCI↓,
Apoptosis↑, API triggers 4T1 apoptosis and modulates the expression levels of apoptotic-associated proteins in 4T1 cells
MMP↑, API triggers the depolarization of ΔΨm in 4T1 cells
ROS↑, API induces ROS generation
p‑PI3K↓, The results revealed a significant downregulation of p-PI3K/PI3K, p-AKT/AKT, and Nrf2 in 4T1 cells following API treatment
PI3K↓,
Akt↓,
NRF2↓,
AntiTum↑, API exhibits anti-tumor activity in mice
OS↑, results of animal survival experiments show that API can appropriately prolong the survival of mice with mammary gland tumors

586- Api,  5-FU,    5-Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma
- in-vivo, HCC, NA
ROS↑,
MMP↓,
Bcl-2↓,
Casp3↑,
PARP↑,

313- Api,    Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells
- in-vitro, Thyroid, BCPAP
LC3s↝, conversion of LC3 protein
p62↓,
ROS↑,
TumCCA↑, G2/M cell cycle arrest.
CDC25↓,
TumAuto↑,
Beclin-1↑,
AVOs↑,
DNAdam↑,

206- Api,    Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress
- in-vitro, Lung, H1299 - in-vitro, Lung, H460 - in-vitro, Lung, A549 - in-vitro, CRC, HCT116 - in-vitro, Melanoma, A375 - in-vitro, Lung, H2030 - in-vitro, CRC, SW480
Glycolysis↓, glucose consumption, lactate production, and ATP production were all strongly decreased by apigenin
lactateProd↓,
PGK1↓,
ALDOA↓,
GLUT1↓, Apigenin reduces GLUT1 expression levels.
ENO1↓,
ATP↓,
Casp9↑,
Casp3↑,
cl‑PARP↑, cleavage
PI3K/Akt↓,
HK1↓, HK1, HK2
HK2↓,
ROS↑, Apigenin causes oxidative stress leading to apoptosis. Because apoptotic signal transduction cascades involving caspase-9, -3 and PARP cleavage can be activated by increased ROS levels
Apoptosis↑,
eff↓, Cancer cells expressing high levels of GLUT1 are resistant to apigenin-induced apoptosis through metabolic compensation of glucose utilization.
NADPH↓, apigenin significantly decreased glucose utilization through suppression of GLUT1 expression, and consequently decreased NADPH production, which led to increased ROS levels.
PPP↓, inhibition of the PPP

171- Api,    Apigenin in cancer therapy: anti-cancer effects and mechanisms of action
- Review, Var, NA
PI3K/Akt↓,
NF-kB↓,
CK2↓,
FOXO↓,
MAPK↝, modulation of MAPKs by apigenin contributed to apigenin-induced cell cycle arrest at G0/G1 phase
ERK↓, p-ERK1/2,
p‑JAK↓, phosphorylation
Wnt/(β-catenin)↓,
ROS↑, accumulation of reactive oxygen species (ROS) production, leading to induction of DNA damage
CDC25↓,
p‑STAT↓,
DNAdam↑,

416- Api,    In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma
- vitro+vivo, NA, NA
Bax:Bcl2↑,
P53↑,
ROS↑,
Casp9↑,
Casp8↑,
cl‑PARP1↑, cleavage
p‑ERK⇅, Here, we demonstrated that API treatment was able to increase ERK1/2 phosphorylation in MM-B1, H-Meso-1, and #40a cells while induced a decrease of ERK1/2 activation in MM-F1 cells.
p‑JNK↓,
p‑p38↑,
p‑Akt↓,
cJun↓,
NF-kB↓,
EGFR↓,
TumCCA↑, increase of the percentage of cells in subG1 phase

3382- ART/DHA,    Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?
- Review, Var, NA
AntiCan↑, antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo.
toxicity↑, safety of artemisinins in long-term cancer therapy requires further investigation.
Ferroptosis↑, Artemisinins acts against cancer cells via various pathways such as inducing apoptosis (Zhu et al., 2014; Zuo et al., 2014) and ferroptosis via the generation of reactive oxygen species (ROS) (Zhu et al., 2021) and causing cell cycle arrest
ROS↑,
TumCCA↑,
BioAv↝, absolute bioavailability was estimated to be 21.6%. ART has good solubility and is not lipophilic
eff↝, ART would not distribute well to the tissues and might be more effective in treating cancers such as leukemia, hepatocellular carcinoma (HCC), or renal cell carcinoma because the liver and kidney are highly perfused organs.
Half-Life↓, Pharmacokinetic studies showed a relatively short t1/2 of artemisinins. For ART, t1/2 was 0.41 h
Ferritin↓, Figure 3
GPx4↓,
NADPH↓,
GSH↓,
BAX↑,
Cyt‑c↑,
cl‑Casp3↑,
VEGF↓, angiogenesis
IL8↓,
COX2↓,
MMP9↓,
E-cadherin↑,
MMP2↓,
NF-kB↓,
p16↑, cell cycle arrest
CDK4↓,
cycD1/CCND1↓,
p62↓, autophagy
LC3II↑,
EMT↓, suppressing EMT and CSCs
CSCs↓,
Wnt↓, Depress Wnt/β-catenin signaling pathway
β-catenin/ZEB1↓,
uPA↓, Inhibit u-PA activity, protein and mRNA expression
TumAuto↑, Emerging evidence suggests that autophagy induction is one of the molecular mechanisms underlying anticancer activity of artemisinins
angioG↓, Inhibition of Angiogenesis
ChemoSen↑, Many studies also reported that the use of artemisinins sensitized cancer cells to conventional chemotherapy and exerted a synergistic effect on apoptosis, inhibition of cell growth, and a reduction of cell viability, leading to a lower IC50 value

3383- ART/DHA,    Dihydroartemisinin: A Potential Natural Anticancer Drug
- Review, Var, NA
TumCP↓, DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stres
Apoptosis↑,
TumMeta↓,
angioG↓,
TumAuto↑,
ER Stress↑,
ROS↑, DHA could increase the level of ROS in cells, thereby exerting a cytotoxic effect in cancer cells
Ca+2↑, activation of Ca2+ and p38 was also observed in DHA-induced apoptosis of PC14 lung cancer cells
p38↑,
HSP70/HSPA5↓, down-regulation of heat-shock protein 70 (HSP70) might participate in the apoptosis of PC3 prostate cancer cells induced by DHA
PPARγ↑, DHA inhibited the growth of colon tumor by inducing apoptosis and increasing the expression of peroxisome proliferator-activated receptor γ (PPARγ)
GLUT1↓, DHA was shown to inhibit the activity of glucose transporter-1 (GLUT1) and glycolytic pathway by inhibiting phosphatidyl-inositol-3-kinase (PI3K)/AKT pathway and downregulating the expression of hypoxia inducible factor-1α (HIF-1α)
Glycolysis↓, Inhibited glycolysis
PI3K↓,
Akt↓,
Hif1a↓,
PKM2↓, DHA could inhibit the expression of PKM2 as well as inhibit lactic acid production and glucose uptake, thereby promoting the apoptosis of esophageal cancer cells
lactateProd↓,
GlucoseCon↓,
EMT↓, regulating the EMT-related genes (Slug, ZEB1, ZEB2 and Twist)
Slug↓, Downregulated Slug, ZEB1, ZEB2 and Twist in mRNA level
Zeb1↓,
ZEB2↓,
Twist↓,
Snail?, downregulated the expression of Snail and PI3K/AKT signaling pathway, thereby inhibiting metastasis
CAFs/TAFs↓, DHA suppressed the activation of cancer-associated fibroblasts (CAFs) and mouse cancer-associated fibroblasts (L-929-CAFs) by inhibiting transforming growth factor-β (TGF-β signaling
TGF-β↓,
p‑STAT3↓, blocking the phosphorylation of STAT3 and polarization of M2 macrophages
M2 MC↓,
uPA↓, DHA could inhibit the growth and migration of breast cancer cells by inhibiting the expression of uPA
HH↓, via inhibiting the hedgehog signaling pathway
AXL↓, DHA acted as an Axl inhibitor in prostate cancer, blocking the expression of Axl through the miR-34a/miR-7/JARID2 pathway, thereby inhibiting the proliferation, migration and invasion of prostate cancer cells.
VEGFR2↓, inhibition of VEGFR2-mediated angiogenesis
JNK↑, JNK pathway activated and Beclin 1 expression upregulated.
Beclin-1↑,
GRP78/BiP↑, Glucose regulatory protein 78 (GRP78, an ER stress-related molecule) was upregulated after DHA treatment.
eff↑, results demonstrated that DHA-induced ER stress required iron
eff↑, DHA was used in combination with PDGFRα inhibitors (sunitinib and sorafenib), it could sensitize ovarian cancer cells to PDGFR inhibitors and achieved effective therapeutic efficacy
eff↑, DHA combined with 2DG (a glycolysis inhibitor) synergistically induced apoptosis through both exogenous and endogenous apoptotic pathways
eff↑, histone deacetylase inhibitors (HDACis) enhanced the anti-tumor effect of DHA by inducing apoptosis.
eff↑, DHA enhanced PDT-induced cell growth inhibition and apoptosis, increased the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway
eff↑, DHA was added to magnetic nanoparticles (MNP), and the MNP-DHA has shown an effect in the treatment of intractable breast cancer
IL4↓, downregulated IL-4;
DR5↑, Upregulated DR5 in protein, Increased DR5 promoter activity
Cyt‑c↑, Released cytochrome c from the mitochondria to the cytosol
Fas↑, Upregulated fas, FADD, Bax, cleaved-PARP
FADD↑,
cl‑PARP↑,
cycE/CCNE↓, Downregulated Bcl-2, Bcl-xL, procaspase-3, Cyclin E, CDK2 and CDK4
CDK2↓,
CDK4↓,
Mcl-1↓, Downregulated Mcl-1
Ki-67↓, Downregulated Ki-67 and Bcl-2
Bcl-2↓,
CDK6↓, Downregulated of Cyclin E, CDK2, CDK4 and CDK6
VEGF↓, Downregulated VEGF, COX-2 and MMP-9
COX2↓,
MMP9↓,

3384- ART/DHA,    Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response‑induced upregulation of CHAC1 expression
- in-vitro, Liver, Hep3B - in-vitro, Liver, HUH7 - in-vitro, Liver, HepG2
Ferroptosis↑, DHA displayed classic features of ferroptosis, such as increased lipid reactive oxygen species
ROS↑,
GSH↓, decreased activity or expression of glutathione (GSH), glutathione peroxidase 4, solute carrier family (SLC) 7 member 11 and SLC family 3 member 2.
UPR↑, DHA activated all three branches of the UPR
GPx4↓, GSH depletion leads to the suppression of glutathione peroxidase (GPX)4, a key glutathione peroxidase known to catalyze the reduction of lipid ROS
PERK↑, DHA was found to activate PERK/eIF2α/ATF4
eIF2α↑,
ATF4↑,

3387- ART/DHA,    Ferroptosis: A New Research Direction of Artemisinin and Its Derivatives in Anti-Cancer Treatment
- Review, Var, NA
BioAv↓, Artemisinin, extracted from Artemisia annua L., is a poorly water-soluble antimalarial drug
lipid-P↑, promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo.
Ferroptosis↑,
Iron↑, Artemisinin and Its Derivatives Upregulate Fe2+ Levels in Cancer Cells
GPx4↓, GPX4-dependent defense system is significantly inhibited
GSH↓, , leading to a significant decrease in GSH, GPX4, and SLC7A11 protein expression
P53↑, ARTEs can upregulate p53 protein expression in multiple cancer cells
ER Stress↑, ARTEs can trigger ERS in cancer cells to activate the PERK-ATF4 pathway and upregulate GRP78 expression
PERK↑,
ATF4↑,
GRP78/BiP↑,
CHOP↑, which activates CHOP
ROS↑, promoting the accumulation of intracellular ROS, and leading to ferroptosis
NRF2↑, ARTEs can activate the nuclear factor erythroid-derived 2-like 2 (Nrf2) -γ-glutamyl-peptide pathway in cancer cells, resulting in cancer cell ferroptosis resistance

3389- ART/DHA,    Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers
- Review, Var, NA
GSH↓, decreasing cellular GSH levels and the presence of iron-induced ROS generation
ROS↑,
NRF2↑, However, ART-mediated killing of cisplatin-resistant HNC cells can simultaneously activate the NRF2-antioxidant response element (ARE) pathway, which contributes to ferroptosis resistance
eff↑, Therefore, the combination of ART with NRF2 genetic silencing or trigonelline may provide a preferable efficacy

3390- ART/DHA,    Ferroptosis: The Silver Lining of Cancer Therapy
Ferroptosis↑, Artesunate induces ferroptosis in tumour cells by enhancing lysosomal activity and increasing lysosomal iron concentration
Iron↑,
NCOA4↝, Artesunate regulates ferroptosis by promoting ferritinophagy by regulating the gene expression of NCOA4, which leads to an increase in the iron levels
ROS↑, overproduction of ROS triggered by the Fenton reaction between iron ion and hydrogen peroxide is a crucial factor for inducing ferroptosis.
Fenton↑,
Tf↓, artesunate can induce ferroptosis in Adriamycin-resistant leukaemia cells by decreasing TF levels

3345- ART/DHA,    Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells
- in-vitro, GBM, NA
ROS↑, Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death
Ferroptosis↑, DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation.
lipid-P↑,
HSP70/HSPA5↑, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5)
ER Stress↑, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4)
ATF4↑,
GRP78/BiP↑, HSPA5
MDA↑, DHA significantly increased lipid ROS and MDA levels in glioma cells in a dose- and time-dependent manner.
GSH↓, As an important antioxidant, reduced form GSH was exhausted by DHA
eff↑, Inhibitor of HSPA5 synergistically enhanced anti-tumor effects of DHA
GPx4↑, DHA induced-ER stress in turn activated cell protection against ferroptosis through PERK-ATF4- HSPA5 activation, which promoted the expression of GPX4 to detoxify peroxidized membrane lipids

3391- ART/DHA,    Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug
- Review, Var, NA
TumCP↓, inhibiting cancer proliferation, metastasis, and angiogenesis.
TumMeta↓,
angioG↓,
TumVol↓, reduces tumor volume and progression
BioAv↓, artemisinin has low solubility in water or oil, poor bioavailability, and a short half-life in vivo (~2.5 h)
Half-Life↓,
BioAv↑, semisynthetic derivatives of artemisinin such as artesunate, arteeter, artemether, and artemisone have been effectively used as antimalarials with good clinical efficacy and tolerability
eff↑, preloading of cancer cells with iron or iron-saturated holotransferrin (diferric transferrin) triggers artemisinin cytotoxicity
eff↓, Similarly, treatment with desferroxamine (DFO), an iron chelator, renders compounds inactive
ROS↑, ROS generation may contribute with the selective action of artemisinin on cancer cells.
selectivity↑, Tumor cells have enhanced vulnerability to ROS damage as they exhibit lower expression of antioxidant enzymes such as superoxide dismutase, catalase, and gluthatione peroxidase compared to that of normal cells
TumCCA↑, G2/M, decreased survivin
survivin↓,
BAX↑, Increased Bax, activation of caspase 3,8,9 Decreased Bc12, Cdc25B, cyclin B1, NF-κB
Casp3↓,
Casp8↑,
Casp9↑,
CDC25↓,
CycB/CCNB1↓,
NF-kB↓,
cycD1/CCND1↓, decreased cyclin D, E, CDK2-4, E2F1 Increased Cip 1/p21, Kip 1/p27
cycE/CCNE↓,
E2Fs↓,
P21↑,
p27↑,
ADP:ATP↑, Increased poly ADP-ribose polymerase Decreased MDM2
MDM2↓,
VEGF↓, Decreased VEGF
IL8↓, Decreased NF-κB DNA binding [74, 76] IL-8, COX2, MMP9
COX2↓,
MMP9↓,
ER Stress↓, ER stress, degradation of c-MYC
cMyc↓,
GRP78/BiP↑, Increased GRP78
DNAdam↑, DNA damage
AP-1↓, Decreased NF-κB, AP-1, Decreased activation of MMP2, MMP9, Decreased PKC α/Raf/ERK and JNK
MMP2↓,
PKCδ↓,
Raf↓,
ERK↓,
JNK↓,
PCNA↓, G2, decreased PCNA, cyclin B1, D1, E1 [82] CDK2-4, E2F1, DNA-PK, DNA-topo1, JNK VEGF
CDK2↓,
CDK4↓,
TOP2↓, Inhibition of topoisomerase II a
uPA↓, Decreased MMP2, transactivation of AP-1 [56, 88] NF-κB uPA promoter [88] MMP7
MMP7↓,
TIMP2↑, Increased TIMP2, Cdc42, E cadherin
Cdc42↑,
E-cadherin↑,

3396- ART/DHA,    Progress on the study of the anticancer effects of artesunate
- Review, Var, NA
TumCP↓, reported inhibitory effects on cancer cell proliferation, invasion and migration.
TumCI↓,
TumCMig↓,
Apoptosis↑, ART has been reported to induce apoptosis, differentiation and autophagy in colorectal cancer cells by impairing angiogenesis
Diff↑,
TumAuto↑,
angioG↓,
TumCCA↑, inducing cell cycle arrest (11), upregulating ROS levels, regulating signal transduction [for example, activating the AMPK-mTOR-Unc-51-like autophagy activating kinase (ULK1) pathway in human bladder cancer cells]
ROS↑,
AMPK↑,
mTOR↑,
ChemoSen↑, ART has been shown to restore the sensitivity of a number of cancer types to chemotherapeutic drugs by modulating various signaling pathways
Tf↑, ART could upregulate the mRNA levels of transferrin receptor (a positive regulator of ferroptosis), thus inducing apoptosis and ferroptosis in A549 non-small cell lung cancer (NSCLC) cells.
Ferroptosis↑,
Ferritin↓, ferritin degradation, lipid peroxidation and ferroptosis
lipid-P↑,
CDK1↑, Cyclin-dependent kinase 1, 2, 4 and 6
CDK2↑,
CDK4↑,
CDK6↑,
SIRT1↑, Sirt1 levels
COX2↓,
IL1β↓, IL-1? ?
survivin↓, ART can selectively downregulate the expression of survivin and induce the DNA damage response in glial cells to increase cell apoptosis and cell cycle arrest, resulting in increased sensitivity to radiotherapy
DNAdam↑,
RadioS↑,

2323- ART/DHA,    Dihydroartemisinin represses esophageal cancer glycolysis by down-regulating pyruvate kinase M2
- in-vitro, ESCC, Eca109 - in-vitro, ESCC, EC9706
PKM2↓, DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited.
lactateProd↓,
GlucoseCon↓,
cycD1/CCND1↓, DHA treatment resulted in the down-regulation of the expression of PKM2, cyclin D1, Bcl-2, matrix metalloproteinase-2 (MMP2), vascular endothelial growth factor A (VEGF-A) and the up-regulation of caspase 3, cleaved-PARP and Bax
Bcl-2↓,
MMP2↓,
VEGF↓,
Casp3↑,
cl‑PARP↑,
BAX↑,
DNAdam↑, The specific mechanism of DHA towards cancer cells include inducing DNA damage and repair (Li et al., 2008), oxidative stress response by reactive oxygen species
ROS↑,

2570- ART/DHA,    Discovery, mechanisms of action and combination therapy of artemisinin
- Review, Nor, NA
*BioAv↓, Because the parent drug of artemisinin is poorly soluble in water or oil, the carbonyl group of artemisinin was reduced to obtain DHA
*Half-Life↓, artemisinins also have a very short elimination half-life (∼1 h)
*toxicity↓, Artemisinin and its derivatives are generally safe and well-tolerated.
*ROS↑, Artemisinins are considered prodrugs that are activated to generate carbon-centered free radicals or reactive oxygen species (ROS).
GSH↓, earlier studies suggest that artemisinins modulate parasite oxidative stress and reduce the levels of antioxidants and glutathione (GSH) in the parasite
selectivity↑, Many publications corroborate the essence of iron-dependent bioactivation

2575- ART/DHA,  docx,    Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC
- in-vitro, Lung, H23
ChemoSen↑, Surprisingly, AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells,
GPx4↓, ollowing the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group
ROS↑,
Ferroptosis↑, predominant contribution of ferroptosis.
eff↑, Our study demonstrated that AS can be a promising chemosensitizer with the combination of conventional chemotherapeutic agent DTX for NSCLC

2578- ART/DHA,  RES,    Synergic effects of artemisinin and resveratrol in cancer cells
- in-vitro, Liver, HepG2 - in-vitro, Cerv, HeLa
Dose↝, The combination of ART and Res exhibited the strongest anticancer effect at the ratio of 1:2 (ART to Res).
TumCMig↓, combination of the two drugs also markedly reduced the ability of cell migration
Apoptosis↑, Apoptosis analysis showed that combination of ART and Res significantly increased the apoptosis and necrosis rather than use singly
necrosis↑,
ROS↑, ROS levels were elevated by combining ART with Res.
eff↑, the data suggested that the IC50 of the combination of ART and Res is lower than that of each drug used alone.

2580- ART/DHA,  VitC,    Effects of Antioxidants and Pro-oxidants on Cytotoxicity of Dihydroartemisinin to Molt-4 Human Leukemia Cells
- in-vitro, AML, NA
eff↓, Compared to control, ascorbate and H 2 O 2 both caused a significant decrease in cell count both at 24-h (p<0.05 and p<0.0001 for ascorbate and H 2 O 2 , respectively)
other↝, Vitamin C, a common supplement, has been shown to act as both a ROS generator in the presence of iron and copper (15) and as an antioxidant
ROS↑, From our results, we can postulate that ROS generation is causing cell death independently and in combination with DHA
eff↓, Ascorbate can convert ferric iron into ferrous iron (18), the active form that reacts with artemisinin, generating short lived free radicals.
eff↓, If this happens in the stomach of a person who is consuming artemisinin along with ascorbate, ascorbate will convert ferric iron in foods to the ferrous form, which may react with artemisinin locally, making the therapy less effective

2582- ART/DHA,  5-ALA,    Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity
- in-vivo, CRC, HCT116 - in-vitro, CRC, HCT116
eff↑, Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels
ROS↑, We found that artesunate significantly increased ROS levels (Figure 4f) in HCT116 cells
selectivity↑, In contrast, heme levels in normal cells and tissues are strictly controlled and maintained at lower levels, minimizing ART’s activation, which could possibly explain the specificity and low toxicity of ART.
TumCG↓, Strikingly, the combination of artesunate and ALA showed significant tumor growth delay in comparison to both the control and the artesunate or ALA single treatment groups
toxicity↓, Since both artesunate and ALA are clinically used and well-tolerated, (52) this combination has the potential to be safely applied to subsequent clinical testing

5380- ART/DHA,    Artemisinin and Its Derivatives as Potential Anticancer Agents
- Review, Var, NA
TumCG↓, Artemisinin (1, Figure 2) could suppress cell growth [16], reduce angiogenesis-related factors [17], and induce ferroptosis [18] in breast cancer cell lines
angioG↓,
Ferroptosis↑,
TumCP↑, Dihydroartemisinin (2, Figure 2) exhibited anticancer effects against breast cancer by suppressing cell proliferation [16], inhibiting angiogenesis [19], inducing autophagy [20] and pyroptosis [21], and targeting cancer stem cells (CSCs) [
TumAuto↑,
CSCs↑,
eff↑, Dihydroartemisinin is more potent than artemisinin, as the IC50 values at 24 h were lower on MCF-7 (129.1 μM versus 396.6 μM) and MDA-MB-231 (62.95 μM versus 336.63 μM)
YAP/TEAD↓, Additionally, dihydroartemisinin was proven to have the ability to reduce the expression of yes-associated protein 1 (YAP1), which has been commonly used as a prognostic marker in liver cancer.
TumCCA↑, induced G0/G1 cell cycle arrest and apoptosis by promoting oxygen species (ROS) accumulation.
ROS↑,
ChemoSen↑, The application of combination treatment using artemisinin and its derivatives with commonly used chemotherapy drugs, such as cisplatin, carboplatin, doxorubicin, temozolomide, etc., always exhibits significantly improved anticancer effects
N-cadherin↓, and inhibiting the proliferation, colony formation, and invasiveness of colon cancer cells by inhibiting NRP2, N-cadherin, and Vimentin expression
Vim↓,
MMP9↓, by decreasing the expression of HuR and matrix metalloproteinase (MMP)-9 proteins [24],
eff↑, Further investigations suggested that both dihydroartemisinin treatment and the loss of PRIM2 could lead to a decreased GSH level and induce cellular lipid ROS and mitochondrial MDA expression.
STAT3↓, Recently, artemisinin and its derivatives were reported to have potential as direct STAT3 inhibitors [98].
CD133↓, dihydroartemisinin treatment could significantly reduce the expression of CSC markers (CD133, CD44, Nanog, c-Myc, and OCT4) by downregulating Akt/mTOR pathway
CD44↓,
Nanog↓,
cMyc↓,
OCT4↓,
Akt↓,
mTOR↓,

5379- ART/DHA,    Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation
Ferritin↓, dihydroartemisinin (DAT, which triggers lysosomal ferritin degradation).
Iron↑, DAT has shown promise in reversing carboplatin resistance in ovarian cancer cell lines by expanding the labile iron pool (LIP) and enhancing Fenton reaction-mediated lipid peroxidation (149).
Fenton↑,
lipid-P↑,
ChemoSen↑, Its advantage lies in synergistic effects with conventional chemotherapies, as iron overload amplifies chemotherapy-induced oxidative stress.
ROS↑,
eff↝, However, DAT requires careful monitoring of systemic iron levels to avoid anemia, and its efficacy is reduced in cancer cells with upregulated ferroportin (an iron export protein).

5378- ART/DHA,    Natural Agents Modulating Ferroptosis in Cancer: Molecular Pathways and Therapeutic Perspectives
- Review, Var, NA
Ferroptosis↑, Artemisinin increases ferroptosis risk in cancer cells by increasing cellular free iron and lipid peroxidation, causing increased membrane permeability and decreased integrity [59]
Iron↑,
lipid-P↑,
MOMP↑,
AntiCan↑, Artemisinin has anticancer and antimalarial properties by upregulating NCOA4 and DMT1 levels, raising ferrous ion levels, and causing ferroptosis by downregulating GSH and GPX4 levels [30, 59, 75].
NCOA4↑,
GSH↓,
GPx4↓,
ROS↑, Artemisinin and its derivatives regulate 20 iron metabolism genes, thereby causing the formation of ROS [76]
ChemoSen↑, Artesunate, when combined with sorafenib, can enhance the susceptibility of hepatocellular carcinoma cells to cisplatin resistance through ferroptosis inhibition [77].
ER Stress↑, artemisinin, specifically ferroptosis, by controlling iron metabolism, producing ROS, and triggering ER‐stress.
DNAdam↑, primary antineoplastic mechanisms of artemisinin are ferroptosis, DNA damage, tumour angiogenesis suppression and cell cycle inhibition [78]
angioG↓,
TumCCA↑,
eff↓, while NAC and ferrostatin‐1 partially reverse these effects [82]

5376- ART/DHA,    Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis
- in-vitro, CRC, HCT116 - in-vitro, CRC, HT29 - in-vitro, CRC, SW48 - in-vitro, BC, MDA-MB-453
Ferroptosis↑, artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation.
Ferritin↓, Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis.
Iron↑,
eff↑, we found that DAT can augment GPX4 inhibition-induced ferroptosis
TumAuto↑, DAT sensitizes cells to ferroptosis by stimulating autophagy.
LC3II↑, it caused an increase of LC3-II production
ROS↑, DAT increases lipid ROS and sensitizes cancer cells to ferroptosis

5137- ART/DHA,    Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin
- vitro+vivo, ESCC, Eca109
tumCV↓, Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose- and time-dependent manner.
TumCCA↑, DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells
ROS↑, Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells
TumAuto↑,
eff↓, blocking ROS by an antioxidant NAC obviously inhibited autophagy
TRF2↓, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation
TumCP↓, DHA inhibits the proliferation ability of Eca109 cells in vitro and in vivo

5133- ART/DHA,    Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, U251
AntiTum↑, (DHA) has been shown to exhibit anti-tumor activity in various cancer cells.
tumCV↓, Our results proved that DHA treatment significantly reduced cell viability in a dose- and time-dependent manner by CCK-8 assay.
Apoptosis↓, DHA induced apoptosis of GBM cells through mitochondrial membrane depolarization, release of cytochrome c and activation of caspases-9.
MMP↓,
Cyt‑c↑,
Casp9↑,
CHOP↑, Enhanced expression of GRP78, CHOP and eIF2α and activation of caspase 12 were additionally confirmed that endoplasmic reticulum (ER) stress pathway of apoptosis
GRP78/BiP↑,
eIF2α↑,
Casp12↑,
ER Stress↑, DHA Induced Apoptosis through Mitochondria and Endoplasmic Reticulum (ER) Stress Pathways of Apoptosis in Human GBM Cells
TumAuto↑, ER stress and mitochondrial dysfunction were involved in the DHA-induced autophagy.
ROS↑, Further study revealed that accumulation of reactive oxygen species (ROS) was attributed to the DHA induction of apoptosis and autophagy.

5132- ART/DHA,    Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1
- in-vitro, Liver, HepG2 - in-vitro, BC, MCF-7
Iron↓, In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners.
TfR1/CD71↓, Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane.
ROS↑, which may be a new action mechanism of DHA independently of oxidative damage.

5130- ART/DHA,    Dihydroartemisinin Induces Apoptosis in Human Bladder Cancer Cell Lines Through Reactive Oxygen Species, Mitochondrial Membrane Potential, and Cytochrome C Pathway
- in-vitro, Bladder, T24/HTB-9
tumCV↓, DHA significantly reduced cell viability in a dose-dependent manner.
eff↓, Cytotoxicity of DHA was suppressed by N-acetylcysteine (NAC)
Apoptosis↑, induction of cell apoptosis, which were manifested by annexin V-FITC staining, activation of caspase-3
Casp3↑,
ROS↑, DHA also increased ROS generation, cytochrome c release, and loss of mitochondrial transmembrane potential (ΔΨm) in cells.
Cyt‑c↑,
MMP↓,
Bcl-2↓, downregulation of regulatory protein Bcl-2 and upregulation of Bax protein by DHA were also observed
BAX↑,
MOMP↑, Dihydroartemisinin increases mitochondrial permeability of EJ-138 and HTB-9 cells by Collapse of ΔΨm
TumCG↓, It has shown that DHA selectively inhibits the growth of many cancer cells types, such as leukemia,[29] pancreas,[30] breast[31] and prostate[32] cancers

575- ART/DHA,    Dihydroartemisinin initiates ferroptosis in glioblastoma through GPX4 inhibition
- in-vitro, GBM, U87MG
GPx4↓,
xCT∅, constant expression of xCT and ACSL4, suggesting GPX4 was a pivotal target for DHA-activated ferroptosis
ROS↑, lipid ROS levels were increased
Ferroptosis↑,
ACSL4∅,

571- ART/DHA,  TMZ,    Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence
- vitro+vivo, GBM, A172 - vitro+vivo, GBM, U87MG
HR↓,
RAD51↓,
Apoptosis↑,
necrosis↑,
ROS↑,
ChemoSen↑, Enhancement of the antitumor effect of TMZ by co-administration of ART was also observed in a mouse tumor model.

556- ART/DHA,    Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing
- Review, NA, NA
IL6↓,
IL1↓, IL-1β
TNF-α↓,
TGF-β↓, TGF-β1
NF-kB↓,
MIP2↓,
PGE2↓,
NO↓,
Hif1a↓,
KDR/FLK-1↓,
VEGF↓,
MMP2↓,
TIMP2↑,
ITGB1↑,
NCAM↑,
p‑ATM↑,
p‑ATR↑,
p‑CHK1↑,
p‑Chk2↑,
Wnt/(β-catenin)↓,
PI3K↓,
Akt↓,
ERK↓, ERK1/2
cMyc↓,
mTOR↓,
survivin↓,
cMET↓,
EGFR↓,
cycD1/CCND1↓,
cycE1↓,
CDK4/6↓,
p16↑,
p27↑,
Apoptosis↑,
TumAuto↑,
Ferroptosis↑,
oncosis↑,
TumCCA↑, G0/G1 into M phase, G0/G1 into S phase, G1 and G2/M
ROS↑, ovarian cancer cell line model, artesunate induced oxidative stress, DNA double-strand breaks (DSBs) and downregulation of RAD51 foci
DNAdam↑,
RAD51↓,
HR↓,

558- ART/DHA,    Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer
- Review, NA, NA
ROS↑,
oncosis↑, low doses of artesunate induced oncosis-like cell death
Apoptosis↑, higher doses of art
LysoPr↑,
TumAuto↑,
Wnt/(β-catenin)↑,
AMP↓,
NF-kB↓,
Myc↓,
CREBBP↓,
mTOR↓,
E-cadherin↑,

559- ART/DHA,    Artemisinin and its derivatives: a promising cancer therapy
- Review, NA, NA
ROS↑, reacts with the iron in cancer cells to produce ROS

566- ART/DHA,  2DG,    Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells
- in-vitro, Lung, A549 - in-vitro, Lung, PC9
GlucoseCon↓,
ATP↓,
lactateProd↓,
p‑S6↓,
mTOR↓,
GLUT1↓,
Casp9↑,
Casp8↑,
Casp3↑,
Cyt‑c↑,
AIF↑,
ROS↑, generation of ROS is critical for the toxic effects of DHA

1076- ART/DHA,    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer
- Review, NA, NA
Ferroptosis↑,
ROS↑, interaction between heme-derived iron and ART will result in the production of ROS
ER Stress↑,
i-Iron↓, DHA can cause intracellular iron depletion in a time- and dose-dependent manner
TumAuto↑,
AMPK↑,
mTOR↑,
P70S6K↑,
Fenton↑,
lipid-P↑,
ROS↑,
ChemoSen↑, combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.
NRF2↑, Liu et al. discovered that ART covalently targets Keap1 at Cys151 to activate the Nrf2-dependent pathway [94
NRF2↓, inhibition of Nrf2-related gene expression accelerated erastin and sorafenib-induced ferroptosis [45]. More importantly, an accumulating body of research suggests that ART may induce ferroptosis in cancer cells by regulating the above molecules.

1026- ART/DHA,    Artemisinin improves the efficiency of anti-PD-L1 therapy in T-cell lymphoma
Ferroptosis↑,
ROS↑,
ERK↓,
PD-L1↓, combination therapy with artemisinin greatly improved the anti-lymphoma effciency of anti-PD-L1 monoclonal antibody.

1369- Ash,    Withaferin A inhibits cell proliferation of U266B1 and IM-9 human myeloma cells by inducing intrinsic apoptosis
- in-vitro, Melanoma, U266
tumCV↓,
Apoptosis↑,
BAX↑,
Cyt‑c↑,
Bcl-2↓,
cl‑PARP↑,
cl‑Casp3↑,
cl‑Casp9↑,
ROS↑,
eff↓, treatment of the U266B1 and IM-9 with ascorbic acid (antioxidant) could prevent the withaferin A mediated ROS production and the withaferin A induced antiproliferative effects.

1368- Ash,  Cisplatin,    Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’
- in-vitro, Colon, HT-29 - in-vitro, BC, MDA-MB-231
tumCV↓,
*toxicity↓, However, in non-cancer cells (MCF10A) there was no reduction in cell viability compared to non-treatment
ROS↑, only in cancer cells ****
mitResp↓,
ChemoSen↑, ‘Priming’ with W. somnifera (treatment: 48 h prior to 100 μM cisplatin)

1366- Ash,    Selective Killing of Cancer Cells by Ashwagandha Leaf Extract and Its Component Withanone Involves ROS Signaling
- in-vitro, BC, MCF-7
ROS↑,
P53↑,

1370- Ash,    Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species
- in-vitro, Lung, A549
ROS↑,
eff↓, while the non-carcinoma cells WI-38 and PBMC were unaffected.

1371- Ash,    Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine
- in-vitro, AML, HL-60
ROS↑,
MMP↓,
cl‑Casp3↑,
cl‑Casp9↑,
cl‑PARP↑,
eff↓, N-acetyl-cysteine rescued all these events suggesting thereby a pro-oxidant effect of withaferinA.

1372- Ash,    Withaferin-A Induces Apoptosis in Osteosarcoma U2OS Cell Line via Generation of ROS and Disruption of Mitochondrial Membrane Potential
- in-vitro, OS, U2OS
Apoptosis↑,
ROS↑,
MMP↓,
Casp3↑,

1355- Ash,    Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, HMEC
eff↑, WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). ****
mt-ROS↑, WA-induced apoptosis in human breast cancer cells is mediated by mitochondria-derived ROS
mitResp↓,
OXPHOS↓, WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity.
compIII↑,
BAX↑,
Bak↑,
other↓, Cu,Zn-Superoxide dismutase (Cu,Zn-SOD) overexpression confers protection against WA-induced ROS production and apoptosis
ATP∅, steady-state levels of ATP were unaffected by WA treatment in either cell line
*ROS∅, but not in a normal human mammary epithelial cell line (HMEC). WA treatment caused ROS production in breast cancer cells, HMEC were resistant to pro-oxidant effect of this agent.

1356- Ash,    Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells
- in-vitro, CRC, HCT116
ROS↑,
TumCCA↑,
MMP↓,
TumCG↓,
Apoptosis↑,
JNK↝,

1357- Ash,    Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vitro, GBM, GL26
TumCP↓,
TumCCA↑, G2/M cell cycle
Akt↓,
mTOR↓,
p70S6↓,
p85S6K↓,
AMPKα↑,
TSC2↑,
HSP70/HSPA5↑,
HO-1↑,
HSF1↓,
Apoptosis↑,
ROS↑, Withaferin A elevates pro-oxidant potential in GBM cells and induces a cellular oxidative stress response
eff↓, Pre-treatment with a thiol-antioxidant protects GBM cells from the anti-proliferative and cytotoxic effects of withaferin A NAC pretreatment was able to completely prevent cell cycle shift to G2/M arrest following 1µM WA treatment at 24h

1358- Ash,    Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms
- Review, Var, NA
TumCCA↑,
Apoptosis↑,
TumAuto↑,
Ferroptosis↑,
TumCP↓,
CSCs↓,
TumMeta↓,
EMT↓,
angioG↓,
Vim↓,
HSP90↓,
annexin II↓, annexin II proteins directly bind to WA
m-FAM72A↓,
BCR-ABL↓,
Mortalin↓,
NRF2↓,
cMYB↓,
ROS↑, WA inhibits proliferation through ROS-mediated intrinsic apoptosis
ChemoSen↑, WA and cisplatin, WA produced ROS, while cisplatin caused DNA damage, suggesting that lower doses of cisplatin combined with suboptimal doses of WA could achieve the same effect
eff↑, sulforaphane and WA showed synergistic effects on epigenetic modifiers and cell proliferation in breast cancer cells
ChemoSen↑, WA and sorafenib caused G2/M arrest in anaplastic and papillary thyroid cancer cells
ChemoSen↑, combination of WA and 5-FU executed PERK axis-mediated endoplasmic reticulum (ER) stress-induced autophagy and apoptosis
eff↑, WA and carnosol also exhibit a synergistic effect on pancreatic cancer
*BioAv↓, Saurabh by Saurabh et al and Tianming et al reported oral bioavailability values 1.8% and 32.4 ± 4.8%, respectively, in male rats.
ROCK1↓, In another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angi
TumCI↓,
Sp1/3/4↓, Furthermore, WA exerts potent anti-angiogenic activity in vivo.174 In the Ehrlich ascites tumor model, WA exerts its anti-angiogenic activity by reducing the binding of the transcription factor specificity protein 1 (Sp1) to VEGF
VEGF↓, n another study, WA reduces macrophage infiltration and inhibits the expression of protein tyrosine kinase-2 (Pyk2), rho-associated kinase 1 (ROCK1), and VEGF in a hepatocellular carcinoma xenograft model, thereby suppressing tumor invasion and angio
Hif1a↓, Furthermore, WA suppresses the AK4-HIF-1α signaling axis and acts as a potent antimetastatic agent in lung cancer.Citation79
EGFR↓, WA synergistically inhibited wild-type epidermal growth factor receptor (EGFR) lung cancer cell viability

1359- Ash,    Withaferin A Induces ROS-Mediated Paraptosis in Human Breast Cancer Cell-Lines MCF-7 and MDA-MB-231
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
MMP↓,
Alix/AIP‑1↓,
ROS↑, ROS inhibitor abrogated the effect of WA on: cell-death
Paraptosis↑,
ER Stress↝,

1360- Ash,  immuno,    Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer
- in-vitro, Lung, H1650 - in-vitro, Lung, A549 - in-vitro, CRC, HCT116 - in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
PD-L1↑,
eff↓, The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process.
ROS↑,
ER Stress↑,
Apoptosis↑,
BAX↑,
Bak↑,
BAD↑,
Bcl-2↓,
XIAP↓,
survivin↓,
cl‑PARP↑,
CHOP↑,
p‑eIF2α↑, phosphorylation of the eukaryotic initiation factor eIF-2
ICD↑,
eff↑, WFA Sensitizes LLC Syngeneic Mouse Tumors to α-PD-L1 In Vivo

1361- Ash,  SRF,    Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells
- in-vitro, Liver, HUH7 - in-vivo, Liver, HUH7
TrxR↓, TrxR1
ROS↑,
DNA-PK↑,
ER Stress↑,
Apoptosis↑,
eff↓, Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment

1362- Ash,  GEM,    Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A
- in-vitro, PC, PANC1 - in-vitro, PC, Hs766t
ChemoSen↑, combination treatment being the most effective
ROS↑, which were attenuated by N-acetylcysteine
Apoptosis↑,
TumCMig↓, strongest inhibition was observed when both compounds were co-administered
F-actin↓, leading to F-actin depolymerization
YMcells↓, greater reduction in cell stiffness compared to individual treatments
NF-kB↓, relative luciferase activity, which reflects NF-κB activity, was markedly elevated following treatment with GC (Figure 7). In contrast, treatment with WFA resulted in a notable decline in luciferase activity, particularly when combined with GC.

1363- Ash,  doxoR,    Withaferin A Synergizes the Therapeutic Effect of Doxorubicin through ROS-Mediated Autophagy in Ovarian Cancer
- in-vitro, Ovarian, A2780S - in-vitro, Ovarian, CaOV3 - in-vivo, NA, NA
ChemoSen↑, thus reducing the dosage requirement of Dox
ROS↑,
DNAdam↑, immense DNA damage
TumCCA↑,
LC3B↑,
TumCG↓, 70 to 80% reduction in tumor growth
cl‑Casp3↑,

1364- Ash,    Withaferin a Triggers Apoptosis and DNA Damage in Bladder Cancer J82 Cells through Oxidative Stress
- in-vitro, Bladder, J82
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
ROS↑,
MMP↓,
DNAdam↑,
eff↓, ROS scavenger N-acetylcysteine reverts all tested WFA-modulating effects.

1365- Ash,    Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells
- in-vitro, Oral, Ca9-22 - in-vitro, Oral, CAL27
ROS↑, Withaferin A (WFA) is one of the most active steroidal lactones with reactive oxygen species (ROS) modulating effects against several types of cancer.
*toxicity↓, killed two oral cancer cells (Ca9-22 and CAL 27) rather than normal oral cells (HGF-1) HGF-1 normal oral cells treated with WFA showed no reduction in viability
Apoptosis↑,
TumCCA↑, G2/M cell cycle arrest
MMP↓,
p‑γH2AX↑,
DNAdam↑,
eff↓, Moreover, pretreating Ca9-22 cells with N-acetylcysteine (NAC) rescued WFA-induced selective killing

1367- Ash,    An anti-cancerous protein fraction from Withania somnifera induces ROS-dependent mitochondria-mediated apoptosis in human MDA-MB-231 breast cancer cells
- in-vitro, BC, MDA-MB-231
Apoptosis↑,
ROS↑, extensive reactive oxygen species generation
Bax:Bcl2↑,
MMP↓,
Casp3↑,
TumCCA↑, G2/M-phase cell cycle arrest

2003- Ash,    Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145 - in-vitro, Nor, TIG-1 - in-vitro, PC, LNCaP
TumCD↑, We report here that 2 μM WA induced cell death selectively in androgen-insensitive PC-3 and DU-145 prostate adenocarcinoma cells
selectivity↑, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD)
cFos↑, WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs) in PC-3 and DU-145, but not in LNCaP and TIG-1.
ROS↑, WA induced generation of reactive oxygen species (ROS) in PC-3 and DU-145, but not in normal fibroblasts
*ROS∅, but not in normal fibroblasts
HSP70/HSPA5↑,
Apoptosis↑, WA induces apoptosis mediated by ER stress
ER Stress↑,
TumCCA↑, WA induces autophagy in breast cancer cells, but the detailed mechanism remains elusive

5394- Ash,    Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial
- Trial, OS, NA
toxicity↝, generally well tolerated. Eleven adverse events of grade 1 or grade 2 severity were observed. No grade 3 or grade 4 adverse events were observed.
hepatoP↓, Elevation of liver enzymes (5/11) and skin rash (2/11) was the most common adverse events.
BioAv↓, However, WA appears to have low oral bioavailability.
Apoptosis↑, WA has been reported to induce apoptosis via intrinsic and extrinsic pathways in human prostate, breast and leukemic cancer cells among others
ROS↑, It has also shown the ability to induce apoptosis in osteosarcoma U2OS cell lines by generating ROS, also causing cell cycle arrest in osteosarcoma cell lines by inhibition of G2/M checkpoint proteins
TumCCA↑,

5396- Ash,    Withania Somnifera (Ashwagandha) and Withaferin A: Potential in Integrative Oncology
- Review, Var, NA
selectivity↑, WS was shown to impede the growth of new cancer cells, but not normal cells,
ROS↑, help induce programmed death of cells by generating reactive oxygen species (ROS), and sensistize cancer cells to apoptosis
Apoptosis↑,
ChemoSen↑, Pre-clinical studies in several cancer types have shown up to 80% inhibition using combination chemotherapy [19].
RadioS↑, It was not until 1996, that WFA’s radiosensitizer activity was reported that caused V79 cell survival reduction where 1-h pre-treatment at 2.1 µM dose before radiation significantly killed cells
NF-kB↓, inhibiting NF-κB activation
ER-α36↓, WFA, it was found the phytochemical downregulated the estrogen receptor-α (ER-α) protein in MCF-7 cells.
P53↑, WFA selectively activated p53 in tumor cells treated with the leaf extract of Ashwagandha [71] leading to growth arrest and apoptosis.
*ROS∅, opposed to the normal human mammary epithelial cells (HMEC) [72] which did not increase ROS production.
γH2AX↑, The group found an increase in γ-H2AX and number of cells expressing the phosphorylated form which is a marker for DNA damage in WFA treated MCF-7 cells.
DNAdam↑,
MMP↓, As ROS is well known to affect mithochondrial membrane potential, they found a change in mitochondrial membrane potential and altered mitochondrial morphology in WFA treated cells.
XIAP↓, XIAP (X-linked inhibitor of apoptosis protein), cIAP-2 (cellular inhibitor of apoptosis protein-2) and Survivin proteins were found to be reduced in MDA-MB-231 and MCF-7 cells when treated with WFA
IAP1↓,
survivin↓,
SOD↓, figure 2
Dose↝, doses of 3 and 4 mg/kg and the authors found 59% reduction of tumor and polyp initiation and progression in the WFA treated mice compared to the controls [80].
IL6↓, WFA downregulated expression of inflammatory markers in these tumors such as IL-6, TNF-α, COX-2 along with pro-survival markers such as pAkt, Notch1 and NF-κβ [80].
TNF-α↓,
COX2↓,
p‑Akt↓,
NOTCH1↓,
FOXO↑, figure 3 prostrate cancer
Casp↑,
MMP2↓,
CSCs↓, WFA treatment significantly reduced ALDH+ CSC population, whereas Cisplatin treatment increased CSC population.
*ROS↓, WFA was found to increase cellular survival in simulated injury and in H2O2-induced cell apoptosis along with inhibition of oxidative stress.
*SOD2↑, Thus, via upregulation of SOD2, SOD3, Prdx-1 by H2O2, WFA treatment leads to inhibition of the antioxidants and Akt-dependent improvement of cardiomyocyte caspase-3 [103].
chemoP↑, First, given the safety record of WS, it can be used as an adjunct therapy that can aid in reducing the adverse effects associated with radio and chemotherapy due to its anti-inflammatory properties.
ChemoSen↑, Second, WS can also be combined with other conventional therapies such as chemotherapies to synergize and potentiate the effects due to radiotherapy and chemotherapy due to its ability to aid in radio- and chemosensitization, respectively.
RadioS↑,

4678- Ash,    Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
- vitro+vivo, NSCLC, H1975
ROS↑, WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects.
AntiTum↑, In vivo research also demonstrated the anti-tumor effect of WA treatment
CSCs↓, We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity
mTOR↓, at least through downregulation of mTOR/STAT3 signaling
STAT3↓,
ChemoSen↑, combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability.
Keap1↑, Interestingly, we found WA treatment gradually increased KEAP1, while it decreased NRF2 in H1975 cells
NRF2↓,

3177- Ash,    Emerging Role of Hypoxia-Inducible Factors (HIFs) in Modulating Autophagy: Perspectives on Cancer Therapy
- Review, Var, NA
Hif1a↓, Withaferin A, a steroidal lactone derived from Withania somnifera (ashwagandha), has demonstrated the ability to decrease HIF-1α production in breast cancer cells (MDA-MB-231)
ROS↑, It also stimulates autophagy by stimulating ROS generation and endoplasmic reticulum (ER) stress pathways
ER Stress↑,

3176- Ash,    Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex
- in-vitro, NA, NA
PKCδ↓, inhibition of PKC by withaferin A is a central event for the induction of apoptosis
TOP1∅, This result suggests that withaferin A and staurosporine do not inhibit topoisomerase I in vitro.
ROS↑, Withaferin A induces oxidative stress, causes decrease in GSH level and leads to subsequent DNA lesions
GSH↓,
DNAdam↑,
MMP↓, Withaferin A inhibits growth of L. donovani promastigotes, induces depolarization of mitochondrial membrane potential and releases cytochrome c into the cytosol.
Cyt‑c↑,

3172- Ash,    Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis
- in-vitro, HCC, HepG2 - in-vitro, Nor, HL7702
Keap1↑, Notably, Withaferin A elevated Keap1 expression to mitigate Nrf2 signaling activation-mediated epithelial to mesenchymal transition (EMT) and ferroptosis-related protein xCT expression
NRF2↓,
EMT↓, Withaferin A suppresses epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer
TumCP↓, Withaferin A restrains proliferation, invasion, and VM of hepatoma cells while preserving normal hepatocytes
TumCI↓,
selectivity↑, , treatment with Withaferin A ranging from 1 to 100 μM had little effect on cell viability of human normal liver cells (HL-7702 cells), indicating the little cytotoxicity on normal hepatocytes.
*toxicity↓,
ROS↑, Withaferin A strikingly enhanced ROS () and MDA levels (), but reduced the GSH levels (), indicating the induction of ferroptosis by Withaferin A
MDA↑,
GSH↓,
Ferroptosis↑,

1142- Ash,    Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer
- Review, BC, MCF-7 - NA, BC, MDA-MB-231 - NA, Nor, HMEC
Apoptosis↑,
ROS↑, anti-cancer effect of WA was significantly attenuated in the presence of anti-oxidants,
DNAdam↑,
OXPHOS↓, WA inhibits oxidative phosphorylation (OXPHOS) in Complex III, accompanied by apoptotic release of DNA fragments associated with histones in the cytosol
*ROS∅, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
Bcl-2↓,
XIAP↓,
survivin↓,
DR5↑,
IKKα↓,
NF-kB↓,
selectivity↑, Moreover, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
*ROS∅, Moreover, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
eff↓, the anti-cancer effect of WA was significantly attenuated in the presence of anti-oxidants, as it has been shown that ectopic expression of Cu and Zn-superoxide dismutase (SOD) significantly weakens its apoptotic properties
Paraptosis↑, WA promotes death in both MCF-7 and MDA-MB-231 cell lines through paraptosis through the action of ROS

3155- Ash,    Overview of the anticancer activity of withaferin A, an active constituent of the Indian ginseng Withania somnifera
- Review, Var, NA
Half-Life↝, The pharmacokinetic study demonstrates that a dose of 4 mg/kg in mice results in 2 μM concentration in plasma (with a half-life of 1.3 h, in the breast cancer model of mice),
Inflam↓, WA has many biological activities: anti-inflammatory (Dubey et al. 2018), immunomodulatory (Davis and Girija 2000), antistress (Singh et al. 2016), antioxidant (Sumathi et al. 2007) and anti-angiogenesis
antiOx↓,
angioG↓,
ROS↑, WA induces oxidative stress (ROS) determining mitochondrial dysfunction as well as apoptosis in leukaemia cells
BAX↑, withaferin mediates apoptosis by ROS generation and activation of Bax/Bak.
Bak↑,
E6↓, The results of the study show that withaferin treatment downregulates the HPV E6 and E7 oncoprotein and induces accumulation of p53 result in the activation of various apoptotic markers (e.g. Bcl2, Bax, caspase-3 and cleaved PARP).
E7↓,
P53↑,
Casp3↑,
cl‑PARP↑,
STAT3↓, WA treatment also decreases the level of STAT3
eff↑, This study concludes that combination of DOX with WA can reduce the doses and side effects of the treatment which gives valuable possibilities for future research.
HSP90↓, by inhibiting the HSP90
TGF-β↓, WA inhibited TGFβ1 and TNFα- induced EMT;
TNF-α↓,
EMT↑,
mTOR↓, by downregulation of mTOR/STAT3 signalling.
NOTCH1↓, WA showed inhibition of pro-survival signalling markers (Notch1, pAKT and NFκB)
p‑Akt↓,
NF-kB↓,
Dose↝, WA dose escalation sets consisted of 72, 108, 144 and 216 mg, fractioned in 2-4 doses/day.

3156- Ash,    Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug
- Review, Var, NA
MAPK↑, Figure 3
p38↑,
BAX↑,
BIM↑,
CHOP↑,
ROS↑,
DR5↑,
Apoptosis↑,
Ferroptosis↑,
GPx4↓,
BioAv↝, WA has a rapid oral absorption and reaches to peak plasma concentration of around 16.69 ± 4.02 ng/ml within 10 min after oral administration of Withania somnifera aqueous extract at dose of 1000 mg/kg, which is equivalent to 0.458 mg/kg of WA
HSP90↓, table 1 10uM) were found to inhibit the chaperone activity of HSP90
RET↓,
E6↓,
E7↓,
Akt↓,
cMET↓,
Glycolysis↓, by suppressing the glycolysis and tricarboxylic (TCA) cycle
TCA↓,
NOTCH1↓,
STAT3↓,
AP-1↓,
PI3K↓,
eIF2α↓,
HO-1↑,
TumCCA↑, WA (1--3 uM) have been reported to inhibit cell proliferation by inducing G2 and M phase cycle arrest inovarian, breast, prostate, gastric and myelodysplastic/leukemic cancer cells and osteosarcoma
CDK1↓, WA is able to decrease the cyclin-dependent kinase 1 (Cdk1) activity and prevent Cdk1/cyclin B1 complex formation, which are key steps in cell cycle progression
*hepatoP↑, A treatment (40 mg/kg) reduces acetaminophen-induced liver injury (AILI) in mouse models and decreases H 2O 2-induced glutathione (GSH) depletion and necrosis in hepatocyte
*GSH↑,
*NRF2↑, WA triggers an anti-oxidant response after acetaminophen overdose by enhancing hepatic transcription of the nuclear factor erythroid 2–related factor 2 (NRF2)-responsive gene
Wnt↓, indirectly inhibit Wnt
EMT↓, WA can also block tumor metastasis through reduced expression of epithelial mesenchymal transition (EMT) markers.
uPA↓, WA (700 nM) exert anti-meta-static activities in breast cancer cells through inhibition of the urokinase-type plasminogen activator (uPA) protease
CSCs↓, s WA (125-500 nM) suppress tumor sphere formation indicating that the self-renewal of CSC is abolished
Nanog↓, loss of these CSC-specific characteristics is reflected in the loss of typical stem cell markers such as ALDH1A, Nanog, Sox2, CD44 and CD24
SOX2↓,
CD44↓,
lactateProd↓, drop in lactate levels compared to control mice.
Iron↑, Furthermore, we found that WA elevates the levels of intracellular labile ferrous iron (Fe +2 ) through excessive activation of heme oxygenase-1 (HMOX1), which independently causes accumulation of toxic lipid radicals and ensuing ferroptosis
NF-kB↓, nhibition of NF-kB kinase signaling pathway

3160- Ash,    Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal
- Review, Var, NA
TumCCA↑, withaferin A suppressed cell proliferation in prostate, ovarian, breast, gastric, leukemic, and melanoma cancer cells and osteosarcomas by stimulating the inhibition of the cell cycle at several stages, including G0/G1 [86], G2, and M phase
H3↑, via the upregulation of phosphorylated Aurora B, H3, p21, and Wee-1, and the downregulation of A2, B1, and E2 cyclins, Cdc2 (Tyr15), phosphorylated Chk1, and Chk2 in DU-145 and PC-3 prostate cancer cells.
P21↑,
cycA1/CCNA1↓,
CycB/CCNB1↓,
cycE/CCNE↓,
CDC2↓,
CHK1↓,
Chk2↓,
p38↑, nitiated cell death in the leukemia cells by increasing the expression of p38 mitogen-activated protein kinases (MAPK)
MAPK↑,
E6↓, educed the expression of human papillomavirus E6/E7 oncogenes in cervical cancer cells
E7↓,
P53↑, restored the p53 pathway causing the apoptosis of cervical cancer cells.
Akt↓, oral dose of 3–5 mg/kg withaferin A attenuated the activation of Akt and stimulated Forkhead Box-O3a (FOXO3a)-mediated prostate apoptotic response-4 (Par-4) activation,
FOXO3↑,
ROS↑, the generation of reactive oxygen species, histone H2AX phosphorylation, and mitochondrial membrane depolarization, indicating that withaferin A can cause the oxidative stress-mediated killing of oral cancer cells [
γH2AX↑,
MMP↓,
mitResp↓, withaferin A inhibited the expansion of MCF-7 and MDA-MB-231 human breast cancer cells by ROS production, owing to mitochondrial respiration inhibition
eff↑, combination treatment of withaferin A and hyperthermia induced the death of HeLa cells via a decrease in the mitochondrial transmembrane potential and the downregulation of the antiapoptotic protein myeloid-cell leukemia 1 (MCL-1)
TumCD↑,
Mcl-1↓,
ER Stress↑, . Withaferin A also attenuated the development of glioblastoma multiforme (GBM), both in vitro and in vivo, by inducing endoplasmic reticulum stress via activating the transcription factor 4-ATF3-C/EBP homologous protein (ATF4-ATF3-CHOP)
ATF4↑,
ATF3↑,
CHOP↑,
NOTCH↓, modulating the Notch-1 signaling pathway and the downregulation of Akt/NF-κB/Bcl-2 . withaferin A inhibited the Notch signaling pathway
NF-kB↓,
Bcl-2↓,
STAT3↓, Withaferin A also constitutively inhibited interleukin-6-induced phosphorylation of STAT3,
CDK1↓, lowering the levels of cyclin-dependent Cdk1, Cdc25C, and Cdc25B proteins,
β-catenin/ZEB1↓, downregulation of p-Akt expression, β-catenin, N-cadherin and epithelial to the mesenchymal transition (EMT) markers
N-cadherin↓,
EMT↓,
Cyt‑c↑, depolarization and production of ROS, which led to the release of cytochrome c into the cytosol,
eff↑, combinatorial effect of withaferin A and sulforaphane was also observed in MDA-MB-231 and MCF-7 breast cancer cells, with a dramatic reduction of the expression of the antiapoptotic protein Bcl-2 and an increase in the pro-apoptotic Bax level, thus p
CDK4↓, downregulates the levels of cyclin D1, CDK4, and pRB, and upregulates the levels of E2F mRNA and tumor suppressor p21, independently of p53
p‑RB1↓,
PARP↑, upregulation of Bax and cytochrome c, downregulation of Bcl-2, and activation of PARP, caspase-3, and caspase-9 cleavage
cl‑Casp3↑,
cl‑Casp9↑,
NRF2↑, withaferin A binding with Keap1 causes an increase in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, which in turn, regulates the expression of antioxidant proteins that can protect the cells from oxidative stress.
ER-α36↓, Decreased ER-α
LDHA↓, inhibited growth, LDHA activity, and apoptotic induction
lipid-P↑, induction of oxidative stress, increased lipid peroxidation,
AP-1↓, anti-inflammatory qualities of withaferin A are specifically attributed to its inhibition of pro-inflammatory molecules, α-2 macroglobulin, NF-κB, activator protein 1 (AP-1), and cyclooxygenase-2 (COX-2) inhibition,
COX2↓,
RenoP↑, showing strong evidence of the renoprotective potential of withaferin A due to its anti-inflammatory activity
PDGFR-BB↓, attenuating the BB-(PDGF-BB) platelet growth factor
SIRT3↑, by increasing the sirtuin3 (SIRT3) expression
MMP2↓, withaferin A inhibits matrix metalloproteinase-2 (MMP-2) and MMP-9,
MMP9↓,
NADPH↑, but also provokes mRNA stimulation for a set of antioxidant genes, such as NADPH quinone dehydrogenase 1 (NQO1), glutathione-disulfide reductase (GSR), Nrf2, heme oxygenase 1 (HMOX1),
NQO1↑,
GSR↑,
HO-1↑,
*SOD2↑, cardiac ischemia-reperfusion injury model. Withaferin A triggered the upregulation of superoxide dismutase SOD2, SOD3, and peroxiredoxin 1(Prdx-1).
*Prx↑,
*Casp3?, and ameliorated cardiomyocyte caspase-3 activity
eff↑, combination with doxorubicin (DOX), is also responsible for the excessive generation of ROS
Snail↓, inhibition of EMT markers, such as Snail, Slug, β-catenin, and vimentin.
Slug↓,
Vim↓,
CSCs↓, highly effective in eliminating cancer stem cells (CSC) that expressed cell surface markers, such as CD24, CD34, CD44, CD117, and Oct4 while downregulating Notch1, Hes1, and Hey1 genes;
HEY1↓,
MMPs↓, downregulate the expression of MMPs and VEGF, as well as reduce vimentin, N-cadherin cytoskeleton proteins,
VEGF↓,
uPA↓, and protease u-PA involved in the cancer cell metastasis
*toxicity↓, A was orally administered to Wistar rats at a dose of 2000 mg/kg/day and had no adverse effects on the animals
CDK2↓, downregulated the activation of Bcl-2, CDK2, and cyclin D1
CDK4↓, Another study also demonstrated the inhibition of Hsp90 by withaferin A in a pancreatic cancer cell line through the degradation of Akt, cyclin-dependent kinase 4 Cdk4,
HSP90↓,

3166- Ash,    Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives
- Review, Var, NA
*p‑PPARγ↓, preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ)
*cardioP↑, cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis.
*AMPK↑,
*BioAv↝, The oral bioavailability was found to be 32.4 ± 4.8% after 5 mg/kg intravenous and 10 mg/kg oral WA administration.
*Half-Life↝, The stability studies of WA in gastric fluid, liver microsomes, and intestinal microflora solution showed similar results in male rats and humans with a half-life of 5.6 min.
*Half-Life↝, WA reduced quickly, and 27.1% left within 1 h
*Dose↑, WA showed that formulation at dose 4800 mg having equivalent to 216 mg of WA, was tolerated well without showing any dose-limiting toxicity.
*chemoPv↑, Here, we discuss the chemo-preventive effects of WA on multiple organs.
IL6↓, attenuates IL-6 in inducible (MCF-7 and MDA-MB-231)
STAT3↓, WA displayed downregulation of STAT3 transcriptional activity
ROS↓, associated with reactive oxygen species (ROS) generation, resulted in apoptosis of cells. The WA treatment decreases the oxidative phosphorylation
OXPHOS↓,
PCNA↓, uppresses human breast cells’ proliferation by decreasing the proliferating cell nuclear antigen (PCNA) expression
LDH↓, WA treatment decreases the lactate dehydrogenase (LDH) expression, increases AMP protein kinase activation, and reduces adenosine triphosphate
AMPK↑,
TumCCA↑, (SKOV3 andCaOV3), WA arrest the G2/M phase cell cycle
NOTCH3↓, It downregulated the Notch-3/Akt/Bcl-2 signaling mediated cell survival, thereby causing caspase-3 stimulation, which induces apoptosis.
Akt↓,
Bcl-2↓,
Casp3↑,
Apoptosis↑,
eff↑, Withaferin-A, combined with doxorubicin, and cisplatin at suboptimal dose generates ROS and causes cell death
NF-kB↓, reduces the cytosolic and nuclear levels of NF-κB-related phospho-p65 cytokines in xenografted tumors
CSCs↓, WA can be used as a pharmaceutical agent that effectively kills cancer stem cells (CSCs).
HSP90↓, WA inhibit Hsp90 chaperone activity, disrupting Hsp90 client proteins, thus showing antiproliferative effects
PI3K↓, WA inhibited PI3K/AKT pathway.
FOXO3↑, Par-4 and FOXO3A proapoptotic proteins were increased in Pten-KO mice supplemented with WA.
β-catenin/ZEB1↓, decreased pAKT expression and the β-catenin and N-cadherin epithelial-to-mesenchymal transition markers in WA-treated tumors control
N-cadherin↓,
EMT↓,
FASN↓, WA intraperitoneal administration (0.1 mg) resulted in significant suppression of circulatory free fatty acid and fatty acid synthase expression, ATP citrate lyase,
ACLY↓,
ROS↑, WA generates ROS followed by the activation of Nrf2, HO-1, NQO1 pathways, and upregulating the expression of the c-Jun-N-terminal kinase (JNK)
NRF2↑,
HO-1↑,
NQO1↑,
JNK↑,
mTOR↓, suppressing the mTOR/STAT3 pathway
neuroP↑, neuroprotective ability of WA (50 mg/kg b.w)
*TNF-α↓, WA attenuate the levels of neuroinflammatory mediators (TNF-α, IL-1β, and IL-6)
*IL1β↓,
*IL6↓,
*IL8↓, WA decreases the pro-inflammatory cytokines (IL-6, TNFα, IL-8, IL-18)
*IL18↓,
RadioS↑, radiosensitizing combination effect of WA and hyperthermia (HT) or radiotherapy (RT)
eff↑, WA and cisplatin at suboptimal dose generates ROS and causes cell death [41]. The actions of this combination is attributed by eradicating cells, revealing markers of cancer stem cells like CD34, CD44, Oct4, CD24, and CD117

3167- Ash,    Withaferin A Inhibits the Proteasome Activity in Mesothelioma In Vitro and In Vivo
- in-vitro, MM, H226
TumCP↓, WA inhibits MPM cell proliferation
cMyc↓, Among the genes that were down-regulated included cell growth and metastasis-promoting oncogenes c-myc, c-fos, c-jun, while tissue inhibitor of metallopeptidases (TIMP)-2 was significantly upregulated
cFos↓,
cJun↓,
TIMP2↑,
Vim↓, WA exposure caused reduced levels of vimentin at 24 h of treatment.
ROS↑, WA treatment generated reactive oxygen species (ROS), causing cell death in HL-60 cells
BAX↑, Consistent with these findings, we found that WA treatments increased pro-apoptotic protein Bax and NF-κB inhibitory protein IκB-α in the patient derived MPM cells.
IKKα↑,
Casp3↑, Indeed, WA treatment induced caspase-3 activation, PARP cleavage,
cl‑PARP↑,

5385- AsP,  GoldNP,  GEM,    Development of ascorbyl palmitate based hydrophobic gold nanoparticles as a nanocarrier system for gemcitabine delivery
- in-vitro, BC, NA
ROS↑, At pharmacologic concentrations, ascorbate undergoes oxidation via ascorbate radical, generating cytotoxic hydrogen peroxide (H₂O₂) through Fenton chemistry
Fenton↑,
BioAv↑, Although AsP is more stable than vitamin C, its poor release capacity and water insolubility limit its bioavailability and therapeutic efficacy15,17. Thus, incorporating it into nanoparticle carriers can enhance circulation time and tumor accumulatio
EPR↑, Nanoparticles sized 30–200 nm enhance cell uptake via increased surface area and membrane wrapping, effectively accumulating in tumors

4817- ASTX,    Low Dose Astaxanthin Treatments Trigger the Hormesis of Human Astroglioma Cells by Up-Regulating the Cyclin-Dependent Kinase and Down-Regulated the Tumor Suppressor Protein P53
- in-vitro, GBM, U251
Dose⇅, At high concentrations (20–40 μM), AXT triggered apoptosis in U251-MG cells, as it has been previously shown in other cancer cell lines. However, low concentrations (4–8 μM) of AXT were found to upregulate the proliferative cell cycle.
ROS∅, low concentrations, AXT did not affect the intracellular ROS levels, while the superoxide dismutase activity increased moderately.
SOD↑,
CDK1↑, Low Dose Astaxanthin Treatments Trigger the Hormesis of Human Astroglioma Cells by Up-Regulating the Cyclin-Dependent Kinase and Down-Regulated the Tumor Suppressor Protein P53
P53↓,
TumCP⇅, we found that U251-MG cells show a biphasic response to AXT, that is low doses of AXT have a proliferative effect, with a maximum survival increase of 130.4 ± 2.4% after treatment with 5 µM of AXT, while AXT concentrations over 20 µM have an apoptoti
ROS↑, Treatment with High AXT Concentrations Increased Intracellular ROS Levels while Low AXT Concentrations did not Affect ROS Levels

5449- ATV,    Pleiotropic effects of statins: A focus on cancer
- NA, Var, NA
lipid-P↓, Statins exhibit “pleiotropic” properties that are independent of their lipid-lowering effects.
TumCG↓, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types.
Apoptosis↑,
ChemoSen↑, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling.
RAS↓,
HMG-CoA↓, Statins are potent, competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR).
HMGCR↓,
LDL↓, Statins reduce blood plasma cholesterol levels by decreasing de novo cholesterol biosynthesis and by inducing changes in low density lipoprotein (LDL) receptor expression [2].
toxicity↓, Due to the well-established safety profile of statins, such studies are less expensive than the development of novel drugs.
Risk↓, statin use in cancer patients was associated with reduced cancer-related mortality. The risk of cancer death was significantly lower in postmenopausal women
P21↑, Other proposed mechanisms leading to an increase of p21 levels include the release of promoter-associated histone deacetylase and inhibition of histone deacetylase
HDAC↓,
Bcl-2↓, Statins trigger the intrinsic apoptosis pathway and decrease Bcl-2 protein expression [[154], [155], [156]], increase Bax and BIM protein expression [[156], [157], [158], [159]], and activate several caspases
BAX↑,
BIM↑,
Casp↑,
cl‑PARP↑, thereby increasing cleaved PARP-1 levels.
MMP↓, different tumor cell lines (breast, brain, and lung) showed that simvastatin-induced apoptosis is dependent on decreasing mitochondrial membrane potential and increasing reactive oxygen species (ROS) production
ROS↑,
angioG↓, Statins inhibit angiogenesis and metastasis
TumMeta↓,
PTEN↑, n breast cancer xenografts, simvastatin prevented tumor growth by reducing Akt phosphorylation and BclXL transcription, while simultaneously increasing the transcription of pro-apoptotic/anti-proliferative PTEN
eff↑, In mice, the administration of a combination of celecoxib and atorvastatin was more effective than each individual treatment, and effectively prevented prostate cancer progression from androgen dependent to androgen independent
OS↑, Long-term statin use may improve survival in GBM patients treated with temozolomide chemotherapy
Remission↑, statin use during or after chemotherapy is not associated with improved disease-free-, recurrence-free-, or overall survival in stage II colon cancer patients

4978- ATV,  Rad,    Atorvastatin Sensitizes Breast and Lung Cancer Cells to Ionizing Radiation
- in-vitro, BC, A549
Apoptosis↑, ATV increased the percentage of apoptotic cells in irradiated breast and lung cancer cells.
RadioS↑, demonstrates that ATV has radiosensitizing effect on breast and lung cancer cells through increasing apoptosis, ROS production and cell death induced by IR.
TumCP↓, ATV exhibited anti-proliferative effect on cancer cells and increased cell death induced by IR.
ROS↑, ATV increased ROS production in irradiated cells.

5362- AV,    Anti-cancer effects of aloe-emodin: a systematic review
- Review, Var, NA
AntiCan↑, Aloe-emodin possesses multiple anti-proliferative and anti-carcinogenic properties in a host of human cancer cell lines, with often multiple vital pathways affected by the same molecule.
eff↝, The effects of aloe-emodin are not ubiquitous across all cell lines but depend on cell type.
TumCP↓, most notable effects include inhibition of cell proliferation, migration, and invasion; cycle arrest; induction of cell death;
TumCMig↓,
TumCI↓,
TumCCA↑,
TumCD↑,
MMP↓, mitochondrial membrane and redox perturbations; and modulation of immune signaling.
ROS↑, which coincide with deleterious effects on mitochondrial membrane permea-bility and/or oxidative stress via exacerbated ROS production.
Apoptosis↑, In bladder cancer cells (T24), aloe-emodin induced time-and dose-dependent apoptosis [7]
CDK1↓, reduced levels of cyclin-dependent kinase (CDK) 1, cyclin B1, and BCL-2 after treatment with aloe-emodin.
CycB/CCNB1↓,
Bcl-2↓,
PCNA↓, Increases in cyclin B1, CDK1, and alkaline phosphatase (ALP) activity were observed along with inhibition of proliferating cell nuclear antigen (PCNA), showing decreased proliferation.
ATP↓, human lung non-small cell car¬cinoma (H460). They found a time- de¬pendent reduction in ATP, lower ATP synthase expression
ER Stress↑, hypothesized to cause apoptosis by augmenting endoplasmic reticulum stress [16].
cl‑Casp3↑, (HepG2) cells underwent apoptosis through a cas-pase-dependent pathway with cleavage and activation of caspases-3/9 and cleavage of PARP [24]
cl‑Casp9↑,
cl‑PARP↑,
MMP2↓, Matrix metalloproteinase-2 was significantly decreased, with an increase in ROS and cytosolic calcium.
Ca+2↑,
DNAdam↑, U87 malignant glioma cells through disruption of mitochondrial membrane potential, cell cycle arrest in the S phase, and DNA fragmentation in a time-dependent manner with minimal necrosis
Akt↓, Prostate cancer. Following treatment with aloe-emodin, mTORC2's down¬stream enzymes, AKT and PKCa, were inhibited
PKCδ↓,
mTORC2↓, Proliferation of PC3 cells was inhibited as a result of aloe-emodin binding to mTORC2, with inhibition of mTORC2 kinase activity.
GSH↓, Skin cancer. Intracellular ROS increased, while intra-cellular-reduced glutathione (GSH) was depleted and BCL-2 (anti-apoptotic protein) was down-regulated.
ChemoSen↑, Aloe-emodin also sensitizes skin cancer cells to chemo-therapy. aloe-emodin and emodin potentiated the therapeutic effects of cisplatin, doxo-rubicin, 5-fluorouracil

5567- B-Gluc,    Trained immunity: A new player in cancer immunotherapy
- Review, Var, NA
Imm↑, One of the most well-studied trained immunity inducers, β-glucan, has been shown to reprogram HSPCs in the bone marrow,
ROS↑, Trained neutrophils induced by β-glucan exhibit enhanced degranulation and increased production of reactive oxygen species, enabling direct tumor cell killing (Kalafati et al., 2020).
Apoptosis↑, orally administered yeast-derived particulate β-glucan treatment reduces tumor burden and decreases the accumulation of PMN-MDSC, while simultaneously inducing oxidative burst and apoptosis in these cells
OS↑, In metastatic breast cancer models, trained immunity induced by particulate β-glucan has been shown to significantly prolong survival and reduce lung metastases
TumMeta↓,
Dose↝, Currently, i.p. injection of β-glucan is considered the gold standard in preclinical studies, as it induces robust trained immunity in mice.

874- B-Gluc,    Potential promising anticancer applications of β-glucans: a review
- Review, NA, NA
AntiCan↑,
TumCG↓, reduced the tumor progression in S180 tumor-bearing mice
BAX↑, β-(1-3)-glucan has increased the Bax expression and decreased the Bcl-2 expression, which leads to apoptosis in S180 tumor-bearing mice.
Bcl-2↓,
IFN-γ↑, soluble β-glucan of low molecular weight enhanced IFN-γ production more efficiently than particle β-glucan of high molecular weight
PI3K/Akt↑, The binding of β-glucans to dectin-1 activates several signaling pathways such as PI3K/Akt, MAPK, NFAT, and NF-κB that result in ROS production, phagocytosis, and cytokine secretion
MAPK↑,
NFAT↑,
NF-kB↑,
ROS↑,
NK cell↑, β-glucans specifically activate and enhance the function of NK cells
TumCCA↑, Some β-glucans significantly induce the cell cycle arrest in the G1-phase due to the restriction of ERK1/2 or the ERK5 pathway, while others induce a gradual dose-dependent accumulation of cells at the G2/M phase along with a decrease in the populat
ERK↓, restricting the activity of the ERK1/2 pathway
Telomerase↓, β-glucans can also induce apoptosis by inhibiting the telomerase activity

996- Ba,  Tam,    Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α
Hif1a↓,
Glycolysis↓,
GlucoseCon↓,
lactateProd↓,
lact/pyru↓,
ROS↑, baicalein significantly increased mitochondrial ROS.
Apoptosis↑,

1053- Ba,  docx,    Baicalin, a Potent Inhibitor of NF-κB Signaling Pathway, Enhances Chemosensitivity of Breast Cancer Cells to Docetaxel and Inhibits Tumor Growth and Metastasis Both In Vitro and In Vivo
- in-vivo, BC, 4T1
TumCP↓,
Apoptosis↑,
ROS↑, cellular induction of reactive oxygen species
Bax:Bcl2↑,
NF-kB↓,
ChemoSen↑, BA sensitized BC cells to docetaxel (DXL) by suppressing the expression of survivin/Bcl-2
survivin↓,

2047- BA,    Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells
- in-vitro, CRC, T24/HTB-9 - in-vitro, Nor, SV-HUC-1 - in-vitro, Bladder, 5637 - in-vivo, NA, NA
HDAC↓, Sodium butyrate (NaB) is a histone deacetylase inhibitor and exerts remarkable antitumor effects in various cancer cells
AntiTum↑,
TumCMig↓, NaB inhibited migration
AMPK↑, induced AMPK/mTOR pathway-activated autophagy and reactive oxygen species (ROS) overproduction via the miR-139-5p/Bmi-1 axis
mTOR↑,
TumAuto↑,
ROS↑, NaB initiates ROS overproduction
miR-139-5p↑, NaB upregulates miR-139-5p and depletes Bmi-1 in bladder cancer cells
BMI1↓,
TumCI?, NaB significantly inhibited cell migration dose-dependently
E-cadherin↑, E-cadherin was markedly increased, while the expression of N-cadherin, Vimentin, and Snail was decreased
N-cadherin↓,
Vim↓,
Snail↓,
cl‑PARP↑, increased expression levels of cleaved PARP, cleaved caspase-3, and Bax and the concurrent decrease in Bcl-2 and Bcl-xl
cl‑Casp3↑,
BAX↑,
Bcl-2↓,
Bcl-xL↓,
MMP↓, impairs mitochondrial membrane potential
PINK1↑, activates the PINK1/ PARKIN pathway
PARK2↑,
TumMeta↓, NaB inhibits tumor metastasis and growth in vivo
TumCG↓,
LC3II↑, a significant increase in the levels of cleaved caspase3, p-AMPK, and LC3B-II along with decreased Bmi-1 and Vimentin
p62↓, elevated LC3B-II levels and degradation of p62
eff↓, NAC abolished the impairment of MMP and ROS overproduction. Interestingly, NAC also significantly inhibited apoptosis induced by NaB

1529- Ba,    Studies on the Inhibitory Mechanisms of Baicalein in B16F10 Melanoma Cell Proliferation
- in-vitro, Melanoma, B16-F10
ROS↑,
eff↓, ROS scavengers effectively reversed cell viability reduction induced by baicalein
tumCV↓,
Casp3↑,
necrosis↑,

1533- Ba,    Baicalein, as a Prooxidant, Triggers Mitochondrial Apoptosis in MCF-7 Human Breast Cancer Cells Through Mobilization of Intracellular Copper and Reactive Oxygen Species Generation
- in-vitro, BrCC, MCF-7 - in-vitro, Nor, MCF10
tumCV↓,
i-ROS↑, enhancement the level of intracellular ROS exhibit pro-oxidant activity in the presence of copper ions
MMP↓,
Bcl-2↓,
BAX↑,
Cyt‑c↑, release of cytochrome C
Casp9↑,
Casp3↑,
eff↓, The pretreatment with NeoCu (I)-specific chelator) remarkably weakened these effects of baicalein exhibit pro-oxidant activity in the presence of copper ions
selectivity↑, baicalein presented little cytotoxicity to normal breast epithelial cells
*toxicity∅, baicalein presented little cytotoxicity to normal breast epithelial cells. explained by the undetectable levels of copper present in MCF-10A cells.
Apoptosis↑,
Fenton↑, results are in further support that the prooxidant action of baicalein involves the reduction of Cu (II) to Cu (I), and the consequent generation of hydroxyl radicals.

1532- Ba,    Baicalein as Promising Anticancer Agent: A Comprehensive Analysis on Molecular Mechanisms and Therapeutic Perspectives
- Review, NA, NA
ROS↑, Baicalein initially incited the formation of ROS, which subsequently aimed at endoplasmic reticulum stress and stimulated the Ca2+/-reliant mitochondrial death pathway.
ER Stress↑,
Ca+2↑,
MMPs↓,
Cyt‑c↑, cytochrome C release
Casp3↑,
ROS↑, Baicalein on apoptosis in human bladder cancer 5637 cells was investigated, and it was found that it induces ROS generation
DR5↑, Baicalein activates DR5 up-regulation
ROS↑, MCF-7 cells by inducing mitochondrial apoptotic cell death. It does this by producing ROS, such as hydroxyl radicals, and reducing Cu (II) to Cu (I) in the Baicalein–Cu (II) system
BAX↑,
Bcl-2↓,
MMP↓,
Casp3↑,
Casp9↑,
P53↑,
p16↑,
P21↑,
p27↑,
HDAC10↑, modulating the up-regulation of miR-3178 and Histone deacetylase 10 (HDAC10), which accelerates apoptotic cell death
MDM2↓, MDM2-mediated breakdown
Apoptosis↑,
PI3K↓, baicalein-influenced apoptosis is controlled via suppression of the PI3K/AKT axis
Akt↓,
p‑Akt↓, by reducing the concentrations of p-Akt, p-mTOR, NF-κB, and p-IκB while increasing IκB expression
p‑mTOR↓,
NF-kB↓,
p‑IκB↓,
IκB↑,
BAX↑,
Bcl-2↓,
ROS⇅, Based on its metabolic activities and intensity, Baicalein can act as an antioxidant and pro-oxidant.
BNIP3↑, Baicalein also increases the production of BNIP3 which is a protein stimulated by ROS and promotes apoptosis
p38↑,
12LOX↓, inhibition of 12-LOX (Platelet-type 12-Lipoxygenase)
Mcl-1↓,
Wnt?, decreasing Wnt activity
GLI2↓, Baicalein significantly reduced the presence of Gli-2, a crucial transcription factor in the SHH pathway
AR↓, downregulating the androgen receptor (AR)
eff↑, PTX/BAI NE could increase intracellular ROS levels, reduce cellular glutathione (GSH) levels, and trigger caspase-3 dynamism in MCF-7/Tax cells. Moreover, it exhibited higher efficacy in inhibiting tumors in vivo

1528- Ba,    Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma
- in-vitro, OS, CAL27
Apoptosis↑,
ROS↑, baicalein triggered reactive oxygen species (ROS) generation in Cal27 cells
eff↓, Furthermore, N-acetyl-cysteine, a ROS scavenger, abrogated the effects of baicalein on ROS-dependent autophagy.
TumAuto↑, baicalein increased autophagy through the promotion of ROS signaling pathways in OSCC.
cl‑PARP↑,
Bax:Bcl2↑,
Beclin-1↑, enhancement of Beclin-1 and degradation of p62
p62↓,

1526- Ba,    Baicalein induces apoptosis through ROS-mediated mitochondrial dysfunction pathway in HL-60 cells
- in-vitro, AML, HL-60
Apoptosis↑, 100 microM for 6 h
cl‑PARP↑,
DNAdam↑, DNA fragmentation.
cl‑BID↑,
Cyt‑c↑, cytochrome c release from mitochondria into cytosol
Casp3↑,
Casp8↑,
Casp9?,
H2O2↑, baicalein caused elevation of intracellular hydrogen peroxide level
ROS↑, apoptotic death program through reactive oxygen species (ROS)-mediated mitochondrial dysfunction pathway

1525- Ba,  almon,    Synergistic antitumor activity of baicalein combined with almonertinib in almonertinib-resistant non-small cell lung cancer cells through the reactive oxygen species-mediated PI3K/Akt pathway
- in-vitro, Lung, H1975 - in-vivo, Lung, NA
eff↑, Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation
TumCP↓,
Apoptosis↑,
cl‑Casp3↑,
cl‑PARP↑,
cl‑Casp9↑,
p‑PI3K↓, combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.
p‑Akt↓,
ROS↑, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS)
eff↓, preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction

1524- Ba,    ROS_and_the_Activation_of_AMPK_in_Human_Lung_Carcinoma_A549_Cells">Baicalein Induces Caspase‐dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells
- in-vitro, Lung, A549
DR5↑, Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase‐8
FADD↑,
FasL↑,
Casp8↑,
cFLIP↓, reducing the levels of FLIPs
Casp3↑, activation of caspase‐9 and −3, and cleavage of poly(ADP‐ribose) polymerase
Casp9↑,
cl‑PARP↑,
MMP↓, baicalein caused a mitochondrial membrane potential (MMP),
BID↑, the truncation of Bid (means that the protein has been converted into an active form (tBid) that supports apoptosis.)
Cyt‑c↑, inducing the release of cytochrome c into the cytosol
ROS↑, baicalein increased the generation of reactive oxygen species (ROS)
eff↓, however, an ROS scavenger, N‐acetylcysteine, notably attenuated baicalein‐mediated loss of MMP and activation of caspases
AMPK↑,
Apoptosis↑,
TumCCA↑, sub-G1 phase
DR5↑, baicalein increased the expression of DR5 and FasL in a concentration-dependent manner, whereas the levels of DR4
FasL↑,
DR4∅,
cFLIP↓, baicalein reduced both FLIP(L) and FLIP(S) protein levels
FADD↑, increased FADD expression
MMPs↓, baicalein treatment reduced MMP levels in a concentrationdependent manner

1523- Ba,    ROS-induced_BNIP3_expression">Baicalein induces human osteosarcoma cell line MG-63 apoptosis via ROS-induced BNIP3 expression
- in-vitro, OS, MG63 - in-vitro, Nor, hFOB1.19
TumCD↑,
Apoptosis↑,
ROS↑, baicalein activated apoptosis through induced intracellular reactive oxygen species (ROS) generation
eff↓, and that ROS scavenger N-acetyl-cysteine (NAC), glutathione (GSH), and superoxide dismutase (SOD) apparently inhibited intracellular ROS production, consequently attenuating the baicalein-induced apoptosis.
Casp3↑, Baicalein treatment markedly increased active caspase-3 expression
Bcl-2↓,
selectivity↑, baicalein influenced little growth reduction of hFOB1.19 cells. (normal cells)
Cyt‑c↑, release of cytochrome c from mitochondrial to cytosol
LDH?, (25 and 50 μM) induced increases of LDH release (2.2- and 3.6-folds) which showed the cytotoxicity of baicalein
BNIP3?, we conclude that baicalein induces ROS production and BNIP3 expression with the subsequent activation of Bax
BAX↑,

1520- Ba,    ROS_Generation_and_CHK2_Activation_in_Highly_Invasive_Human_Ovarian_Cancer_Cells">Baicalein Induces G2/M Cell Cycle Arrest Associated with ROS Generation and CHK2 Activation in Highly Invasive Human Ovarian Cancer Cells
- in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, TOV-21G
TumCG↓,
TumCCA↑, G2/M phase
ROS↑, Baicalein-induced G2/M phase arrest is associated with an increased reactive oxygen species (ROS) production, DNA damage, and CHK2 upregulation and activation
DNAdam↑,
Chk2↑,
Dose∅, produced significant ROS in a dose- and time-dependent manner in SKOV-3 cells
p‑γH2AX↑, baicalein treatment increased the phosphorylation of H2AX (γH2AX)
CDC25↓,
CHK1↓,
cycD1/CCND1↓,
eff↓, CHK2 inhibitor indeed reduced the extent of CHK2 phosphorylation (Figure 4A) and protected SKOV-3 cells from baicalein-mediated G2/M arrest (Fig
12LOX↓, the pro-oxidative effect of baicalein, a specific inhibitor of 12-LOX, on ovarian cancer cells may occur through inhibiting the activity of 12-LOX, thereby inducing the accumulation of hydroxyl radicals.

1519- Ba,    ROS">Baicalein inhibits KB oral cancer cells by inducing apoptosis via modulation of ROS
- in-vitro, Oral, KB
Apoptosis↑,
Dose∅, Baicalein at 40 μM significantly hindered human oral cancer KB cells
ROS↑, anticancer effect of baicalein is likely due to its potential to improve ROS level and hence the increased apoptotic activity.

2476- Ba,    Baicalein Induces Caspase-dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells
- in-vitro, Lung, A549
TumCG↓, baicalein-induced growth inhibition was associated with the induction of apoptosis in human lung carcinoma A549 cells.
Apoptosis↑,
DR5↑, Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase-8 by reducing the levels of FLIPs (FLICE-inhibitory proteins).
FasL↑,
FADD↑,
Casp8↑,
cFLIP↓,
Casp9↑, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase
Casp3↑,
cl‑PARP↑,
MMP↓, Additionally, baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro-apoptotic Bax to the mitochondria, thereby inducing the release of cytochrome c into the cytosol.
BID↑,
BAX↑,
Cyt‑c↑,
ROS↑, In turn, baicalein increased the generation of reactive oxygen species (ROS)
eff↓, however, an ROS scavenger, N-acetylcysteine, notably attenuated baicalein-mediated loss of MMP and activation of caspases.
AMPK↑, connected with ROS generation and AMPK activation.

2474- Ba,    Anticancer properties of baicalein: a review
- Review, Var, NA - in-vitro, Nor, BV2
ROS⇅, Like other flavonoids, baicalein can be either anti-oxidant or pro-oxidant, depending on its metabolism and concentration.
ROS↑, It is reported that baicalein generated ROS, subsequently caused endoplasmic reticulum (ER) stress, activated Ca2+-dependent mitochondrial death pathway, finally triggered apoptosis
ER Stress↑,
Ca+2↑,
Apoptosis↑,
eff↑, Due to this, ROS production is a mechanism shared by all non-surgical therapeutic approaches for cancer, including chemotherapy, radiotherapy and photodynamic therapy
DR5↑, baicalein-induced ROS generation up-regulated DR5 expression and then activated the extrinsic apoptotic pathway in human prostate cancer cells
12LOX↓, Baicalein is known as a 12-LOX inhibitor.
Cyt‑c↑, It markedly induced the release of Cytochrome c from mitochondria into the cytosol and activated Caspase-9, Caspase-7, and Caspase-3, concomitant with cleavage of the Caspase-3 substrate poly(ADP-ribose) polymerase
Casp7↑,
Casp9↑,
Casp3↑,
cl‑PARP↑,
TumCCA↑, Baicalein induces G1/S arrest due to increased Cyclin E expression, a major factor in the regulation of the G1/S checkpoint of the cell cycle, accompanied by reduced levels of Cdk 4 and Cyclin D1 in human lung squamous carcinoma (CH27) cells
cycE/CCNE↑,
CDK4↓,
cycD1/CCND1↓,
VEGF↓, In ovarian cancer cells, baicalein effectively lowered the protein level of VEGF, c-Myc, HIF-α, and NFκB
cMyc↓,
Hif1a↓,
NF-kB↓,
BioEnh↑, curcumin and high-dose (−)-epicatechin were demonstrated to subsequently increase the absorption of baicalein
BioEnh↑, Baicalein can increase the oral bioavailability of tamoxifen by inhibiting cytochrome P450 (CYP) 3A4-mediated metabolism of tamoxifen in the small intestine and/or liver,
P450↓,
*Hif1a↓, In BV2 microglia, baicalein suppressed expression of hypoxia-induced HIF-1α and hypoxia responsive genes, including inducible nitric oxide synthase (iNOS), COX-2, and VEGF, by inhibiting ROS and PI3K/Akt pathway (Hwang et al. 2008).
*iNOS↓,
*COX2↓,
*VEGF↓,
*ROS↓,
*PI3K↓,
*Akt↓,

2479- Ba,    Baicalein Overcomes Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance via Two Different Cell-Specific Pathways in Cancer Cells but not in Normal Cells
- in-vitro, HCC, SW480 - in-vitro, Pca, PC3
12LOX↓, Baicalein is also known as a selective 12-lipoxygenase (12-LOX) inhibitor
DR5↑, Baicalein induces DR5 mRNA and protein expression in SW480 cells
CHOP↑, CHOP is increased by baicalein and responsible for DR5 up-regulation in SW480 cells
ROS↑, ROS are responsible for DR5 up-regulation in PC3 cells, but not in SW480 cells
*ROS∅,
selectivity↑, ROS are responsible for DR5 up-regulation in PC3 cells, but not in SW480 cells

2606- Ba,    Baicalein: A review of its anti-cancer effects and mechanisms in Hepatocellular Carcinoma
- Review, HCC, NA
ChemoSen↑, In addition, the combination of baicalein and silymarin eradicates HepG2 cells efficiently superior to baicalein or silymarin alone
TumCP↓, Cell viability assays have demonstrated that baicalein is significantly cytotoxic against several HCC cell lines and can inhibit the proliferation of HCC cells through arresting the cell cycle.
TumCCA↑,
TumCMig↓, Baicalein has been proved to inhibit migration and invasion of human HCC cells by reducing the expression and their proteinase activity of matrix metalloproteinases (MMPs),
TumCI↓,
MMPs↓,
MAPK↓, A large number of studies found that baicalein could inhibit migration and invasion of cancer cells by targeting the MAPK, TGF-b/Smad4, GPR30 pathway and molecules such as, ezrin, zinc-finger protein X-linked (ZFX),
TGF-β↓,
ZFX↓,
p‑MEK↓, Baicalein could inhibited the phosphorylation of MEK1 and ERK1/2, leading to decreased expression and proteinase activity of MMP-2/9 and urokinase-type plasminogen activator (u-PA),
ERK↓,
MMP2↓,
MMP9↓,
uPA↓,
TIMP1↓, as well as increased expression of TIMP-1 and TIMP-2
TIMP2↓,
NF-kB↓, Additionally, the nuclear translocation of NF-kB/p50 and p65/RelA and the phosphorylation of I-kappa-B (IKB)-b could be down-regulated by baicalein
p65↓,
p‑IKKα↓,
Fas↑, Hep3 B cells via activating Fas, Caspase -2, -3, -8, -9, down-regulating Bcl-xL, and upregulating Bax [
Casp2↑,
Casp3↑,
Casp8↑,
Casp9↑,
Bcl-xL↓,
BAX↑,
ER Stress↑, baicalein could induced apoptosis via endoplasmic reticulum (ER) stress in SMMC-7721 and Bel-7402
Ca+2↑, increasing intracellular calcium(Ca2+ ), and activating JNK pathwa
JNK↑,
P53↑, selectively induce apoptosis in HCC J5 cells via upregulation of p53
ROS↑, baicalein could induced cell apoptosis through regulating ROS via increasing intracellular H2O 2 level [
H2O2↑,
cMyc↓, baicalein could promote apoptosis in HepG2 and Bel-7402 cells through inhibiting c-Myc and CD24 expression
CD24↓,
12LOX↓, baicalein could induced cell apoptosis in SMMC-7721 and HepG2 cells by specifically inhibiting expression of 12-lipoxygenase(12-LOX), a critical anti-apoptotic genes

2617- Ba,    Potential of baicalein in the prevention and treatment of cancer: A scientometric analyses based review
- Review, Var, NA
Ca+2↑, MDA-MB-231 ↑Ca2+
MMP2↓, MDA-MB-231 ↓MMP-2/9
MMP9↓,
Vim↓, ↓Vimentin, ↓SNAIL, ↑E-cadherin, ↓Wnt1, ↓β-catenin
Snail↓,
E-cadherin↑,
Wnt↓,
β-catenin/ZEB1↓,
p‑Akt↓, MCF-7 ↓p-Akt, ↓p-mTOR, ↓NF-κB
p‑mTOR↓,
NF-kB↓,
i-ROS↑, MCF-7 ↑Intracellular ROS, ↓Bcl-2, ↑Bax, ↑cytochrome c, ↑caspase-3/9
Bcl-2↓,
BAX↑,
Cyt‑c↑,
Casp3↑,
Casp9↑,
STAT3↓, 4T1, MDA-MB-231 ↓STAT3, ↓ IL-6
IL6↓,
MMP2↓, HeLa ↓MMP-2, ↓MMP-9
MMP9↓,
NOTCH↓, ↓Notch 1
PPARγ↓, ↓PPARγ
p‑NRF2↓, HCT-116 ↓p-Nrf2
HK2↓, ↓HK2, ↓LDH-A, ↓PDK1, ↓glycolysis, PTEN/Akt/HIF-1α regulation
LDHA↓,
PDK1↓,
Glycolysis↓,
PTEN↑, Furthermore, baicalein inhibited hypoxia-induced Akt phosphorylation by promoting PTEN accumulation, thereby attenuating hypoxia-inducible factor-alpha ( HIF-1a) expression in AGS cells.
Akt↓,
Hif1a↓,
MMP↓, SGC-7901 ↓ΔΨm
VEGF↓, ↓VEGF, ↓VEGFR2
VEGFR2↓,
TOP2↓, ↓Topoisomerase II
uPA↓, ↓u-PA, ↓TIMP1, ↓TIMP2
TIMP1↓,
TIMP2↓,
cMyc↓, ↓β-catenin, ↓c-Myc, ↓cyclin D1, ↓Axin-2
TrxR↓, EL4 ↓Thioredoxin reductase, ↑ASK1,
ASK1↑,
Vim↓, ↓vimentin
ZO-1↑, ↑ZO-1
E-cadherin↑, ↑E-cadherin
SOX2↓, PANC-1, BxPC-3, SW1990 ↓Sox-2, ↓Oct-4, ↓SHH, ↓SMO, ↓Gli-2
OCT4↓,
Shh↓,
Smo↓,
Gli1↓,
N-cadherin↓, ↓N-cadherin
XIAP↓, ↓XIAP

2626- Ba,    Molecular targets and therapeutic potential of baicalein: a review
- Review, Var, NA - Review, AD, NA - Review, Stroke, NA
AntiCan↓, anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects
*neuroP↑,
*cardioP↑, Cardioprotective action of baicalein
*hepatoP↑,
*RenoP↑, baicalein’s capacity to lessen cisplatin-induced nephrotoxicity is probably due, at least in part, to the attenuation of renal oxidative and/or nitrative stress
TumCCA↑, Baicalein induces G1/S arrest in lung squamous carcinoma (CH27) cells by downregulating CDK4 and cyclin D1, as well as upregulating cyclin E
CDK4↓,
cycD1/CCND1↓,
cycE/CCNE↑,
BAX↑, SGC-7901 cells showed that when baicalein was administered, Bcl-2 was downregulated and Bax was increased
Bcl-2↓,
VEGF↓, Baicalein inhibits the synthesis of vascular endothelial growth factor (VEGF), HIF-1, c-Myc, and nuclear factor kappa B (NF-κB) in the G1 and S phases of ovarian cancer cell
Hif1a↓,
cMyc↓,
NF-kB↓,
ROS↑, Baicalein produced intracellular reactive oxygen species (ROS) and activated BNIP3 to slow down the development and hasten the apoptosis of MG-63,OS cell
BNIP3↑,
*neuroP↑, Baicalein exhibits neuroprotective qualities against amyloid (AN) functions by preventing AN from aggregating in PC12 neuronal cells to cause A𝛽-induced cytotoxicity
*cognitive↑, baicalein encourages non-amyloidogenic processing of APP, which lowers the generation of A𝛽 and enhances cognitive function
*NO↓, baicalein effectively reduced NO generation and iNOS gene expression
*iNOS↓,
*COX2↓, Baicalein therapy significantly decreased the expression of COX-2 and iNOS, as well as PGE2 and NF-κB, indicating a protective effect against cerebral I/R injury.
*PGE2↓,
*NRF2↑, Baicalein therapy markedly elevated nuclear Nrf2 expression and AMPK phosphorylation in the ischemic cerebral cortex
*p‑AMPK↑,
*Ferroptosis↓, Baicalein suppressed ferroptosis associated with 12/15-LOX, hence lessening the severity of post-traumatic epileptic episodes generated by FeCl3
*lipid-P↓, HT22 cells were damaged by ferroptosis, which is mitigated by baicalein may be due to its lipid peroxidation inhibitor
*ALAT↓, Baicalin lowers the raised levels of hepatic markers alanine transaminase (ALT), aspartate aminotransferase (AST)
*AST↓,
*Fas↓, Baicalin has also been shown to suppress apoptosis, decrease FAS protein expression, block the caspase-8 pathway, and decrease Bax protein production
*BAX↓,
*Apoptosis↓,

2615- Ba,    The Multifaceted Role of Baicalein in Cancer Management through Modulation of Cell Signalling Pathways
- Review, Var, NA
*AntiCan↓, Baicalein is known to display anticancer activity through the inhibition of inflammation and cell proliferation
*Inflam↓,
TumCP↓,
NF-kB↓, baicalein decreased the activation of nuclear factor-κB (NF-κB)
PPARγ↑, anti-inflammatory effects of baicalein might be initiated via PPARγ activation.
TumCCA↑, baicalein inhibited cell cycle progression and cell growth, and promoted apoptosis of cancer cells
JAK2↓, inactivation of the signaling pathway JAK2/STAT3 [63]
STAT3↓,
TumCMig↓, baicalein suppressed migration as well as invasion through decreasing the aerobic glycolysis and expression of MMP-2/9 proteins.
Glycolysis↓,
MMP2↓,
MMP9↓,
selectivity↑, Furthermore, baicalein and baicalin had less inhibitory effects on normal ovarian cells’ viability.
VEGF↓, baicalein is more effective in inhibiting the expressions of VEGF, HIF-1α, cMyc, and NFκB
Hif1a↓,
cMyc↓,
ChemoSen↑, baicalein enhanced the cisplatin sensitivity of SGC-7901/DDP gastric cancer cells by inducing autophagy and apoptosis through the Akt/mTOR and Keap 1/Nrf2 pathways
ROS↑, oral squamous cell carcinoma Cal27 cells. Significantly, it was noticed that baicalein activated reactive oxygen species (ROS) generation in Cal27 cells
p‑mTOR↓, results suggest that p-mTOR, p-Akt, p-IκB, and NF-κB protein expressions were decreased
PTEN↑, Baicalein upregulated PTEN expression, downregulated miR-424-3p, and downregulated PI3K and p-Akt.

2295- Ba,  5-FU,    Baicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1α signaling pathway
- in-vitro, GC, AGS
ChemoSen↑, baicalein increased the sensitivity of AGS cells to 5-FU treatment under hypoxia
HK2↓, hypoxia-enhanced glycolytic flux and expression of several critical glycolysis-associated enzymes (HK2, LDH-A and PDK1) in the AGS cells were suppressed by baicalein
LDHA↓,
PDK1↓,
Akt↓, baicalein inhibited hypoxia-induced Akt phosphorylation by promoting PTEN accumulation, thereby attenuating hypoxia-inducible factor-1α (HIF-1α) expression in AGS cells
PTEN↑,
Hif1a↓,
Glycolysis↓, results together suggest that inhibition of glycolysis via regulation of the PTEN/Akt/HIF-1α signaling pathway may be one of the mechanisms whereby baicalein reverses 5-FU resistance in cancer cells under hypoxia.
ROS↑, Taniguchi et al found that baicalein overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in cancer cells through DR5 upregulation mediated by ROS induction and CHOP/GADD153 activation
CHOP↑,

2296- Ba,    The most recent progress of baicalein in its anti-neoplastic effects and mechanisms
- Review, Var, NA
CDK1↓, graphical abstract
Cyc↓,
p27↑,
P21↑,
P53↑,
TumCCA↑, Cell cycle arrest
TumCI↓, Inhibit invastion
MMP2↓,
MMP9↓,
E-cadherin↑,
N-cadherin↓,
Vim↓,
LC3A↑,
p62↓,
p‑mTOR↓,
PD-L1↓,
CAFs/TAFs↓,
VEGF↓,
ROCK1↓,
Bcl-2↓,
Bcl-xL↓,
BAX↑,
ROS↑,
cl‑PARP↑,
Casp3↑,
Casp9↑,
PTEN↑, A549, H460
MMP↓, ↓mitochondrial transmembrane potential, redistribution of cytochrome c,
Cyt‑c↑,
Ca+2↑, ↑Ca2+
PERK↑, ↑PERK, ↑IRE1α, ↑CHOP,
IRE1↑,
CHOP↑,
Copper↑, ↑Cu+2
Snail↓, ↓Snail, ↓vimentin, ↓Twist1,
Vim↓,
Twist↓,
GSH↓, ↑ROS, ↓GSH, ↑MDA, ↓MMP, ↓NRF2, ↓HO-1, ↓GPX4, ↓FTH1, ↑TFR1, ↓p-JAK2, ↓p-STAT3
NRF2↓,
HO-1↓,
GPx4↓,
XIAP↓, ↓Bcl-2, ↓Bcl-xL, ↓XIAP, ↓surviving
survivin↓,
DR5↑, ↑ROS, ↑DR5

5501- Ba,    Therapeutic effects and mechanisms of action of Baicalein on stomach cancer: a comprehensive systematic literature review
- Review, GC, NA
AntiCan↑, The review demonstrated that BC exerts therapeutic effects on GC through multiple biochemical mechanisms.
Apoptosis↑, BC plays an important role in inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis in GC cells.
TumCP↓,
TumMeta↓,
BAX↑, graphical abstract
TumAuto↑,
ROS↑,
NRF2↝, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
PI3K↓,
Akt↓,
NF-kB↓,
TGF-β↓,
SMAD4↓,
GPx4↓, It induces autophagy and ferroptosis, partly through p53 activation and suppression of SLC7A11/GPX4, and disrupts mitochondrial membrane potential via reactive oxygen species (ROS) generation [31, 37]
MMP↓,
*HO-1↑, BC stabilizes Nrf2, leading to the induction of antioxidant enzymes such as HO-1, GST, and NQO1, which mitigate oxidative stress and contribute to its antitumor effects [38].
*GSTs↑,
*antiOx↑,
*AntiTum↑,
*NRF2↑,
ChemoSen↑, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
Akt↓,
mTOR↓,
FAK↓, reducing FAK expression
Ki-67↓, Immunohistochemical analysis also revealed lower Ki-67 levels, indicating reduced cellular proliferation.

5502- Ba,    An overview of pharmacological activities of baicalin and its aglycone baicalein: New insights into molecular mechanisms and signaling pathways
- Review, Var, NA
*AntiCan↑, antibacterial, antiviral, anticancer, anticonvulsant, anti-oxidant, hepatoprotective, and neuroprotective effects.
*antiOx↑,
*hepatoP↑,
*neuroP↑,
*ROS↓, pharmacological properties of baicalin and baicalein are due to their abilities to scavenge reactive oxygen species (ROS)
Ca+2↑, Baicalein mainly induced apoptosis through Ca+2 influx via Ca2+ release from the reticulum to cytosol dependent on phospholipase C protein
ROS↑, ROS production is associated with baicalein-induced apoptosis via Ca2+-dependent apoptosis in tongue and breast cancer cells (78, 79)
BAX↑, The level of Bax/Bcl-2 increased and caspase-3 and -9 were activated following the release of cytochrome C (80).
Casp3↑,
Casp9↑,
Cyt‑c↑,
MMP↓, In gastric cancer cells, baicalein mediated apoptosis in a dose-dependent manner through disruption of mitochondrial membrane potential
Mcl-1↓, In pancreatic cancer cells, baicalein induced apoptosis via suppression of the Mcl-1 protein.
PI3K↓, In HepG2 cells, baicalin-copper induced apoptosis through down-regulation of phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway
Akt↓,
mTOR↓,
BAD↓, Studies demonstrated that baicalein treatment suppressed Bad, ERK1/2 phosphorylation, and MEK1 expression both in vitro and in vivo.
ERK↓,
MEK↓,
DR5↑, Baicalein enhanced the activity of death receptor-5 (DR5) in prostate cancer PC3 cells.
Fas↑, baicalin is the active ingredient that acts as Fas ligand and caused up-regulation of Fas protein (89).
TumMeta↓, Baicalin/baicalein not only induced apoptosis in cancer cells but also suppressed metastasis.
EMT↓, both baicalin and baicalein inhibited epithelial-mesenchymal transition (EMT) through the suppression of TGF-β in breast epithelial cells through the NF-κB pathway (92).
SMAD4↓, baicalein suppressed metastasis in gastric cancer through inactivation of the Smad4/TGF-β pathway (93).
TGF-β↓,
MMP9↓, baicalin and baicalein inhibition of the expression level of matrix metalloproteinases (MMP) such as MMP-9 and MMP-2 in liver, breast, lung, ovarian, gastric, and colorectal cancers and glioma
MMP2↓,
HIF-1↓, Baicalin attenuated lung metastasis through inhibition of hypoxia-inducible factor (HIF)
12LOX↓, Baicalein acts as an anticancer agent via inhibiting 12-lipooxygenase (12-LOX),

5250- Ba,    Exploring baicalein: A natural flavonoid for enhancing cancer prevention and treatment
- Review, Var, NA
Apoptosis↑, Baicalein is thought to prevent cancer progression by inducing apoptosis, autophagy, and genome instability, and its ability to promote chemo-potentiation, anti-metastatic effects, and regulate specific signalling molecules and transcription factors.
TumAuto↑,
DNAdam↑,
*antiOx↑, Baicalein has already been proven to be a radical scavenger that acts as an antioxidant [14,15
Inflam↓, it can also reduce inflammation [16] and act as an E2 prostaglandin inhibitor [17].
PGE2↓,
TumCCA↑, Baicalein properties prevent cell proliferation, induce apoptosis, autophagy, cell cycle arrest, cancer cell migration and invasion, and decrease angiogenesis [18,19].
TumCMig↓,
TumCI↓,
angioG↓,
selectivity↑, Furthermore, some studies have suggested that baicalein has a lower toxicity on normal cells than cancer cells, indicating some selectivity for cancer cells.
ChemoSen↑, the current review emphasises baicaleins' synergistic potential with other chemotherapeutic agents
HIF-1↓, baicalein against ovarian cancer by demonstrating that it can limit tumour cell viability by downregulating the expression of cancer-promoting genes such as HIF-1, cMyc, NFkB, and VEGF
cMyc↓,
NF-kB↓,
VEGF↓,
P53↑, Baicalein has been shown to activate p53, a tumour suppressor protein that regulates cell growth and division [26].
MMP2↓, anticancer properties of baicalein are mediated through various molecular mechanisms, including inhibition of MMP-2;
CSCs↓, inhibition of cancer stem cells
Bcl-xL↓, after bladder cancer cells were treated with baicalein, the expression of antiapoptotic genes (Bcl2, Bcl-xL, XIAP, and survivin) was reduced, and cell viability was decreased [38].
XIAP↓,
survivin↓,
tumCV↓,
Casp3↑, upregulating the expression of caspase-3 and caspase-8 and decreased the BCL-2/BAX ratio [16]
Casp8↑,
Bax:Bcl2↑,
Akt↓, in lung cancer cells, apoptosis was induced through the downregulation of the Akt/mTOR signalling pathway [25].
mTOR↓,
PCNA↓, baicalein treatment promoted apoptosis in mice with U87 gliomas by downregulating PCNA expression, enhancing the expression of caspase-3 and caspase-9 and improving the Bax/Bcl-2 ratio
MMP↓, baicalein treatment of lung cancer cells caused a collapse of the mitochondrial membrane potential (MMP), an increase in ROS generation, and enhanced PARP, caspase 3, and caspase 9 cleavage,
ROS↑,
PARP↑,
Casp9↑,
BioAv↑, Baicalein has been found to enhance the cytotoxicity and bioavailability of certain cancer therapy drugs when combined [85]
eff↑, combination of baicalein with silymarin differentially decreased the viability of HepG2 cells, enhanced the proportion of cells in the G0/G1 phase, upregulated tumour suppressors such as Rb and p53 and CDK inhibitors, and downregulated cyclin D1, cyc
P-gp↓, By inhibiting P-glycoprotein (P-gp), baicalein can increase the accumulation of chemotherapeutic drugs within cancer cells [21]
BioAv↑, selenium–baicalein nanoparticles as a targeted therapeutic strategy for NSCLC. This strategy significantly improves the bioavailability of baicalein through several mechanisms.
selectivity↑, ome studies have suggested that baicalein has a lower toxicity on normal cells than cancer cells, indicating some selectivity for cancer cells

5251- Ba,    The Fascinating Effects of Baicalein on Cancer: A Review
- Review, Var, NA
AntiTum↑, The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammali
TumCCA↓,
ROS↓,
MAPK↓,
Akt↓,
mTOR↓,
Casp3↑, , to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9).
Casp9↑,
TumCI↓,
TumMeta↓,
MMP2↓,
MMP9↓,
Securin↓, Baicalein also induced cell death by reducing the expression of securin, while also inhibiting cancer cell death by affecting the expression of p-AKT and γ-H2AX [26].
γH2AX↝,
N-cadherin↓, Baicalein also decreased the expression of metastasis-associated molecules, including N-cadherin, vimentin, ZEB1, and ZEB2.
Vim↓,
Zeb1↓,
ZEB2↓,
TumCMig↓, researchers demonstrated that baiclalein inhibited cellular adhesion, migration, invasion, and growth of HCC cells both in vitro and in vivo.
TumCG↑,
12LOX↓, Baicalein is an inhibitor of 12-LOX and induced apoptosis, morphological changes, and carbonic anhydrase expression in PaCa cells.
DR5↑, Baicalein lessened this resistance to TRAIL by upregulating DR5 expression and promoting the expression of ROS, thus causing TRAIL sensitization in PC3 cells [85]
ROS↑,
RadioS↑, baicalein increased the sensitivity of prostate cancer cells to radiation without affecting this sensitivity in normal cells
ChemoSen↑, Combination therapy of baicalein with paclitaxel, which were assembled by nanoparticles, was demonstrated to have synergistic anticancer effects in A549 lung cancer cells and in mice bearing A549/PTX drug-resistant lung cancer xenografts [97].
BioAv↓, It is worth noting that the bioavailability of baicalein in vivo remains low.

5544- BBM,    Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis
- in-vitro, AML, THP1
ROS↑, BBM increased intracellular reactive oxygen species (ROS)
Ca+2↑, the increased intracellular Ca2+ concentration induced by BBM

5542- BBM,    Pharmacological profiling of a berbamine derivative for lymphoma treatment
- vitro+vivo, lymphoma, NA
CaMKII ↓, PA4 is a potent CAMKIIγ inhibitor.
TumCG↓, PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model.
cMyc↓, PA4 reduced c-Myc levels and induced ROS in lymphoma cells
ROS↑,
UPR↑, Unfolded protein response (UPR) was elevated after PA4 treatment
ER Stress↑, UPR induces ER stress
PERK↑, PA4 treatment significantly increased protein kinase RNA-like ER kinase (PERK)
BioAv↑, Both BBM and PA4 were rapidly absorbed into the blood and detected 5 minutes after oral administration.
toxicity↓, mice received oral gavage with 50 mg/kg PA4 daily for 12 consecutive days (n = 6). After 12 days, there were no mortalities and no significant reductions in body weight (Figure 7D). Serum alanine aminotransferase and aspartate aminotransferase levels

5536- BBM,    Regulation of Cell-Signaling Pathways by Berbamine in Different Cancers
- Review, Var, NA
JAK↝, In this review, we comprehensively analyze how berbamine modulates deregulated pathways (JAK/STAT, CAMKII/c-Myc) in various cancers.
STAT3↓, Berbamine physically interacted with STAT3 and inhibited its activation [8].
p‑CaMKII ↓, An orally administered, bioactive small molecule analog of berbamine, tosyl chloride-berbamine (TCB), considerably reduced phosphorylated levels of CaMKIIγ
TGF-β↑, berbamine induces activation of the TGF/SMAD pathway for the effective inhibition of cancer progression.
Smad1↑,
ChemoSen↑, Berbamine enhanced the chemosensitivity of gefitinib against PANC-1 and MIA PaCa-2 cancer cells [8].
RadioS↑, Moreover, berbamine and radiation effectively induced a regression of the tumors in mice subcutaneously injected with FaDu cells [10].
TumCI↓, berbamine-GMO-TPGS nanoparticles showed superior cellular toxicity, as well as an inhibition of migration and invasion in metastatic breast cancer MDA-MB-231,
TumCMig↓,
ROS↑, Berbamine increased the intracellular ROS levels via the downregulation of antioxidative genes such as NRF2, SOD2, GPX-1 and HO-1.
NRF2↓,
SOD2↓,
GPx1↓,
HO-1↓,

5549- BBM,    Synergistic Anticancer Effect of a Combination of Berbamine and Arcyriaflavin A against Glioblastoma Stem-like Cells
- in-vitro, GBM, NA
eff?, Combined treatment with berbamine and ArcA synergistically inhibited cell viability and tumorsphere formation in U87MG- and C6-drived GSCs.
tumCV↓,
TumCG↓, both compounds potently inhibited tumor growth in a U87MG GSC-grafted chick embryo chorioallantoic membrane (CAM) model.
ROS↑, anticancer effect of berbamine and ArcA on GSC growth is associated with the promotion of reactive oxygen species (ROS)- and calcium-dependent apoptosis
P53↑, ia strong activation of the p53-mediated caspase cascade.
CSCs↓, co-treatment with both compounds significantly reduced the expression levels of key GSC markers, including CD133, integrin α6, aldehyde dehydrogenase 1A1 (ALDH1A1), Nanog, Sox2, and Oct4.
CD133↓,
ALDH1A1↓,
Nanog↓,
SOX2↓,
OCT4↓,
CDK1↓, downregulation of cell cycle regulatory proteins, such as cyclins and CDKs, by potent inactivation of the CaMKIIγ-mediated STAT3/AKT/ERK1/2 signaling pathway.
CaMKII ↓,
STAT3↓,
Akt↓,
ERK↓,

5553- BBM,    A review on berbamine–a potential anticancer drug
- Review, Var, NA
P-gp↓, Treatment with berbamine decreased P-glycoprotein (P-gp) expression and down-regulated expression of MDR1 (multi-drug resistance1) and survivin mRNA in K562/A02 cells
MDR1↓,
survivin↓,
NF-kB↓, decrease expression of nuclear factor-B (NF-B), phosphoIB, IKK, and survivin.
TumCP↓, In a chronic myeloid leukemia cell line KU812, berbamine inhibited cell proliferation in a time- and dose-dependent manner, with IC50 values for treatments of 24, 48, and 72 h at 5.83, 3.43, and 0.75 μg/ml, respectively.
TumCCA↑, Berbamine induced cell cycle arrest at the G1 phase and also induced apoptosis.
Apoptosis↑,
SMAD3↑, The compound up-regulated transcriptions of Smad3 and p21, and increased protein levels of both total Smad3 and phosphorylated Smad3.
P21↑,
cycD1/CCND1↓, The protein levels of cyclin D1 and c-Myc were reduced.
cMyc↑,
Bcl-2↓, The levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL were decreased, and the level of the pro-apoptotic protein Bax was increased.
Bcl-xL↓,
BAX↑,
CaMKII ↓, The compound has been shown to specifically bind to the ATP-binding pocket of calmodulin kinase (CAMK)II, inhibit its phosphorylation, and trigger apoptosis.
ChemoSen↑, Berbamine also significantly enhanced the activity of anticancer drugs like trichostatin A and celecoxib.
MMP2↓, EBB down-regulated the activities and mRNA levels of matrix metalloproteinases (MMP) 2 and 9, and up-regulated the mRNA levels of tissue inhibitor of metalloproteinases (TIMP) 1.
MMP9↓,
TIMP1↑,
cl‑Casp3↑, induction of apoptosis, including activation and cleavage of caspases 3, 8, 9 and PARP.
cl‑Casp9↑,
cl‑Casp8↑,
cl‑PARP↑,
IL6↓, BBD inhibited autocrine IL-6 production, and down-regulated membrane IL-6 receptor (IL-6R) expression.
ROS↑, Production of reactive oxygen species (ROS) was increased by BBMD3 in these cells.

5551- BBM,    Berbamine Suppresses the Progression of Bladder Cancer by Modulating the ROS/NF-κB Axis
- vitro+vivo, Bladder, NA
tumCV↓, our results showed that berbamine inhibited cell viability, colony formation, and proliferation.
TumCP↓,
TumCCA↑, Additionally, berbamine induced cell cycle arrest at S phase by a synergistic mechanism involving stimulation of P21 and P27 protein expression
P21↑,
p27↑,
cycD1/CCND1↓, as well as downregulation of CyclinD, CyclinA2, and CDK2 protein expression.
cycA1/CCNA1↓,
CDK2↓,
EMT↓, In addition to suppressing epithelial-mesenchymal transition (EMT), berbamine rearranged the cytoskeleton to inhibit cell metastasis.
TumMeta↓,
p65↓, Mechanistically, the expression of P65, P-P65, and P-IκBα was decreased upon berbamine treatment
p‑p65↓,
IKKα↓,
NF-kB↑, berbamine attenuated the malignant biological activities of BCa cells by inhibiting the NF-κB pathway.
ROS↑, More importantly, berbamine increased the intracellular reactive oxygen species (ROS) level through the downregulation of antioxidative genes such as Nrf2, HO-1, SOD2, and GPX-1.
NRF2↓,
HO-1↓,
SOD2↓,
GPx1↓,
Bax:Bcl2↑, increase in the ratio of Bax/Bcl-2.
TumVol↓, berbamine successfully inhibited tumor growth and blocked the NF-κB pathway in our xenograft model

1385- BBR,  5-FU,    Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
eff↓, Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents
ROS↑, LDB mildly while HDB greatly stimulated ROS generation BBR-induced ROS generation may activate the antioxidant response therefore to promote cancer cell proliferation.
TumCP↑,
NRF2↑,
ChemoSen↓, These findings revealed a potential negative impact of BBR on its adjuvant anti-breast cancer therapy

1398- BBR,    Berberine inhibits the progression of renal cell carcinoma cells by regulating reactive oxygen species generation and inducing DNA damage
- in-vitro, Kidney, NA
TumCP↓,
TumCMig↓,
ROS↑,
Apoptosis↑,
BAX↑,
BAD↑,
Bak↑,
Cyt‑c↑,
cl‑Casp3↑,
cl‑Casp9↑,
E-cadherin↑,
TIMP1↑,
γH2AX↑,
Bcl-2↓,
N-cadherin↓,
Vim↓,
Snail↓,
RAD51↓,
PCNA↓,

1397- BBR,  Chemo,    Effects of Coptis extract combined with chemotherapeutic agents on ROS production, multidrug resistance, and cell growth in A549 human lung cancer cells
- in-vitro, Lung, A549
TumCG↓,
ROS↑, COP and BER increased ROS production and reduced MDR in A549 cells.
MDR1↓, reduce MDR

1395- BBR,    Analysis of the mechanism of berberine against stomach carcinoma based on network pharmacology and experimental validation
- in-vitro, GC, NA
Apoptosis↑,
ROS↑,
MMP↓,
ATP↓,
AMPK↑,
TP53↑,
p‑MAPK↓, decreased phosphorylated-MAPK3/1 expression
p‑ERK↓,

1394- BBR,  DL,    Synergistic Inhibitory Effect of Berberine and d-Limonene on Human Gastric Carcinoma Cell Line MGC803
- in-vitro, GC, MGC803
eff↑, Berberine and d-limonene at a combination ratio of 1:4 exhibited a synergistic effect
ROS↑,
MMP↓,
Casp3↑,
Bcl-2↓,
TumCCA↑,

1393- BBR,  EPI,    Berberine promotes antiproliferative effects of epirubicin in T24 bladder cancer cells by enhancing apoptosis and cell cycle arrest
- in-vitro, Bladder, T24/HTB-9
ChemoSen↑, Ber enhanced the inhibitory effect of EPI on the viability of T24 cells
TumCCA↑, cycle arrest at G0/G1
Apoptosis↑,
cl‑Casp3↑,
cl‑Casp9↑,
BAX↑,
P53↑,
P21↑,
Bcl-2↓,
ROS↑, Ber significantly increased ROS production

1392- BBR,    Based on network pharmacology and experimental validation, berberine can inhibit the progression of gastric cancer by modulating oxidative stress
- in-vitro, GC, AGS - in-vitro, GC, MKN45
TumCG↓,
TumCMig↓,
ROS↑, intracellular
MDA↑, intracellular
SOD↓, intracellular
NRF2↓,
HO-1↓,
Hif1a↓,
EMT↓,
Snail↓,
Vim↓,

1390- BBR,  Rad,    Berberine Inhibited Radioresistant Effects and Enhanced Anti-Tumor Effects in the Irradiated-Human Prostate Cancer Cells
- in-vitro, Pca, PC3
RadioS↑, cytotoxic effect of the combination of berberine and irradiation was superior to that of berberine or irradiation alone
Apoptosis↑,
ROS↑, ROS generation was elevated by berberine with or without irradiation.
eff↑, antioxidant NAC inhibited berberine and radiation-induced cell death.
BAX↑,
Casp3↑,
P53↑,
p38↑,
JNK↑,
Bcl-2↓,
ERK↓,
HO-1↓,

1389- BBR,  Lap,    Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS
- in-vitro, BC, BT474 - in-vitro, BC, AU-565
ChemoSen↑, combination therapy of berberine with lapatinib overcame lapatinib resistance.
Apoptosis↑,
ROS↑,
NRF2↓, Berberine reverses lapatinib resistance by inhibiting the Nrf2 signaling pathway

1299- BBR,    Effects of Berberine and Its Derivatives on Cancer: A Systems Pharmacology Review
- Review, NA, NA
TumCCA↑, G1 phase, G0/G1 phase, or G2/M phase
TP53↑,
COX2↓,
Bax:Bcl2↑,
ROS↑,
VEGFR2↓,
Akt↓,
ERK↓,
MMP2↓, Berberine also decreased MMP-2, MMP-9, E-cadherin, EGF, bFGF, and fibronectin in the breast cancer cells.
MMP9↓,
IL8↑,
P21↑,
p27↑,
E-cadherin↓,
Fibronectin↓,
cMyc↓, The results indicated that these derivatives could selectively induce and stabilize the formation of the c-myc in the parallel molecular G-quadruplex. Accordingly, transcription of c-myc was down-regulated in the cancer cell line

1387- BBR,    Antitumor Activity of Berberine by Activating Autophagy and Apoptosis in CAL-62 and BHT-101 Anaplastic Thyroid Carcinoma Cell Lines
- in-vitro, Thyroid, CAL-62
TumCG↓,
Apoptosis↑,
LC3B↑, LC3B-II
ROS↑,
PI3K↓,
Akt↓,
mTOR↓,

1386- BBR,    Berberine-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species generation and mitochondrial-related apoptotic pathway
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
tumCV↓,
ROS↑,
JNK↑,
MMP↓,
Bcl-2↓,
BAX↑,
Cyt‑c↑, increased the release of cytochrome c
AIF↝,

1396- BBR,    Berberine induced down-regulation of matrix metalloproteinase-1, -2 and -9 in human gastric cancer cells (SNU-5) in vitro
- in-vitro, GC, SNU1041 - in-vitro, GC, SNU5
tumCV↓,
ROS↑,
MMP1↓, berberine induced downregulation of MMP-1 -2, and -9 but did not affect the level of MMP-7
MMP2↓,
MMP9↓,
MMP7∅,

1384- BBR,    Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines
- in-vitro, PC, PANC1
TumCCA↑, inducing G1-phase arrest
ROS↑, In cells treated with 10 µM berberine, ROS production increased 2.6-fold relative to control cells
Apoptosis↑,

1374- BBR,  PDT,    Berberine associated photodynamic therapy promotes autophagy and apoptosis via ROS generation in renal carcinoma cells
- in-vitro, RCC, 786-O - in-vitro, RCC, HK-2
ROS↑,
TumAuto↑,
Apoptosis↑,
Casp3↑,
eff↑, HK-2 treated with BBR associated with PDT showed a significant decrease in the cellular viability compared to the control cells

1375- BBR,    13-[CH2CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein
- in-vitro, CRC, HCT8 - in-vivo, NA, NA
ROS↑,
TumCP↓, 2-5X lower IC50 than normal BBR
XIAP↓,
TumCG↓,
*toxicity↓, 13-Cys-BBR Had No Kidney And Liver Toxicity

1376- BBR,  immuno,    Berberine sensitizes immune checkpoint blockade therapy in melanoma by NQO1 inhibition and ROS activation
- in-vivo, Melanoma, NA
OS↑, BBR could sensitize ICB to inhibit tumor growth and increased the survival rate of mice.
ROS↑,
NQO1↓,
ICD↑,

1379- BBR,    Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells
- in-vitro, lymphoma, NA
TumCP↓,
CDK4↓,
CDK6↓,
cycD1/CCND1↓,
TumCCA↑, G0/G1 phase
MMP↓,
Ca+2↑,
ATP↓, decreased intracellular adenosine triphosphate production,
mtDam↑, mitochondrial dysfunction
Apoptosis↑,
ROS↑,
JNK↑,
eff↓, treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358.

1381- BBR,  Rad,    Berberine enhances the sensitivity of radiotherapy in ovarian cancer cell line (SKOV-3)
- in-vitro, Ovarian, SKOV3
RadioS↑, berberine might be a capable radiosensitizer for treating SKOV-3, because of oxidative DNA damage
ROS↑,
GSH↓, decreased level of (GSH) content supported the elevated ROS generation data
Apoptosis↑,

1382- BBR,    Berberine increases the expression of cytokines and proteins linked to apoptosis in human melanoma cells
- in-vitro, Melanoma, SK-MEL-28
Apoptosis↑,
necrosis↑,
DNAdam↑, increase in the DNA damage index
TumCCA↑, G1/G0 phase
ROS↑, The alcaloid increased (****p < 0.001) ROS production compared to untreated controls with an increase in activated caspase 3 and phosphorylated p53 protein levels
Casp3↑,
p‑P53↑,
ERK↑, BBR significantly enhanced ERK as well as both pro- and anti-inflammatory cytokine expression compared to untreated controls.

1400- BBR,    Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells
- in-vitro, Melanoma, U266
ROS↑,
TumCCA↑, G2/M phase arrest
Apoptosis↑,
miR-21↓,
Bcl-2↓,
NF-kB↓, 80 μmol/L
Set9↑, 2 fold

1401- BBR,    Berberine induces apoptosis in glioblastoma multiforme U87MG cells via oxidative stress and independent of AMPK activity
- in-vitro, GBM, U87MG
TumCP↓, 25 µM of 24 h
Apoptosis↑,
ROS↑, BBR (25 μM/24 h) increased oxidative stress in U87MG cells

1399- BBR,  Rad,    Radiotherapy Enhancing and Radioprotective Properties of Berberine: A Systematic Review
- Review, NA, NA
*ROS↓, normal cells
*MDA↓, normal cells
*TNF-α↓, normal cells
*TGF-β↓, TGF-β1 normal cells
*IL10↑, normal cells
ROS↑, cancer cells
DNAdam↑, cancer cells
mtDam↑, cancer cells
MMP↓, cancer cells
Apoptosis↑, cancer cells
TumCCA↑, cancer cells
Hif1a↓, cancer cells
VEGF↓, cancer cells
RadioS↑, revealed radiosensitizing properties

1402- BBR,    Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction
- in-vitro, GBM, T98G
tumCV↓,
ROS↑,
Ca+2↑,
ER Stress↑,
eff↓, administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis
Bax:Bcl2↑,
MMP↓,
Casp9↑,
Casp3↑,
cl‑PARP↑,

1404- BBR,    Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation
- in-vitro, Pca, PC3
Apoptosis↑,
*Apoptosis∅, not seen in non-neoplastic human prostate epithelial cells (PWR-1E)
MMP↓,
cl‑Casp3↑,
cl‑Casp9↑,
cl‑PARP↑,
ROS↑,
eff↓, Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells.
Cyt‑c↑, release of cytochrome c

1405- BBR,  Chit,    Chitosan/alginate nanogel potentiate berberine uptake and enhance oxidative stress mediated apoptotic cell death in HepG2 cells
- in-vitro, Liver, HepG2
*BioAv↑, we reported to develop a hydrophilic nanogel (NG) composed of Chitosan (Chi) and sodium alginate (Alg) using the ion gelation method for delivering Berberine hydrochloride (BBR),
ROS↑,
MMP↓,
TumCP↓,

2023- BBR,    Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor
- in-vitro, Colon, NA - in-vitro, Nor, YAMC
TumCD↑, Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells.
*toxicity↓, In contrast, YAMC(normal) cells were not sensitive to berberine-induced cell death. less cytotoxic effects on normal colon epithelial cells.
selectivity↑, see figure 2
ROS↑, berberine-stimulated ROS production
*ROS∅, ROS production in a concentration-dependent manner only in IMCE cells, but not in YAMC cells. In YAMC cells, berberine did not induce ROS production
MMP↓, berberine induced mitochondrial depolarization in a concentration-dependent manner in IMCE cells, but not in YAMC cells
*MMP∅, but not in YAMC cells
PARP↑, Berberine Activation of PARP
BioAv↝, absorption of berberine by YAMC is lower than that by IMCE cells

2021- BBR,    Berberine: An Important Emphasis on Its Anticancer Effects through Modulation of Various Cell Signaling Pathways
- Review, NA, NA
*antiOx?, Berberine has been noted as a potential therapeutic candidate for liver fibrosis due to its antioxidant and anti-inflammatory activities
*Inflam↓,
Apoptosis↑, Apoptosis induced by berberine in liver cancer cells caused cell cycle arrest at the M/G1 phase and increased the Bax expression
TumCCA↑,
BAX↑,
eff↑, mixture of curcumin and berberine effectively decreases growth in breast cancer cell lines
VEGF↓, berberine also prevented the expression of VEGF
PI3K↓, berberine plays an important role in cancer management through inhibition of the PI3K/AKT/mTOR pathway
Akt↓,
mTOR↓,
Telomerase↓, Berberine decreased the telomerase activity and level of the colorectal cancer cell line,
β-catenin/ZEB1↓, berberine and its derivatives have the ability to inhibit β-catenin/Wnt signaling in tumorigenesis
Wnt↓,
EGFR↓, berberine treatment decreased cell proliferation and epidermal growth factor receptor expression levels in the xenograft model.
AP-1↓, Berberine efficiently targets both the host and the viral factors accountable for cervical cancer development via inhibition of activating protein-1
NF-kB↓, berberine inhibited lung cancer cell growth by concurrently targeting NF-κB/COX-2, PI3K/AKT, and cytochrome-c/caspase signaling pathways
COX2↑,
NRF2↓, Berberine suppresses the Nrf2 signaling-related protein expression in HepG2 and Huh7 cells,
RadioS↑, suggesting that berberine supports radiosensitivity through suppressing the Nrf2 signaling pathway in hepatocellular carcinoma cells
STAT3↓, regulating the JAK–STAT3 signaling pathway
ERK↓, berberine prevented the metastatic potential of melanoma cells via a reduction in ERK activity, and the protein levels of cyclooxygenase-2 by a berberine-caused AMPK activation
AR↓, Berberine reduced the androgen receptor transcriptional activity
ROS↑, In a study on renal cancer, berberine raised the levels of autophagy and reactive oxygen species in human renal tubular epithelial cells derived from the normal kidney HK-2 cell line, in addition to human cell lines ACHN and 786-O cell line.
eff↑, berberine showed a greater apoptotic effect than gemcitabine in cancer cells
selectivity↑, After berberine treatment, it was noticed that berberine showed privileged selectivity towards cancer cells as compared to normal ones.
selectivity↑, expression of caspase-1 and its downstream target Interleukin-1β (IL-1β) was higher in osteosarcoma cells as compared to normal cells
BioAv↓, several studies have been undertaken to overcome the difficulties of low absorption and poor bioavailability through nanotechnology-based strategies.
DNMT1↓, In human multiple melanoma cell U266, berberine can inhibit the expression of DNMT1 and DNMT3B, which leads to hypomethylation of TP53 by altering the DNA methylation level and the p53-dependent signal pathway
cMyc↓, Moreover, berberine suppresses SLC1A5, Na+ dependent transporter expression through preventing c-Myc

5177- BBR,    Berberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway
- in-vitro, Oral, HMC3
TumCCA↑, Evidence has accumulated that berberine is able to induce cell cycle arrest and apoptosis in many human cancer cell lines.
Apoptosis↑,
TumCG↓, Berberine induced dose- and time-dependent irreversible inhibition of cell growth and cellular DNA synthesis
Casp3↑, induced apoptosis correlated with caspase-3 activation.
TumCCA↑, berberine induced mainly G0/G1-phase arrest
ROS↑, berberine induced reactive oxygen species (ROS) and Ca2+ production
Ca+2↑,
MMP↓, as well as the dysfunction of mitochondrial membrane potential (MMP), which were correlated with apoptosis
ER Stress↑, our data support that berberine initially induces an endoplasmic reticulum stress response based on ROS and Ca2+ production which is followed by dysfunctions of the mitochondria, resulting in apoptosis of these oral cancer HSC-3 cells.
Cyt‑c↑, Prolonged exposure of the HSC-3 cells to berberine causes increased apoptosis through reduced levels of MMP, release of cytochrome c and activation of caspase-3.

2699- BBR,    Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line
- in-vitro, Lung, A549
HDAC↓, BBR represses total HDAC and also class I, II, and IV HDAC activity through hyperacetylation of histones.
TumCCA↑, BBR triggers positive regulation of the sub-G0/G1 cell cycle progression phase in A549 cells.
TNF-α↓, BBR downregulates oncogenes (TNF-α, COX-2, MMP-2, and MMP-9) and upregulates tumor suppressor genes (p21 and p53) mRNA and protein expressions.
COX2↓,
MMP2↓, BBR Induces Downregulation of MMP-2 and MMP-9
MMP9↓,
P21↑,
P53↑,
Casp↑, triggered the caspase cascade apoptotic pathway in A549 cells
ac‑H3↑, BBR Increases the Acetylation State of Histones H3 and H4.
ac‑H4↑,
ROS↑, BBR Induces ROS Generation, Δψm Alteration, Membrane Loss, and Nuclear Fragmentation
MMP↓,

2680- BBR,  PDT,    Photodynamic therapy-triggered nuclear translocation of berberine from mitochondria leads to liver cancer cell death
- in-vitro, Liver, HUH7
TumCD↑, blue light irradiation (488 nm). The results showed that berberine rapidly translocated from the mitochondria to the nucleus upon light exposure, ultimately inducing cell death in SNU449 and Huh7 cells.
ROS↑, Additionally, we observed a significant increase in reactive oxygen species, linking the phototoxic effects to oxidative stress
TumCCA↑, indicating cell cycle arrest following treatment with berberine and PDT
ER Stress↑, Western blotting confirmed that ER stress was significantly induced

2674- BBR,    Berberine: A novel therapeutic strategy for cancer
- Review, Var, NA - Review, IBD, NA
Inflam↓, anti-inflammatory, antidiabetic, antibacterial, antiparasitic, antidiarrheal, antihypertensive, hypolipidemic, and fungicide.
AntiCan↑, elaborated on the anticancer effects of BBR through the regulation of different molecular pathways such as: inducing apoptosis, autophagy, arresting cell cycle, and inhibiting metastasis and invasion.
Apoptosis↑,
TumAuto↑,
TumCCA↑,
TumMeta↓,
TumCI↓,
eff↑, BBR is shown to have beneficial effects on cancer immunotherapy.
eff↑, BBR inhibited the release of Interleukin 1 beta (IL-1β), Interferon gamma (IFN-γ), Interleukin 6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α) from LPS stimulated lymphocytes by acting as a dopamine receptor antagonist
CD4+↓, BBR inhibited the proliferation of CD4+ T cells and down-regulated TNF-α and IL-1 and thus, improved autoimmune neuropathy.
TNF-α↓,
IL1↓,
BioAv↓, On the other hand, P-Glycoprotein (P-gp), a secretive pump located in the epithelial cell membrane, restricts the oral bioavailability of a variety of medications, such as BBR. The use of P-gp inhibitors is a common and effective way to prevent this
BioAv↓, Regardless of its low bioavailability, BBR has shown great therapeutic efficacy in the treatment of a number of diseases.
other↓, BBR has been also used as an effective therapeutic agent for Inflammatory Bowel Disease (IBD) for several years
AMPK↑, inhibitory effects on inflammation by regulating different mechanisms such as 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK. Increase of AMPK
MAPK↓, Mitogen-Activated Protein Kinase (MAPK), and NF-κB signaling pathways
NF-kB↓,
IL6↓, inhibiting the expression of proinflammatory genes such as IL-1, IL-6, Monocyte Chemoattractant Protein 1 (MCP1), TNF-α, Prostaglandin E2 (PGE2), and Cyclooxygenase-2 (COX-2)
MCP1↓,
PGE2↓,
COX2↓,
*ROS↓, BBR protected PC-12 cells (normal) from oxidative damage by suppressing ROS through PI3K/AKT/mTOR signaling pathways
*antiOx↑, BBR therapy improved the antioxidant function of mice intestinal tissue by enhancing the levels of glutathione peroxidase and catalase enzymes.
*GPx↑,
*Catalase↑,
AntiTum↑, Besides, BBR leaves great antitumor effects on multiple types of cancer such as breast cancer,69 bladder cancer,70 hepatocarcinoma,71 and colon cancer.72
TumCP↓, BBR exerts its antitumor activity by inhibiting proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis and metastasis
angioG↓,
Fas↑, by increasing the amounts of Fas receptor (death receptor)/FasL (Fas ligand), ROS, ATM, p53, Retinoblastoma protein (Rb), caspase-9,8,3, TNF-α, Bcl2-associated X protein (Bax), BID
FasL↑,
ROS↑,
ATM↑,
P53↑,
RB1↑,
Casp9↑,
Casp8↑,
Casp3↓,
BAX↑,
Bcl-2↓, and declining Bcl2, Bcl-X, c-IAP1 (inhibitor of apoptosis protein), X-linked inhibitor of apoptosis protein (XIAP), and Survivin levels
Bcl-xL↓,
IAP1↓,
XIAP↓,
survivin↓,
MMP2↓, Furthermore, BBR suppressed Matrix Metalloproteinase-2 (MMP-2), and MMP-9 expression.
MMP9↓,
CycB/CCNB1↓, Inhibition of cyclin B1, cdc2, cdc25c
CDC25↓,
CDC25↓,
Cyt‑c↑, BBR inhibited tumor cell proliferation and migration and induced mitochondria-mediated apoptosis pathway in Triple Negative Breast Cancer (TNBC) by: stimulating cytochrome c release from mitochondria to cytosol
MMP↓, decreased the mitochondrial membrane potential, and enabled cytochrome c release from mitochondria to cytosol
RenoP↑, BBR significantly reduced the destructive effects of cisplatin on the kidney by inhibiting autophagy, and exerted nephroprotective effects.
mTOR↓, U87 cell, Inhibition of m-TOR signaling
MDM2↓, Downregulation of MDM2
LC3II↑, Increase of LC3-II and beclin-1
ERK↓, BBR stimulated AMPK signaling, resulting in reduced extracellular signal–regulated kinase (ERK) activity and COX-2 expression in B16F-10 lung melanoma cells
COX2↓,
MMP3↓, reducing MMP-3 in SGC7901 GC and AGS cells
TGF-β↓, BBR suppressed the invasion and migration of prostate cancer PC-3 cells by inhibiting TGF-β-related signaling molecules which induced Epithelial-Mesenchymal Transition (EMT) such as Bone morphogenetic protein 7 (BMP7),
EMT↑,
ROCK1↓, inhibiting metastasis-associated proteins such as ROCK1, FAK, Ras Homolog Family Member A (RhoA), NF-κB and u-PA, leading to in vitro inhibition of MMP-1 and MMP-13.
FAK↓,
RAS↓,
Rho↓,
NF-kB↓,
uPA↓,
MMP1↓,
MMP13↓,
ChemoSen↑, recent studies have indicated that it can be used in combination with chemotherapy agents

2681- BBR,  PDT,    Berberine-photodynamic induced apoptosis by activating endoplasmic reticulum stress-autophagy pathway involving CHOP in human malignant melanoma cells
- in-vitro, Melanoma, NA
Apoptosis↑, BBR-PDT induced apoptosis via up-regulating the expression of cleaved caspase-3 protein.
cl‑Casp3↑,
LC3s↑, LC3-related autophagy level was upregulated in MMCs with BBR-PDT.
ER Stress↑, BBR-PDT activated endoplasmic reticulum (ER) stress, involving a dramatic increase in reactive oxygen species (ROS).
ROS↑,
CHOP↑, knockdown of CHOP protein expression inhibited apoptosis, autophagy and ER stress levels caused by BBR-PDT, suggesting that CHOP protein may be related to apoptosis, autophagy and ER stress in MMCs with BBR-PDT

2686- BBR,    Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs
- Review, Nor, NA
Inflam↓, BBR has documented to have anti-diabetic, anti-inflammatory and anti-microbial (both anti-bacterial and anti-fungal) properties.
IL6↓, BBRs can inhibit IL-6, TNF-alpha, monocyte chemo-attractant protein 1 (MCP1) and COX-2 production and expression.
MCP1↓,
COX2↓,
PGE2↓, BBRs can also effect prostaglandin E2 (PGE2)
MMP2↓, and decrease the expression of key genes involved in metastasis including: MMP2 and MMP9.
MMP9↓,
DNAdam↑, BBR induces double strand DNA breaks and has similar effects as ionizing radiation
eff↝, In some cell types, this response has been reported to be TP53-dependent
Telomerase↓, This positively-charged nitrogen may result in the strong complex formations between BBR and nucleic acids and induce telomerase inhibition and topoisomerase poisoning
Bcl-2↓, BBR have been shown to suppress BCL-2 and expression of other genes by interacting with the TATA-binding protein and the TATA-box in certain gene promoter regions
AMPK↑, BBR has been shown in some studies to localize to the mitochondria and inhibit the electron transport chain and activate AMPK.
ROS↑, targeting the activity of mTOR/S6 and the generation of ROS
MMP↓, BBR has been shown to decrease mitochondrial membrane potential and intracellular ATP levels.
ATP↓,
p‑mTORC1↓, BBR induces AMPK activation and inhibits mTORC1 phosphorylation by suppressing phosphorylation of S6K at Thr 389 and S6 at Ser 240/244
p‑S6K↓,
ERK↓, BBR also suppresses ERK activation in MIA-PaCa-2 cells in response to fetal bovine serum, insulin or neurotensin stimulation
PI3K↓, Activation of AMPK is associated with inhibition of the PI3K/PTEN/Akt/mTORC1 and Raf/MEK/ERK pathways which are associated with cellular proliferation.
PTEN↑, RES was determined to upregulate phosphatase and tensin homolog (PTEN) expression and decrease the expression of activated Akt. In HCT116 cells, PTEN inhibits Akt signaling and proliferation.
Akt↓,
Raf↓,
MEK↓,
Dose↓, The effects of low doses of BBR (300 nM) on MIA-PaCa-2 cells were determined to be dependent on AMPK as knockdown of the alpha1 and alpha2 catalytic subunits of AMPK prevented the inhibitory effects of BBR on mTORC1 and ERK activities and DNA synthes
Dose↑, In contrast, higher doses of BBR inhibited mTORC1 and ERK activities and DNA synthesis by AMPK-independent mechanisms [223,224].
selectivity↑, BBR has been shown to have minimal effects on “normal cells” but has anti-proliferative effects on cancer cells (e.g., breast, liver, CRC cells) [225–227].
TumCCA↑, BBR induces G1 phase arrest in pancreatic cancer cells, while other drugs such as gemcitabine induce S-phase arrest
eff↑, BBR was determined to enhance the effects of epirubicin (EPI) on T24 bladder cancer cells
EGFR↓, In some glioblastoma cells, BBR has been shown to inhibit EGFR signaling by suppression of the Raf/MEK/ERK pathway but not AKT signaling
Glycolysis↓, accompanied by impaired glycolytic capacity.
Dose?, The IC50 for BBR was determined to be 134 micrograms/ml.
p27↑, Increased p27Kip1 and decreased CDK2, CDK4, Cyclin D and Cyclin E were observed.
CDK2↓,
CDK4↓,
cycD1/CCND1↓,
cycE/CCNE↓,
Bax:Bcl2↑, Increased BAX/BCL2 ratio was observed.
Casp3↑, The mitochondrial membrane potential was disrupted and activated caspase 3 and caspases 9 were observed
Casp9↑,
VEGFR2↓, BBR treatment decreased VEGFR, Akt and ERK1,2 activation and the expression of MMP2 and MMP9 [235].
ChemoSen↑, BBR has been shown to increase the anti-tumor effects of tamoxifen (TAM) in both drug-sensitive MCF-7 and drug-resistant MCF-7/TAM cells.
eff↑, The combination of BBR and CUR has been shown to be effective in suppressing the growth of certain breast cancer cell lines.
eff↑, BBR has been shown to synergize with the HSP-90 inhibitor NVP-AUY922 in inducing death of human CRC.
PGE2↓, BBR inhibits COX2 and PEG2 in CRC.
JAK2↓, BBR prevented the invasion and metastasis of CRC cells via inhibiting the COX2/PGE2 and JAK2/STAT3 signaling pathways.
STAT3↓,
CXCR4↓, BBR has been observed to inhibit the expression of the chemokine receptors (CXCR4 and CCR7) at the mRNA level in esophageal cancer cells.
CCR7↓,
uPA↓, BBR has also been shown to induce plasminogen activator inhibitor-1 (PAI-1) and suppress uPA in HCC cells which suppressed their invasiveness and motility.
CSCs↓, BBR has been shown to inhibit stemness, EMT and induce neuronal differentiation in neuroblastoma cells. BBR inhibited the expression of many genes associated with neuronal differentiation
EMT↓,
Diff↓,
CD133↓, BBR also suppressed the expression of many genes associated with cancer stemness such as beta-catenin, CD133, NESTIN, N-MYC, NOTCH and SOX2
Nestin↓,
n-MYC↓,
NOTCH↓,
SOX2↓,
Hif1a↓, BBR inhibited HIF-1alpha and VEGF expression in prostate cancer cells and increased their radio-sensitivity in in vitro as well as in animal studies [290].
VEGF↓,
RadioS↑,

1473- BCA,  SFN,    An Insight on Synergistic Anti-cancer Efficacy of Biochanin A and Sulforaphane Combination Against Breast Cancer
- in-vitro, BC, MCF-7
eff↑, cytotoxicity of BCA and SFN was found to be around 24.5 µM and 27.2 µM respectively, while the combination of BCA and SFN had shown an inhibitory activity at about 20.1 µM.
ROS↑,
other↑, profound increase in apoptogenic activity of compounds when treated in combination at lower dose.
ERK↓,
Apoptosis↑,

5591- BetA,    Advances and challenges in betulinic acid therapeutics and delivery systems for breast cancer prevention and treatment
- Review, BC, NA
BioAv↓, However, its poor water solubility limits its optimal therapeutic potential.
BioAv↑, nano-drug delivery systems (NDDSs) have gained significant attention as a method to substantially improve low solubility and poor drug bioavailability, enhance targeted drug delivery, and reduce side effects.
selectivity↑, reviews by Simone Fulda23,24 strengthened BA's potential for cancer treatment and prevention, particularly its ability to selectively trigger apoptosis in cancer cells while causing minimal harm to normal cells.
eff↑, It is important to note that the anticancer effects of BA on different types of tumors are more potent at a pH lower than 6.8.34
angioG↓, figure 3
*antiOx↑,
*Inflam↓,
MMP↓, BA-induced mitochondrial depolarization
Bcl-2↓, BA treatment has been shown to lower Bcl-2 expression and increase Bax, resulting in the activation of caspase-9 and caspase-3 through the mitochondrial pathway.63
BAX↑,
Casp9↑,
Casp3↑,
GRP78/BiP?, BA directly targets GRP78, triggering ER stress by activating the PERK-eIF2α-CHOP apoptotic cascade
ER Stress↑,
PERK↑,
CHOP↑,
ChemoSen↑, BA's ability to chemosensitize BC cells to taxanes highlights its importance in situations of drug resistance
SESN2↑, Under hypoxia, BA strongly increases SESN2 expression.
ROS↑, Reducing SESN2 levels enhances BA-induced ROS production, DNA damage, and radiosensitivity, while decreasing autophagic flux, indicating that SESN2-mediated autophagy serves as a protective adaptive response.68
MOMP↓, decreases the mitochondrial outer membrane potential (MOMP),
MAPK↑, This leads to the activation of p38 Mitogen-activated protein kinase (p38 MAPK), the release of cytochrome C, apoptosis-inducing factor (AIF),
Cyt‑c↑,
AIF↑,
STAT3↓, BA suppresses the signal transducer and activator of transcription (STAT) 3 signaling pathways
FAK↓, BA's inhibition of STAT3, as well as FAK, leads to decreased expression of MMPs and elevated TIMP-2, thereby impairing cancer cell migration and invasion
TIMP2↑,
TumCMig↓,
TumCI↓,
Sp1/3/4↓, Sp inhibition reduces cancer gene expression, inhibiting cancer cell growth.
TumCCA↑, It increases cell numbers in the G2/M phase, leading to cell cycle arrest.
DNAdam↑, causes DNA damage, thereby inhibiting the progression and invasion of cancer cells.

5583- BetA,    Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells
- vitro+vivo, NA, NA
ROS↑, Formation of reactive oxygen species [6], modulation of BCL-2 and BAX levels [8] and topoisomerases Ia and IIa [11] have been suggested to be involved in its mechanisms of action.
Bcl-2↓,
BAX↑,
TOP1↝,
eff↝, betulinic acid was more than ten times less potent than doxorubicin
toxicity↓, Thus on normal PBL betulinic acid was at least 1000-fold less toxic than doxorubicin.
toxicity↓, Mice treated with betulinic acid did not show any sign of apparent toxicity or body weight loss compared with controls.
selectivity↑, Moreover, in spite of the lower potency compared with doxorubicin, betulinic acid seems to be selective for tumor cells, since minimal toxicity against normal cells was observed

5582- BetA,    Targeting mitochondrial apoptosis by betulinic acid in human cancers
- Review, Var, NA
Apoptosis↑, BA has been reported to induce apoptosis via a direct effect on mitochondria.
MMP↓, BA triggered loss of mitochondrial membrane potential
Cyt‑c↑, BA was shown to trigger cytochrome c in a permeability transition pore-dependent
ROS↑, Generation of ROS upon treatment with BA has been reported to be involved in initiating mitochondrial membrane permeabilization [15].
NF-kB↑, These findings indicate that the activation of NF-kB by BA promotes BA-induced apoptosis in a cell type- specific manner.
angioG↓, antiangiogenic activity of BA was linked to its mitochondrial damaging effects [33]
mtDam↑,
TOP1↓, BA can inhibit the catalytic activity of topoisomerase I
selectivity↑, normal cells of different origin have been reported to be much more resistant to BA than cancer cells pointing to some tumor selectivity [19,25,44,45].
ChemoSen↑, his suggests that BA can be used as a sensitizer in combination regimens to enhance the efficacy of anticancer therapy or to bypass some forms of drug resistance
TumCG↓, BA also suppressed tumor growth in several animal models of human cancer.
chemoPv↑, BA has also been reported to act as a chemopreventive agent.
RadioS↑, BA may also be used in combination protocols to enhance its antitumor activity, for example with chemo- or radiotherapy or with the death receptor ligand TRAIL. B

2722- BetA,    Betulinic Acid for Cancer Treatment and Prevention
- Review, Var, NA
MMP↓, betulinic acid induced loss of mitochondrial membrane potential
Cyt‑c↑, betulinic acid was shown to trigger cytochrome c
cl‑Casp3↑, Cleavage of caspase-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species.
cl‑Casp8↑,
ROS↑,
NF-kB↑, Betulinic acid was identified as a potent activator of NF-κB in a number of cancer cell lines
TOP1↓, betulinic acid was shown to inhibit the catalytic activity of topoisomerase I

2723- BetA,    Betulinic acid and oleanolic acid modulate CD81 expression and induce apoptosis in triple-negative breast cancer cells through ROS generation
- in-vitro, BC, MDA-MB-231
Apoptosis↑, Triterpenoids such as betulinic acid (BA) and oleanolic acid (OA) have anticancer effects by inducing apoptosis in TNBC cells.
tumCV↓, The result showed that BA and OA inhibited viability of MDA-MB-231 cells.
ROS↑, BA and OA also increased intracellular ROS levels and induced apoptosis.

2718- BetA,    The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis
- in-vitro, AML, U937
TumCCA↑, BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA.
Apoptosis↑,
i-ROS↑,
cycA1/CCNA1↓, down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA.
CycB/CCNB1↓,
P21↑,
Cyt‑c↑, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio.
MMP↓,
Bax:Bcl2↑,
Casp9↑, BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase.
Casp3↑,
PARP↓,
eff↓, However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment.
*antiOx↑, Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects
*Inflam↓,
*hepatoP↑,
selectivity↑, BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells
NF-kB↓, Shen et al. (2019) recently reported that the suppression of the nuclear factor-kappa B pathway increased downstream oxidant effectors, thereby promoting the generation of reactive oxygen species (ROS) in BA-stimulated multiple myeloma cells.
*ROS↓, Although BA is known to have antioxidant activity that blocks the accumulation of ROS due to oxidative stress in normal cells (Cheng et al. 2019;

2721- BetA,    Proteomic Investigation into Betulinic Acid-Induced Apoptosis of Human Cervical Cancer HeLa Cells
- in-vitro, Cerv, HeLa
ROS↑, Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells
Dose↝, The level of ROS in BA-treated cells was 9.28-fold and 12.77-fold higher than the level of ROS in control cells for treatments of 15 µmol/L and 30 µmol/L, respectively,
Bcl-2↓, The expression level of Bcl-2 was observed to be significantly lower than the control level. In contrast, the expression of proapoptotic Bax was significantly increased compared to the controls by qRT-PCR
BAX↑,
ER Stress↑, In the present work, up-regulated protein expression was detected, which may mediate the ER process of BA in HeLa cells.

2720- BetA,    Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo
- in-vitro, Cerv, HeLa
Keap1↝, The findings revealed that BA activated Keap1/Nrf2 pathway and triggered mitochondria-dependent apoptosis due to ROS production.
ROS↑,
Ca+2↑, Furthermore, BA increased the intracellular Ca2+ levels
Beclin-1↓, inhibited the expression of Beclin1 and promoted the expression of GRP78, LC3-II, and p62 associated with ERS and autophagy.
GRP78/BiP↑,
LC3II↑,
p62↑,
ERStress↑,
TumAuto↑,

2734- BetA,    Betulinic Acid Modulates the Expression of HSPA and Activates Apoptosis in Two Cell Lines of Human Colorectal Cancer
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW480
tumCV↓, viability of both cancer cells was reduced after they were treated with an increasing dosage of BA.
HSP70/HSPA5⇅, HSPA was increased at lower BA concentrations while at higher BA concentrations HSPA expression was decreased.
ROS↑, In CRC cells, BA was found to increase the production of the reactive oxygen species (ROS), Bax and cleaved caspase-3, leading to mitochondrial apoptosis in the HCT116 cell line
cl‑Casp3↑,
mt-Apoptosis↑,
Dose↝, HSPA was increased after treatment with the BA at 1.25, 2.5 and 5 µM in both of CRC, while the HSPA level was significantly reduced to about 0.7-fold at 10 µM of BA

2726- BetA,    Betulinic acid induces DNA damage and apoptosis in SiHa cells
- in-vitro, Cerv, SiHa
tumCV↓, BA was shown to destroy SiHa cells preferentially in a concentration dependent manner with a 50% inhibition of the cells at 39.83 μg/ml.
DNAdam↑, BA was coupled with DNA strand breaks, morphological changes, disruption of MMP, reactive oxygen species (ROS) generation and the cell arrest at G0/G1 stage of cell cycle.
MMP↓,
ROS↑,
TumCCA↑,
TOP1↓, It has been previously reported that inhibition of topoisomerases might be an additional mechanism of BA-induced cell death

2727- BetA,    Betulinic acid in the treatment of breast cancer: Application and mechanism progress
- Review, BC, NA
mt-ROS↑, Its mechanisms mainly include inducing mitochondrial oxidative stress, regulating specific protein (Sp) transcription factors, inhibiting breast cancer metastasis, inhibiting glucose metabolism and NF-κB pathway.
Sp1/3/4↓, By triggering the degradation of Sp1, Sp3, and Sp4, betulinic acid reduces the transcriptional activity of these factors
TumMeta↓,
GlucoseCon↓,
NF-kB↓,
ChemoSen↑, BA can also increase the sensitivity of breast cancer cells to other chemotherapy drugs such as paclitaxel and reduce its toxic side effects.
chemoP↑,
m-Apoptosis↑, variety of mechanisms, including inducing mitochondrial apoptosis, inhibiting topoisomerase
TOP1↓, betulinic acid may inhibit the ability of topoisomerase I or II to properly cleave and re-ligate DNA strands.

2729- BetA,    Betulinic acid in the treatment of tumour diseases: Application and research progress
- Review, Var, NA
ChemoSen↑, Betulinic acid can increase the sensitivity of cancer cells to other chemotherapy drugs
mt-ROS↑, BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress
STAT3↓, inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways.
NF-kB↓,
selectivity↑, A main advantage of BA and its derivatives is that they are cytotoxic to different human tumour cells, while cytotoxicity is much lower in normal cells.
*toxicity↓, It can kill cancer cells but has no obvious effect on normal cells and is also nontoxic to other organs in xenograft mice at a dose of 500 mg/kg
eff↑, BA combined with chemotherapy drugs, such as platinum and mithramycin A, can induce apoptosis in tumour cells
GRP78/BiP↑, In animal xenograft tumour models, BA enhanced the expression of glucose-regulated protein 78 (GRP78)
MMP2↓, reduced the levels of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, in lung metastatic lesions of breast cancer, indicating that BA can reduce the invasiveness of breast cancer in vivo and block epithelial mesenchymal transformation (EMT
P90RSK↓,
TumCI↓,
EMT↓,
MALAT1↓, MALAT1, a lncRNA, was downregulated in hepatocellular carcinoma (HCC) cells treated with BA in vivo,
Glycolysis↓, Suppressing aerobic glycolysis of cancer cells by GRP78/β-Catenin/c-Myc signalling pathways
AMPK↑, activating AMPK signaling pathway
Sp1/3/4↓, inhibiting Sp1. BA at 20 mg/kg/d, the tumour volume and weight were significantly reduced, and the expression levels of Sp1, Sp3, and Sp4 in tumour tissues were lower than those in control mouse tissues
Hif1a↓, Suppressing the hypoxia-induced accumulation of HIF-1α and expression of HIF target genes
angioG↓, PC3: Having anti-angiogenesis effect
NF-kB↑, LNCaP, DU145 — Inducing apoptosis and NF-κB pathway
NF-kB↓, U266 — Inhibiting NF-κB pathway.
MMP↓, BA produces ROS and reduces mitochondrial membrane potential; the mitochondrial permeability transition pore of the mitochondrial membrane plays an important role in apoptosis signal transduction.
Cyt‑c↑, Mitochondria release cytochrome C and increase the levels of Caspase-9 and Caspase-3, inducing cell apoptosis.
Casp9↑,
Casp3↑,
RadioS↑, BA could be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.
PERK↑, BA treatment increased the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptosis pathway and decreased the expression of Sp1.
CHOP↑,
*toxicity↓, BA at a concentration of 50 μg/ml did not inhibit the growth of normal peripheral blood lymphocytes, indicating that the toxicity of BA was at least 1000 times less than that of doxorubicin

2730- BetA,    Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells
- in-vitro, Bladder, T24/HTB-9
tumCV↓, The present study showed that BA exposure significantly suppressed viability, proliferation, and migration of EJ and T24 human bladder cancer cells
TumCP↓,
TumCMig↓,
Casp↑, These effects reflected caspase 3-mediated apoptosis
TumAuto↑, BA-induced autophagy was evidenced by epifluorescence imaging of lentivirus-induced expression of mCherry-GFP-LC3B and increased expression of two autophagy-related proteins, LC3B-II and TEM.
LC3B-II↑,
p‑AMPK↑, Moreover, enhanced AMPK phosphorylation and decreased mTOR and ULK-1 phosphorylation suggested BA activates autophagy via the AMPK/mTOR/ULK1 pathway.
mTOR↓,
BMI1↓, decreased Bmi-1 expression in BA-treated T24 cell xenografts in nude mice suggested that downregulation of Bmi-1 is the underlying mechanism in BA-mediated, autophagy-dependent apoptosis.
ROS↑, BA induced ROS production dose-dependently
eff↓, Co-incubation with NAC effectively blocked ROS production (Figure 4B), rescued cell viability,

2717- BetA,    Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma
- in-vitro, Melanoma, U266 - in-vivo, Melanoma, NA - in-vitro, Melanoma, RPMI-8226
Apoptosis↑, BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation.
TumCCA↑, S-Phase Arrest in U266 Cells
MMP↓,
ROS↑, exhibited concentration-dependent increases in intracellular ROS
eff↓, ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed
NF-kB↓, BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM
Cyt‑c↑, BA mediated the release of cyt c and activated cleaved caspase-3, caspase-8, and caspase-9 and cleaved PARP1
Casp3↑,
Casp8↑,
Casp9↑,
cl‑PARP1↑,
MDA↑, here is a concentration-dependent increase in MDA contents and reduction in SOD activities, especially for the high concentration group.
SOD↓,
SOD2↓, expression of genes SOD2, FHC, GCLM, and GSTM was all decreased following treatment with BA (40 μM)
GCLM↓,
GSTA1↓,
FTH1↓, FHC
GSTs↓, GSTM
TumVol↓, BA Inhibits the Growth of MM Xenograft Tumors In Vivo. BA-treated group were significantly reduced (inhibition ratio of approximately 72.1%).

2716- BetA,    Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment
- Review, Var, NA
AntiCan↑, BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities
TumCD↑, anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling
TumCCA↑,
ROS↑,
NF-kB↓,
Bcl-2↓,
Half-Life↝, The half-life eliminations were 11.8 and 11.5 h after 500 and 250 mg/kg of intraperitoneal (i.p.) BA administration
GLUT1↓, the expression of HIF target genes, such as GLUT1, VEGF, and PDK1 was also suppressed by BA
VEGF↓,
PDK1↓,

2733- BetA,    Betulinic Acid Inhibits Cell Proliferation in Human Oral Squamous Cell Carcinoma via Modulating ROS-Regulated p53 Signaling
- in-vitro, Oral, KB - in-vivo, NA, NA
TumCP↓, BA dose-dependently inhibited KB cell proliferation and decreased implanted tumor volume.
TumVol↓,
mt-Apoptosis↑, BA significantly promoted mitochondrial apoptosis, as reflected by an increase in TUNEL+ cells and the activities of caspases 3 and 9, an increase in Bax expression, and a decrease in Bcl-2 expression and the mitochondrial oxygen consumption rate.
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↑,
OCR↓, BA dose-dependently decreased the oxygen consumption rate, indicating that BA induced a significant mitochondrial dysfunction
TumCCA↑, BA significantly increased cell population in the G0/G1 phase and decreases the S phase cell number, indicating the occurrence of G0/G1 cell cycle arrest.
ROS↑, ROS generation was significantly increased by BA
eff↓, and antioxidant NAC treatment markedly inhibited the effect of BA on apoptosis, cell cycle arrest, and proliferation.
P53↑, BA dose-dependently increased p53 expression in KB cells and implanted tumors.
STAT3↓, Inhibition of STAT3 Signaling Is Involved in BA-Induced Suppression of Cell Proliferation
cycD1/CCND1↑, We found that BA mainly increased the mRNA expression of cyclin D1 but had no significant effect on cyclin E, CDK2, CDK4, or CDK6 expression.

2735- BetA,    Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications
- Review, Var, NA
mt-Apoptosis↑, BA and analogues (BAs) have been known to exhibit potential antitumor action via provoking the mitochondrial pathway of apoptosis
Casp↑, cytosolic caspase activation
p38↑, inhibition of pro-apoptotic p38, MAPK and SAP/JNK kinases [8],
MAPK↓,
JNK↓,
VEGF↓, decreased expression of pro-apoptotic proteins and vascular endothelial growth factor (VEGF)
AIF↑, BA was recognized to trigger the process of apoptosis in human metastatic melanoma cells (Me-45) by releasing apoptosis inducing factor (AIF) and cytochrome c (Cyt C) through mitochondrial membrane
Cyt‑c↑,
ROS↑, BA also stimulates the increased production of reactive oxygen species (ROS) that is considered a stress factor involved in initiating mitochondrial membrane permeabilization
Ca+2↑, Moreover, the calcium overload and thereby ATP depletion are other stress factors causing enhanced inner mitochondrial membrane permeability via nonspecific pores formation
ATP↓,
NF-kB↓, BA has also known to be involved in activation of nuclear factor kappa B (NF-κB) that is responsible for apoptosis induction in variety of cancer cells
ATF3↓, According to Zhang et al. [14], BA stimulates apoptosis through the suppression of cyclic AMP-dependent transcription factor ATF-3 and NF-κB pathways and downregulation of p53 gene.
TOP1↓, inhibition of topoisomerases
VEGF↓, ecreased expression of vascular endothelial growth (VEGF) and the anti-apoptotic protein surviving in LNCaP prostate cancer cells.
survivin↓,
Sp1/3/4↓, selective proteasome-dependent targeted degradation of transcription factors specificity proteins (Sp1, Sp3, and Sp4), which generally regulate VEGF and survivin expression and highly over-expressed in tumor conditions
MMP↓, perturbed mitochondrial membrane potential
ChemoSen↑, BA can support as sensitizer in combination therapy to enhance the anticancer effects with minimum side effects.
selectivity↑, Normal human fibroblasts [41], peripheral blood lymphoblasts [41], melanocytes [32] and astrocytes [30] were found to be resistant to BA in vitro
BioAv↓, The clinical use of BA is seriously challenging due to high hydrophobicity which subsequently causes poor bioavailability
BioAv↑, A BA-loaded oil-in-water nanoemulsion was developed using phospholipase-catalyzed modified phosphatidylcholine as emulsifier in an ultrasonicator [120].
BioAv↑, Aqueous solubility of BA may also be increased through grinding with hydrophilic polymers (polyethylene glycol, polyvinylpyrrolidone, arabinogalactan) [121,122].
BioAv↑, Subsequently, for further improvement in biocompatibility, a technique of nanotube coating was employed with four biopolymers i.e. polyethylene glycol (PEG), chitosan, tween 20 and tween 80.
BioAv↑, Similarly, BA-coated silver nanoparticles displayed an improved antiproliferative and antimigratory activity, particularly against melanoma cells (A375: murine melanoma cells)

2736- BetA,  Chemo,    Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis
- Review, Var, NA
chemoPv↑, reviews about cancer chemopreventive role of betulinic acid against wide variety of cancers [18,19,20,21].
p‑STAT3↓, betulinic acid reduced the levels of p-STAT3 in tumor tissues derived from KB cells
JAK1↓, Betulinic acid exerted inhibitory effects on the constitutive phosphorylation of JAK1 and JAK2
JAK2↓,
VEGF↓, betulinic acid mediated inhibition of VEGF
EGFR↓, evaluation of betulinic acid as a next-generation EGFR inhibitor
Cyt‑c↑, release of SMAC/DIABLO and cytochrome c from mitochondria in SHEP neuroblastoma cells
Diablo↑,
AMPK↑, Betulinic acid induced activation of AMPK and consequently reduced the activation of mTOR.
mTOR↓,
Sp1/3/4↓, Betulinic acid significantly reduced the quantities of Sp1, Sp3 and Sp4 in the tissues of the tumors derived from RKO cells
DNAdam↑, Betulinic acid efficiently triggered DNA damage (γH2AX) and apoptosis (caspase-3 and p53 phosphorylation) in temozolomide-sensitive and temozolomide-resistant glioblastoma cells.
Gli1↓, Betulinic acid effectively reduced GLI1, GLI2 and PTCH1 in RMS-13 cells.
GLI2↓,
PTCH1↓,
MMP2↓, betulinic acid exerted inhibitory effects on MMP-2 and MMP-9 in HepG2 cells.
MMP9↓,
miR-21↓, Collectively, p53 increased miR-21 levels and inhibited SOD2 levels, leading to significant increase in the accumulation of ROS levels and apoptotic cell death.
SOD2↓,
ROS↑,
Apoptosis↑,

2738- BetA,    Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, BT549 - in-vivo, NA, NA
TumCI↓, BA inhibited invasion and migration of highly aggressive breast cancer cells.
TumCMig↓,
Glycolysis↓, Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins.
lactateProd↓, lactate production in both MDA-MB-231 and BT-549 cells was significantly reduced following BA administration
GRP78/BiP↑, (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis.
ER Stress↑, Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK.
PERK↑,
p‑eIF2α↑, Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis.
β-catenin/ZEB1↓,
cMyc↓, These findings suggested that BA inhibited the β-catenin/c-Myc pathway by interrupting the binding between GRP78 and PERK and ultimately suppressed the glycolysis of breast cancer cells.
ROS↑, (i) the induction of cancer cell apoptosis via the mitochondrial pathway induced by the release of soluble factors or generation of reactive oxygen species (ROS)
angioG↓, (ii) the inhibition of angiogenesis [24];
Sp1/3/4↓, (iii) the degradation of transcription factor specificity protein 1 (Sp1)
DNAdam↑, (iv) the induction of DNA damage by suppressing topoisomerase I
TOP1↓,
TumMeta↓, BA Inhibits Metastasis of Highly Aggressive Breast Cancer Cells
MMP2↓, BA significantly decreased the expression of MMP-2 and MMP-9 secreted by breast cancer cells
MMP9↓,
N-cadherin↓, BA downregulated the levels of N-cadherin and vimentin as the mesenchymal markers, while increased E-cadherin which is an epithelial marker (Figure 2(c)), validating the EMT inhibition effects of BA in breast cancer cells.
Vim↓,
E-cadherin↑,
EMT↓,
LDHA↓, the levels of glycolytic enzymes, including LDHA and p-PDK1/PDK1, were all decreased in a dose-dependent manner by BA
p‑PDK1↓,
PDK1↓,
ECAR↓, extracellular acidification rate (ECAR), which reflects the glycolysis activity, was retarded following BA administration.
OCR↓, oxygen consumption rate (OCR), which is a marker of mitochondrial respiration, was also decreased simultaneously
Hif1a↓, BA could reduce prostate cancer angiogenesis via inhibiting the HIF-1α/stat3 pathway [39]
STAT3↓,

2759- BetA,    Chemopreventive and Chemotherapeutic Potential of Betulin and Betulinic Acid: Mechanistic Insights From In Vitro, In Vivo and Clinical Studies
- Review, Var, NA
chemoPv↑, chemopreventive and chemotherapeutic effects of betulin and betulinic acid by presenting in vitro, in vivo
ChemoSen↑,
*Inflam↓, right side depicts anti-inflammatory effect by suppressing proinflammatory mediators
*NRF2↑, boosting NRF2 (antioxidant/anti-inflammatory).
*NF-kB↓, suppressing proinflammatory mediators (NF-κB and COX)
*COX2↓,
ROS↑, By rapidly increasing the generation of reactive oxidative species and concurrently dissipating mitochondrial membrane potential in a dose- and time-dependent manner, betulinic acid also has an anticancer effect on melanoma cells
MMP↓,
Sp1/3/4↓, nude mice bearing LNCaP cell xenografts has been observed by betulinic acid treatment and this result was associated with reduction in the expression of Sp1, Sp3, and Sp4 proteins and vascular endothelial growth factor (VEGF)
VEGF↓,

2737- BetA,    Multiple molecular targets in breast cancer therapy by betulinic acid
- Review, Var, NA
TumCP↓, Betulinic acid (BA), a pipeline anticancer drug, exerts anti-proliferative effects on breast cancer cells is mainly through inhibition of cyclin and topoisomerase expression, leading to cell cycle arrest.
Cyc↓,
TOP1↓,
TumCCA↑,
angioG↓, anti-angiogenesis effect by inhibiting the expression of transcription factor nuclear factor kappa B (NF-κB), specificity protein (Sp) transcription factors, and vascular endothelial growth factor (VEGF) signaling.
NF-kB↓, Inhibition of NF-kB signaling pathway
Sp1/3/4↓,
VEGF↓,
MMPs↓, inhibiting the expression of matrix metalloproteases
ChemoSen↑, Synergistically interactions of BA with other chemotherapeutics are also described in the literature.
eff↑, BA is highly lipid soluble [74,75], and it readily passes through membranes, including plasma and mitochondrial membranes. BA acts directly on mitochondria
MMP↓, decreases mitochondrial outer membrane potential (MOMP), leading to increased outer membrane permeability, generation of reactive oxygen species (ROS),
ROS↑,
Bcl-2↓, reducing expression of anti-apoptotic proteins Bcl-2, Bcl-XL and Mcl-1
Bcl-xL↓,
Mcl-1↓,
lipid-P↑, BA inhibits the growth of breast cancer cells via lipid peroxidation resulting from the generation of ROS
RadioS↑, The cytotoxicity effect of BA on glioblastoma cells is not strong; however, some studies indicate that the combination of BA and radiotherapy could represent an advancement in treatment of glioblastoma [
eff↑, BA and thymoquinone inhibit MDR and induce cell death in MCF-7 breast cancer cells by suppressing BCRP [

2739- BetA,    Glycolytic Switch in Response to Betulinic Acid in Non-Cancer Cells
- in-vitro, Nor, HUVECs - in-vitro, Nor, MEF
*Glycolysis↑, BA elevates the rates of cellular glucose uptake and aerobic glycolysis in mouse embryonic fibroblasts with concomitant reduction of glucose oxidation.
*GlucoseCon↑, BA increases cellular glucose uptake
*Apoptosis↓, Without eliciting signs of obvious cell death BA leads to compromised mitochondrial function, increased expression of mitochondrial uncoupling proteins (UCP) 1 and 2, and liver kinase B1 (LKB1)-dependent activation AMP-activated protein kinase.
*UCP1↓,
*AMPK↑, AMPK activation accounts for the increased glucose uptake and glycolysis which in turn are indispensable for cell viability upon BA treatment.
GLUT1↑, The expression of glucose transporter GLUT1 was elevated upon BA treatment for 16 h
mt-ROS↑, We observed increased production of mitochondrial ROS (Fig. 4A) and elevated expression of uncoupling proteins UCP1 and UCP2 in BA-treated MEF

2743- BetA,    Betulinic acid and the pharmacological effects of tumor suppression
- Review, Var, NA
ROS↑, BA improves the level of reactive oxygen species (ROS) production and alters the mitochondrial membrane potential gradient, followed by the release of cytochrome c (Cyt c), which causes the mitochondrial-mediated apoptosis of tumor cells via a caspas
MMP↓,
Cyt‑c↑,
Apoptosis↑,
TumCCA↑, BA can inhibit cancer cell growth and proliferation via cell cycle arrest
Sp1/3/4↓, BA, can inhibit the protein expression of Sp1, Sp2 and Sp4 through the microRNA (miR)-27a-ZBTB10-Sp1 axis
STAT3↓, BA can downregulate the activation of STAT3 through the upregulation of Src homology 2 domain-containing phosphatase 1 (SHP-1)
NF-kB↓, NF-κB can be inhibited by reducing the activation of inhibitor of NF-κB (IκBα) kinase (IKKβ) and phosphorylation of IκBα with BA
EMT↓, nvasion and metastasis of malignancies is prevented via epithelial-mesenchymal transition (EMT) and inhibition of topoisomerase I
TOP1↓,
MAPK↑, BA leads to the activation, via phosphorylation, of pro-apoptotic MAPK proteins, P38 and SAP/JNK, the formation of ROS and the upregulation of caspase
p38↑,
JNK↑,
Casp↑,
Bcl-2↓, BA downregulates Bcl-2 and upregulates the Bax gene in HeLa cell lines
BAX↑,
VEGF↓, BA can decrease the expression of VEGF via Sp proteins, thus having an antiangiogenic role
LAMs↓, BA suppresses the expression of lamin B1 in pancreatic cancer cells

2744- BetA,    Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential
- Review, Var, NA
Apoptosis↓, Various studies have demonstrated that BE is able to induce apoptosis in numerous cancer cell lines (
TumCCA↑, 10 uM concentration, BE arrests cell cycle of murine melanoma B164A5 cells in S phase.
Casp9↑, BE is involved in the sequential activation of caspase-9, caspases 3 and 7, and cleaving of poly(ADP-ribose) polymerase (PARP) (Potze et al. 2014).
Casp3↑,
Casp7↑,
cl‑PARP↑,
MMP↓, mitochondrial membrane potential loss (Li et al. 2010; Potze et al. 2014).
ROS↑, increased reactive oxygen species (ROS) production
TOP1↓, BA was also shown to inhibit the proliferation of topoisomerases and therefore express anti-proliferative activity
NF-kB↓, BA was demonstrated to inhibit activating of NF-kB

2745- BetA,    Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors
- in-vitro, CRC, RKO - in-vitro, CRC, SW480 - in-vivo, NA, NA
Apoptosis↑, BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft
TumCG↓,
Sp1/3/4↓, BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells
survivin↓, decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1.
VEGF↓,
p65↓,
EGFR↓,
cycD1/CCND1↓,
ROS↑, due to induction of reactive oxygen species (ROS),
MMP↓, BA decreases MMP and induces ROS in RKO cells.

2746- BetA,    Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo
- in-vitro, CRC, HCT116 - in-vivo, CRC, NA
TumCG↓, BA inhibited colorectal cancer cell lines in vitro with a time-dependent and dose-dependent manner.
BAX↑, upregulating expression of Bax and cleaved caspase-3 and downregulating protein of Bcl-2
Bcl-2↓,
ROS↑, BA could increase the production of reactive oxygen species and reduce mitochondrial membrane potential of cancer cell, suggesting that BA induced cancer cells apoptosis by mitochondrial mediated pathways
MMP↓,
TIMP2↑, BA significantly inhibited the migration and invasion of colorectal cancer cells, reduced the expression of matrix metalloproteinase (MMPs) and increased the expression of MMPs inhibitor (TIMP-2).
TumVol↓,

2747- BetA,    Betulinic acid, a natural compound with potent anticancer effects
- Review, Var, NA
selectivity↑, potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells
Cyt‑c↑, induces Bax/Bak-independent cytochrome-c release.
*toxicity↓, In general, BetA is concluded to be less toxic to cells from healthy tissues.
TOP1↓, topoisomerase I/II
NF-kB↓, transcription factor NF-kB
ROS↑, Consistently, in glioma cells BetA-induced ROS generation
RadioS↑, Treatment with BetA in combination with irradiation resulted in additive growth inhibition of melanoma cells.
ChemoSen↑, BetA cooperated with anticancer drugs, doxorubicin and etoposide, to induce apoptosis and to inhibit clonogenic survival in SHEP neuroblastoma cells

2752- BetA,    Betulinic acid: a natural product with anticancer activity
- Review, Var, NA
selectivity↑, nontransformed cells of different origin, e.g., fibroblasts, melanocytes, neuronal cells and peripheral blood lymphocytes, have been reported to be much more resistant to the cytotoxic effect of BA than cancer cells
ChemoSen↑, BA was found to cooperate with various chemotherapeutic drugs, including doxorubicin, etoposide, cisplatin, taxol, and actinomycin D, to induce apoptosis and to inhibit clonogenic survival of tumor cells
RadioS↑, These reports suggest that using BetA as sensitizer in chemotherapy-, radiotherapy-, or TRAIL-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy.
MMP↓, BA directly induces loss of mitochondrial membrane potenti
cl‑Casp3↑, BA, induced cleavage of both caspases-8 and -3 in cytosolic extracts.
Cyt‑c↑, cytochrome c, released from mitochondria undergoing BA-mediated permeability transition, activated caspase-3 but not caspase-8 in a cell-free system.
ROS↑, Cleavage of caspases-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species (ROS).
NF-kB↑, BA is a potent activator of NF-kB in a variety of tumor cell lines.
TOP1↓, BA blocks the catalytic activity of topoisomerase I by abrogating the inter- action of the enzyme and the DNA substrate

2753- BetA,    Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells
- in-vitro, Cerv, HeLa
PI3K↓, BA treatment acted through downregulating a phosphatidylinositol 3-kinase (PI3K) subunit and suppressing the Akt phosphorylation at Thr308 and Ser473 after increasing the generation of intracellular reactive oxygen species
p‑Akt↓,
ROS↑,
TumCCA↑, BA induced cell cycle arrest at the G0/G1 phase, which was consistent with the cell cycle-related protein results in which BA significantly enhanced the expression of p27Kip and p21Waf1/Cip1 in HeLa cells.
p27↑,
P21↑,
mt-Apoptosis↑, mitochondrial apoptosis, as reflected by the increased expression of Bad and caspase-9
BAD↑,
Casp9↑,
MMP↓, decline in mitochondrial membrane potential.
eff↓, preincubation of the cells with glutathione (antioxidant) blocked the process of apoptosis, prevented the phosphorylation of downstream substrates.

2756- BetA,    Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway
- in-vitro, HCC, HUH7 - in-vitro, HCC, H1299
TumCP↓, betulinic acid could suppress proliferation and migration of hepatoma cells, raised ROS level and inhibited antioxidation level in cells
ROS↑,
antiOx↓,
TumCG↓, These findings indicate that betulinic acid has the capacity to significantly impede hepatoma cells growth and migration
TumCMig↓,
NRF2↓, The expression of antioxidant proteins Nrf2, GPX4 and HO-1 was also considerably lower in the BETM and BETH groups than in the Control group
GPx4↓,
HO-1↓,
NCOA4↑, suggesting that betulinic acid activates ferritinophagy by boosting NCOA4 expression and FTH1 degradation.
FTH1↓, betulinic acid groups (10 mg/kg, 20 mg/kg, and 40 mg/kg) greatly boosted LC3II and NCOA4 expressions and suppressed FTH1
Ferritin↑, In summation, betulinic acid decreases antioxidation in tumour tissues from nude mice, inhibits ferritin expression, enhances the expression of ferritinophagy-associated protein, activates ferritinophagy, and initiates ferroptosis in tumour cells.
Ferroptosis↑,
GSH↓, In comparison to the Control group, the betulinic acid groups (10 mg/kg, 20 mg/kg and 40 mg/kg) reduced dramatically GSH and hydroxyl radical inhibition capacity in serum, considerably increased serum Fe2+), and decreased dramatically serum MDA
MDA↓,

1566- betaCar,  Lyco,    Antioxidant and pro-oxidant effects of lycopene in comparison with beta-carotene on oxidant-induced damage in Hs68 cells
- in-vitro, Nor, HS68
*ROS↑, beta-carotene is known to have pro-oxidant activity in vitro
*ROS⇅, The present study in Hs68 cells demonstrates that lycopene can be either an antioxidant or a pro-oxidant depending on the oxidants used, and that lycopene and beta-carotene behave similarly under the in vitro oxidative conditions.
*Dose?, Both the antioxidant and pro-oxidant effects of lycopene tended to be dose-dependent

746- Bor,    Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope
- Review, NA, NA
eff↑, newly developed boron-containing compounds have already demonstrated highly promising activities
*toxicity↓, Boronic acid/ester has been successfully incorporated into cancer treatments and therapy mainly due to its remarkable oxophilicity and low toxicity levels in the body
ROS↑, can trigger tumour microenvironmental abnormalities such as high levels of reactive oxygen species (ROS) and overexpressed enzymes
LAT↓, boron accumulation were observed to counterpart LAT-1 expression in a bone metastasis model of breast cancer
AntiCan↑, high concentration of boron in males reduces the probability of prostate cancer by 54% compared to males with low boron concentrations
AR↓, bortezomib
PSMB5↓, bortezomib
IGF-1↓, insulin-like growth factor 1 (IGF-1) in tumours was markedly reduced by boric acid.
PSA↓, exposure to both low-and high-dose boron supplementation, prostate-specific antigen (PSA) levels dropped by an average of 87%, while tumour size declined by an average of 31.5%
TumVol↓,
eff↑, phenylboronic acid is a more potent inhibitor than boric acid in targeting metastatic and proliferative properties of prostate cancer cells
Rho↓, RhoA, Rac1
Cdc42↓,
Ca+2↓, ER Ca+2 depletion occurred after the treatment of DU-145 prostate cancer cells with the physiological concentrations of boric acid
eff↑, boric acid (BA), sodium pentaborate pentahydrate (NaB), and sodium perborate tetrahydrate (SPT) against SCLC cell line using DMS-114 cells

720- Bor,    High Concentrations of Boric Acid Trigger Concentration-Dependent Oxidative Stress, Apoptotic Pathways and Morphological Alterations in DU-145 Human Prostate Cancer Cell Line
- in-vitro, Pca, DU145
ROS↑, boric acid, known as an antioxidant, may prevent cell proliferation by acting as an oxidant in certain doses
TumCG↓,
Apoptosis↑,

722- Bor,    Boric acid as a promising agent in the treatment of ovarian cancer: Molecular mechanisms
- in-vitro, Ovarian, MDAH-2774
TumCP↓,
TumCI↓,
TumCMig↓,
Apoptosis↑,
ROS↑,
miR-21↓,
miR-130a↓,
Casp8∅, Caspase-8, Caspase-10, Cyclin D1, Cyclin D2, CDK6, CDK4, FADD, TRADD, FAS, DR4 and DR5 gene mRNA expression changes were found insignificant in boric acid treated group compared with control
Casp10∅,
cycD1/CCND1∅,
CDK6∅,
CDK4∅,
FADD∅,
DR4∅,
DR5∅,

727- Bor,  RSL3,  erastin,    Enhancement of ferroptosis by boric acid and its potential use as chemosensitizer in anticancer chemotherapy
- in-vitro, Liver, HepG2
ROS↑, at high, pharmacological concentrations
GSH↓, BA can increase intracellular ROS,
TBARS↑,
Ferroptosis↑,
ChemoSen↑, These observations suggest that BA could be exploited as a chemo-sensitizer agent in order to overcome cancer drug resistance in selected conditions.

726- Bor,    Redox Mechanisms Underlying the Cytostatic Effects of Boric Acid on Cancer Cells—An Issue Still Open
- Review, NA, NA
NAD↝, high affinity for the ribose moieties of NAD+
SAM-e↝, high affinity for S-adenosylmethione
PSA↓,
IGF-1↓,
Cyc↓, reduction in cyclins A–E
P21↓,
p‑MEK↓,
p‑ERK↓, ERK (P-ERK1/2)
ROS↑, induce oxidative stress by decreasing superoxide dismutase (SOD) and catalase (CAT)
SOD↓,
Catalase↓,
MDA↑,
GSH↓,
IL1↓, IL-1α
IL6↓,
TNF-α↓,
BRAF↝,
MAPK↝,
PTEN↝,
PI3K/Akt↝,
eIF2α↑,
ATF4↑,
ATF6↑,
NRF2↑,
BAX↑,
BID↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
Bcl-xL↓,

3522- Bor,    The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry
- Review, Var, NA
Hif1a↓, One compound, GN26361 (Table 2), potently inhibited the accumulation of HIF-1α under hypoxic conditions via the inhibition of hypoxia-induced HIF-1α transcriptional activity in HeLa cells (IC50 = 0.74 μM) [54].
HDAC↓, Peptidic boronic acids have also been studied for other microbial targets including as a hepatitis C virus (HCV) NS3/4A protease inhibitor [55], an antitubercular drug [56], penicillin-binding proteins [57], histone deacetylase (HDAC) inhibitors [58]
*CXCR2↑, reported boronic acid chemokine antagonist for CXCR 1 and 2 and was able to significantly inhibit inflammation in vivo
ROS↑, In addition to being used as ROS-activated prodrugs, boron-containing drugs have also been modified to form a prodrug, with the intention of increasing the favourability of their pharmacokinetic properties.

1421- Bos,    Coupling of boswellic acid-induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes
- in-vitro, AML, HL-60 - in-vitro, Nor, NA
ROS↑, AKBA and KBA strongly upregulated the formation of ROS, whereas β-BA and A-β-BA had only moderate effects
NADPH↝, AKBA-induced ROS formation involves NADPH oxidase, PI 3-K, and p42/44MAPK, and requires Ca2+
5LO↓, With respect to inhibition of 5-LO, 3-acetyl-11-keto-BA (AKBA) was the most potent BA, whereas BAs lacking an 11-keto-group were weak 5-LO inhibitor s
Ca+2↑, 11-keto-BAs potently stimulate the elevation of intracellular Ca2+ levels and activate p38 MAPK as well as p42MAPK
p38↑,
p42↑,

2024- Bos,    Antiproliferative and cell cycle arrest potentials of 3-O-acetyl-11-keto-β-boswellic acid against MCF-7 cells in vitro
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
MMP↓, mitochondrial membrane potential (ΔΨm) was reduced by increasing AKBA concentration with a significant release of cytochrome c.
Cyt‑c↑,
ROS↑, A significant increase in reactive oxygen species formation was observed. Compared with the untreated control, 1.32-, 1.61- and 2.44-fold ROS generation increases were achieved following 50, 100 and 200 µg mL−1 AKBA
Casp8↑, activated the production of caspase 8 and caspase 9 in a dose-dependent pattern
Casp9↑,
AntiTum↑, antitumoral activity against MCF-7 cells in a dose-dependent pattern with a reduction rate of 21.65 ± 6.63, 32.37 ± 6.97, 54.29 ± 5.35 and 61.42 ± 4.14% for the concentrations 50, 100, 200 and 400 µg mL−1, respectively
selectivity↑, cell inhibition rate with calculated IC50 of 101.1 and 275.2 for MCF-7 and MCF-10A, respectively
TumCCA↑, finally arrested the MCF-7 cell cycle at the G1 phase.

1448- Bos,    A triterpenediol from Boswellia serrata induces apoptosis through both the intrinsic and extrinsic apoptotic pathways in human leukemia HL-60 cells
- in-vitro, AML, HL-60
TumCP↓,
Apoptosis↑,
ROS↑, initial events involved massive reactive oxygen species (ROS) and nitric oxide (NO) formation
NO↑,
cl‑Bcl-2↑,
BAX↑, translocation of Bax to mitochondria
MMP↓, loss of mitochondrial membrane potential
Cyt‑c↑, release of cytochrome c to the cytosol
AIF↑, release to the cytosol
Diablo↑, release to the cytosol
survivin↓,
ICAD↓,
Casp↑,
cl‑PARP↑,
DR4↑,
TNFR 1↑,

1447- Bos,    Boswellia carterii n-hexane extract suppresses breast cancer growth via induction of ferroptosis by downregulated GPX4 and upregulated transferrin
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vivo, BC, 4T1 - in-vitro, Nor, MCF10
tumCV↓,
AntiCan↑, BCHE exhibited potent anti-BC activity in vivo
*toxicity↓, no significant toxic effects
Ferroptosis↑,
i-Iron↑, intracellular accumulation of Fe2+
GPx4↓,
ROS↑, upregulation of reactive oxygen species
lipid-P↑, induced lipid peroxidation in BC cells
Tf↑, Transferrin upregulation in tumor-bearing mice
TumCG↓,

1450- Bos,  Cisplatin,    3-Acetyl-11-keto-β-boswellic acid (AKBA) induced antiproliferative effect by suppressing Notch signaling pathway and synergistic interaction with cisplatin against prostate cancer cells
- in-vitro, Pca, DU145
ROS↑, increased reactive oxygen species (ROS) generation
MMP↓,
Casp↑,
Apoptosis↑,
Bax:Bcl2↑,
TumCCA?, induce G0/G1 arrest
cycD1/CCND1↓,
CDK4↓,
P21↑,
p27↑,
NOTCH↓, AKBA demonstrated significant downregulation of Notch signaling mediators
ChemoSen↑, AKBA has the potential to synergistically enhance the cytotoxic efficacy of cisplatin

2776- Bos,    Anti-inflammatory and anti-cancer activities of frankincense: Targets, treatments and toxicities
- Review, Var, NA
*5LO↓, Arthritis Human primary chondrocytes: 5-LOX↓, TNF-α↓, MMP3↓
*TNF-α↓,
*MMP3↓,
*COX1↓, COX-1↓, Leukotriene synthesis by 5-LOX↓
*COX2↓, Arthritis Human blood in vitro: COX-2↓, PGE2↓, TH1 cytokines↓, TH2 cytokines↑
*PGE2↓,
*Th2↑,
*Catalase↑, Ethanol-induced gastric ulcer: CAT↑, SOD↑, NO↑, PGE-2↑
*SOD↑,
*NO↑,
*PGE2↑,
*IL1β↓, inflammation Human PBMC, murine RAW264.7 macrophages: TNFα↓ IL-1β↓, IL-6↓, Th1 cytokines (IFNγ, IL-12)↓, Th2 cytokines (IL-4, IL-10)↑; iNOS↓, NO↓, phosphorylation of JNK and p38↓
*IL6↓,
*Th1 response↓,
*Th2↑,
*iNOS↓,
*NO↓,
*p‑JNK↓,
*p38↓,
GutMicro↑, colon carcinogenesis: gut microbiota; pAKT↓, GSK3β↓, cyclin D1↓
p‑Akt↓,
GSK‐3β↓,
cycD1/CCND1↓,
Akt↓, Prostate Ca: AKT and STAT3↓, stemness markers↓, androgen receptor↓, Sp1 promoter binding↓, p21(WAF1/CIP1)↑, cyclin D1↓, cyclin D2↓, DR5↑,CHOP↑, caspases-3/-8↑, PARP cleavage, NFκB↓, IKK↓, Bcl-2↓, Bcl-xL↓, caspase 3↑, DNA
STAT3↓,
CSCs↓,
AR↓,
P21↑,
DR5↑,
CHOP↑,
Casp3↑,
Casp8↑,
cl‑PARP↑,
DNAdam↑,
p‑RB1↓, Glioblastoma: pRB↓, FOXM1↓, PLK1↓, Aurora B/TOP2A pathway↓,CDC25C↓, pCDK1↓, cyclinB1↓, Aurora B↓, TOP2A↓, pERK-1/-2↓
FOXM1↓,
TOP2↓,
CDC25↓,
p‑CDK1↓,
p‑ERK↓,
MMP9↓, Pancreas Ca: Ki-67↓, CD31↓, COX-2↓, MMP-9↓, CXCR4↓, VEGF↓
VEGF↓,
angioG↓, Apoptosis↑, G2/M arrest, angiogenesis↓
ROS↑, ROS↑,
Cyt‑c↑, Leukemia : cytochrome c↑, AIF↑, SMAC/DIABLO↑, survivin↓, ICAD↓
AIF↑,
Diablo↑,
survivin↓,
ICAD↓,
ChemoSen↑, Breast Ca: enhancement in combination with doxorubicin
SOX9↓, SOX9↓
ER Stress↑, Cervix Ca : ER-stress protein GRP78↑, CHOP↑, calpain↑
GRP78/BiP↑,
cal2↓,
AMPK↓, Breast Ca: AMPK/mTOR signaling↓
mTOR↓,
ROS↓, Boswellia extracts and its phytochemicals reduced oxidative stress (in terms of inhibition of ROS and RNS generation)

2775- Bos,    The journey of boswellic acids from synthesis to pharmacological activities
- Review, Var, NA - Review, AD, NA - Review, PSA, NA
ROS↑, modulation of reactive oxygen species (ROS) formation and the resulting endoplasmic reticulum stress is central to BA’s molecular and cellular anticancer activities
ER Stress↑,
TumCG↓, Cell cycle arrest, growth inhibition, apoptosis induction, and control of inflammation are all the effects of BA’s altered gene expression
Apoptosis↑,
Inflam↓,
ChemoSen↑, BA has additional synergistic effects, increasing both the sensitivity and cytotoxicity of doxorubicin and cisplatin
Casp↑, BA decreases viability and induces apoptosis by activat- ing the caspase-dependent pathway in human pancreatic cancer (PC) cell lines
ERK↓, BA might inhibit the activation of Ak strain transforming (Akt) and extracellular signal–regulated kinase (ERK)1/2,
cl‑PARP↑, initiation of cleavage of PARP were prompted by the treatment with AKBA
AR↓, AKBA affects the androgen receptor by reducing its expression,
cycD1/CCND1↓, decrease in cyclin D1, which inhibits cellular proliferation
VEGFR2↓, In prostate cancer, the downregulation of vascular endothelial growth factor receptor 2–mediated angiogenesis caused by BA
CXCR4↓, Figure 6
radioP↑,
NF-kB↓,
VEGF↓,
P21↑,
Wnt↓,
β-catenin/ZEB1↓,
Cyt‑c↑,
MMP2↓,
MMP1↓,
MMP9↓,
PI3K↓,
MAPK↓,
JNK↑,
*5LO↓, Table 1 (non cancer)
*NRF2↑,
*HO-1↑,
*MDA↓,
*SOD↑,
*hepatoP↑, Preclinical studies demonstrated hepatoprotective impact for BA against different models of hepatotoxicity via tackling oxidative stress, and inflammatory and apoptotic indices
*ALAT↓,
*AST↓,
*LDH↑,
*CRP↓,
*COX2↓,
*GSH↑,
*ROS↓,
*Imm↑, oral administration of biopolymeric fraction (BOS 200) from B. serrata in mice led to immunostimulatory effects
*Dose↝, BA at low concentration tend to stimulate an immune response, as those utilized in the study of Beghelli et al. (2017) however, utilizing higher concentration suppressed the immune response
*eff↑, Useful actions on skin and psoriasis
*neuroP↑, AKBA has substantially diminished the levels of inflammatory markers such as 5-LOX, TNF-, IL-6, and meliorated cognition in lipopolysaccharide-induced neuroinflammation rodent models
*cognitive↑,
*IL6↓,
*TNF-α↓,

3032- CA,    Carnosic Acid Induces Apoptosis Through Reactive Oxygen Species-mediated Endoplasmic Reticulum Stress Induction in Human Renal Carcinoma Caki Cells
- in-vitro, Kidney, Caki-1
cl‑PARP↑, Carnosic acid induced sub-diploid DNA content, sub-G1, population and poly (ADP-ribose) polymerase (PARP) cleavage and activated caspase-3.
ROS↑, Carnosic acid promoted intracellular ROS production,
ER Stress↑, carnosic acid also induced expression of ER stress marker proteins, including activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP), in a dose- and time-dependent manner.
ATF4↑,
CHOP↑,
selectivity↑, Carnosic acid induced apoptosis in other cancer cells, but not normal cells

1651- CA,  PBG,    Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer
- Review, Var, NA
Apoptosis↑,
TumCCA↓, CAPE (1-80 uM) can stimulate apoptosis and cell cycle arrest (G1 phase
TumCMig↓,
TumMeta↓,
ChemoSen↑,
eff↑, Nanoparticles promote therapeutic effect of CA and CAPE in reducing cancer cell malignancy.
eff↑, improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid
eff↓, Currently, solvent extraction is utilized by methanol and ethyl acetate combination at high temperatures. However, a low amount of CA is yielded via this pathway
eff↝, Decyl CA (DCA) is a novel derivative of CA but its role in affecting colorectal cancer has not been completely understood.
Dose∅, The CAPE administration (0-60 uM) induces both autophagy and apoptosis in C6 glioma cells.
AMPK↑, CAPE induces autophagy via AMPK upregulation.
p62↓, CAPE can induce autophagy via p62 down-regulation and LC3-II upregulation
LC3II↑,
Ca+2↑, CA (0-1000 uM) enhances Ca2+ accumulation in cells in a concentration-dependent manner
Bax:Bcl2↑, CA can promote Bax/Bcl-2 ratio i
CDK4↑, The administration of CAPE (1–80 μM) can stimulate apoptosis and cell cycle arrest (G1 phase) via upregulation of Bax, CDK4, CDK6 and Rb
CDK6↑,
RB1↑,
EMT↓, CAPE has demonstrated high potential in inhibiting EMT in nasopharyngeal caner via enhancing E-cadherin levels, and reducing vimentin and β-catenin levels.
E-cadherin↑,
Vim↓,
β-catenin/ZEB1↓,
NF-kB↓,
angioG↑, CAPE (0.01-1ug/ml) inhibited angiogenesis via VEGF down-regulation
VEGF↓,
TSP-1↑, and furthermore, CAPE is capable of increasing TSP-1 levels
MMP9↓, CAPE was found to reduce MMP-9 expression
MMP2↓, CAPE can also down-regulate MMP-2
ChemoSen↑, role of CA and its derivatives in enhancing therapy sensitivity of cancer cells.
eff↑, CA administration (100 uM) alone or its combination with metformin (10 mM) can induce AMPK signaling
ROS↑, CA can promote ROS levels to induce cell death in human squamous cell carcinoma
CSCs↓, CA can reduce self-renewal capacity of CSCs and their migratory ability in vitro and in vivo.
Fas↑, CAPE (0-100 uM) is capable of inducing Fas signaling to promote p53 expression, leading to apoptotic cell death via Bax and caspase activation
P53↑,
BAX↑,
Casp↑,
β-catenin/ZEB1↓, anti-tumor activity of CAPE is mediated via reducing β-catenin levels
NDRG1↑, CAPE (30 uM) can promote NDRG1 expression via MAPK activation and down-regulation of STAT3
STAT3↓,
MAPK↑, CAPE stimulates mitogen-activated protein kinase (MAPK) and ERK
ERK↑,
eff↑, Res, thymoquinone and CAPE mediate lung tumor cell death via Bax upregulation and Bcl-2 down-regulation.
eff↑, co-administration of CA (100 μM) and metformin (10 mM) is of interest in cervical squamous cell carcinoma therapy.
eff↑, in addition to CA, propolis contains other agents such as chrysin, p-coumaric acid and ferulic acid that are beneficial in tumor suppression.

1652- CA,    Caffeic Acid and Diseases—Mechanisms of Action
- Review, Var, NA
Dose∅, Black chokeberries seem to be the most potent source of caffeic acid (645 mg/100 g of dry weight)
ROS⇅, Therefore, we will mention the antioxidant (and prooxidant) effects of caffeic acid only briefly
NF-kB↓, In HepG2 cells, caffeic acid (100 µM) inhibited the activity of NF-κB/IL-6/STAT3 signaling, which decreased the expression of VEGF
STAT3↓,
VEGF↓,
MMP9↓, inhibited another downstream product of NF-κB: matrix metalloproteinase 9 (MM-9), which promotes tumor invasiveness and metastases
HSP70/HSPA5↑, caffeic acid (20 μM) also decreased the expression of mortalin(mitochondrial 70 kDa heat shock protein),
AST↝, normalized levels of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acid, total cholesterol, HDL and LD
ALAT↝,
ALP↝,
Hif1a↓,
IL6↓,
IGF-1R↓,
P21↑,
iNOS↓,
ERK↓,
Snail↓,
BID↑,
BAX↑,
Casp3↑,
Casp7↑,
Casp9↑,
cycD1/CCND1↓,
Vim↓,
β-catenin/ZEB1↓,
COX2↓,
ROS↑, the chelating ability of caffeic acid is also responsible for its occasional pro-oxidant ability. After chelating Cu2+, the Cu2+ can be reduced to Cu+. combination of caffeic acid and endogenous copper ions can result in oxidative damage

1640- CA,  MET,    Caffeic Acid Targets AMPK Signaling and Regulates Tricarboxylic Acid Cycle Anaplerosis while Metformin Downregulates HIF-1α-Induced Glycolytic Enzymes in Human Cervical Squamous Cell Carcinoma Lines
- in-vitro, Cerv, SiHa
GLS↓, downregulation of Glutaminase (GLS) and Malic Enzyme 1 (ME1)
NADPH↓, CA alone and co-treated with Met caused significant reduction of NADPH
ROS↑, increased ROS formation and enhanced cell death
TumCD↑,
AMPK↑, activation of AMPK
Hif1a↓, Met inhibited Hypoxia-inducible Factor 1 (HIF-1α). CA treatment at 100 μM for 24 h also inhibited HIF-1α
GLUT1↓,
GLUT3↓,
HK2↓,
PFK↓, PFKFB4
PKM2↓,
LDH↓,
cMyc↓, Met suppressed the expression of c-Myc, BAX and cyclin-D1 (CCND1) a
BAX↓,
cycD1/CCND1↓,
PDH↓, CA at a concentration of 100 µM caused inhibition of PDK activity
ROS↑, CA Regulates TCA Cycle Supply via Pyruvate Dehydrogenase Complex (PDH), Induces Mitochondrial ROS Generation and Evokes Apoptosis
Apoptosis↑,
eff↑, both drugs inhibited the expression of ACLY and FAS, but the greatest effect was detected after co-treatment
ACLY↓,
FASN↓,
Bcl-2↓,
Glycolysis↓, Met acts as a glycolytic inhibitor under normoxic and hypoxic conditions

1650- CA,    Adjuvant Properties of Caffeic Acid in Cancer Treatment
- Review, Var, NA
ROS↑, CA can become a pro-oxidant due to its ability to chelate metals such as copper (Cu)
antiOx↑, CA, including its antioxidant, anti-inflammatory, and anticancer properties.
Inflam↓,
AntiCan↑,
NF-kB↓, ability to modulate several pathways, such as inhibiting NFkB, STAT3, and ERK1/2
STAT3↓,
ERK↓,
ChemoSen↑, mitigation of chemotherapy and radiotherapy-induced toxicity
RadioS↑,
AMPK↑, CA (100 μM) alone or in combination with metformin (10 mM) is efficient in stimulating the AMPK signaling pathway, which acts by preventing de novo synthesis of unsaturated fatty acids, consequently reducing cancer cell survival
eff↑, combined treatment with cisplatin (5 µM) and CA (10 µM) restored the chemo-sensitizing effect against cisplatin-resistant ovarian endometrioid adenocarcinoma cells (A2780)
selectivity↑, dual capacity of CA to act as an antioxidant during carcinogenesis and as a pro-oxidant against cancer cells, promoting their apoptosis or sensitizing them to chemotherapeutic drugs
COX2↓, CA has been discovered to impede Cyclooxygenase-2 (COX-2), an enzyme pivotal in the inflammatory cascade.
Dose∅, 50 to 10 µM, effectively suppresses COX-2
PHDs↓, CA serves as a potent inhibitor of prolyl hydroxylase-2 (PHD2),
MMP9↓, CA has been identified as an inhibitor of MMP-9
MMP2↓, CA and CAPE at doses of 5 mg/kg subcutaneously or 20 mg/kg orally. Both compounds exhibited the inhibition of MMP-2 and -9,
Dose∅, CA (0–200 μM) induces apoptosis and cell cycle arrest by increasing the expression profile of caspase 1 and caspase 3
Dose∅, CA (200–800 μM) has been shown to promote Ca2+ accumulation
Ca+2↑,
Dose?, Treatment with CA at a concentration of 20 μM disrupts mitochondrial function, which leads to several effects: increased Caspase-9 activity, elevated levels of ROS, and a decrease in membrane potential (Δψm)
MMP↓,
RadioS↑, Studies conducted on cells and animals indicate that CA enhances the efficacy of chemotherapy and radiotherapy, potentially mitigating their adverse effects and improving patient outcomes with minimal side effects

5204- CAP,    Low-concentration capsaicin promotes colorectal cancer metastasis by triggering ROS production and modulating Akt/mTOR and STAT-3 pathways
- in-vitro, Colon, SW480 - in-vitro, Colon, CT26
TumCP↓, high-concentration of capsaicin (≥ 200 µM for SW480 and CT-26 cell lines; ≥ 25 µM for HCT116 cell line) inhibited CRC cell proliferation in a dose-dependent manner
TumCMig↑, low-concentration of capsaicin (100 µM for SW480 and CT-26 cell lines; 12.5 µM for HCT116 cell line) enhanced both migratory and invasive capability of these cells
TumCI↑,
EMT↑, 100 µM capsaicin induced epithelial-to-mesenchymal (EMT), up-regulated expression of MMP-2 and MMP-9, and activated Akt/mTOR and STAT-3 pathways in SW480 cells.
MMP2↓,
MMP9↑,
STAT3↑,
TumMeta↑, capsaicin-induced metastasis of CRC cells was mediated by modulating reactive oxygen species (ROS) production.
ROS↑,

5202- CAP,    Capsaicin Suppresses Cell Proliferation, Induces Cell Cycle Arrest and ROS Production in Bladder Cancer Cells through FOXO3a-Mediated Pathways
- vitro+vivo, Bladder, 5637 - in-vitro, Bladder, T24/HTB-9
antiOx↑, Capsaicin (CAP), a highly selective agonist for transient receptor potential vanilloid type 1 (TRPV1), has been widely reported to exhibit anti-oxidant, anti-inflammation and anticancer activities.
Inflam↓,
AntiCan↓,
TRPV1↑, CAP could specifically activate TRPV1 [12,13] and interfere with the calcium signaling pathway
TumCP↓, CAP could suppress BCa tumorigenesis by inhibiting its proliferation both in vitro and in vivo.
TumCCA↑, CAP induced cell cycle arrest at G0/G1 phase and ROS production.
ROS↑,
FOXO3↑, strong increase of FOXO3a after treatment with CAP.
TumCMig↓, CAP Inhibited BCa Cell Proliferation and Migration

5201- CAP,    Inhibiting ROS-STAT3-dependent autophagy enhanced capsaicin-induced apoptosis in human hepatocellular carcinoma cells
- NA, HCC, HepG2
AntiCan↓, Capsaicin, which is the pungent ingredient of red hot chili peppers, has been reported to possess anticancer activity, including that against hepatocellular carcinoma.
Apoptosis↑, Capsaicin can induce apoptosis in HepG2 cells.
cl‑PARP↑, The expression levels of CL-PARP and Bcl-2 were significantly increased.
Bcl-2↑,
TumAuto↑, capsaicin can trigger autophagy in HepG2 cells.
LC3II↑, Capsaicin increased LC3-II and beclin-1 expression and GFP-LC3-positive autophagosomes.
eff↑, Pharmacological or genetic inhibition of autophagy further sensitized HepG2 cells to capsaicin-induced apoptosis.
STAT3↑, capsaicin upregulated the Stat3 activity which contributed to autophagy
ROS↑, capsaicin triggered reactive oxygen species (ROS) generation in hepatoma cells
eff↓, and that the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger.

5198- CAP,    Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines
- in-vitro, CRC, LoVo - in-vitro, CRC, Colo320
tumCV↓, Capsaicin decreased cell viability in a dose-dependent manner in Colo320DM and LoVo cells.
DNAdam↑, capsaicin produced cell morphology changes and DNA fragmentation, decreased the DNA contents, and induced phosphatidylserine translocation, which is a hallmark of apoptotic cell death
Apoptosis↑, We showed that capsaicin-induced apoptosis is associated with an increase in ROS generation and a disruption of the mitochondrial transmenbrane potential.
ROS↑,
MMP↑,
Casp3↑, capsaicin induced a dramatic increase in caspase 3 activity
chemoPv↑, it may be a beneficial agent for colon cancer treatment and chemoprevention.

2652- CAP,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
chemoPv↑, capsaicin has been reported as both a chemopreventive and as an anticancer agent
AntiCan↑,
ROS↑, Capsaicin has been reported to induce ROS-dependent cell death in various cancers, including colorectal [63], prostate [64,65], bladder [66,67,68], and pancreatic [69,70] cancers.
TumCG↓, reported to inhibit tumor growth in vivo in mouse xenograft models of prostate [64] and bladder [66] cancers.
ROS↑, Mechanistically, capsaicin-mediated ROS accumulation
MMP↑, leads to mitochondrial membrane depolarization [63,64,66],
Apoptosis↑, which further triggers mitochondria-dependent apoptosis
TumCCA↑, as well as G0/G1 cell cycle arrest
JNK↑, in bladder cancer cells, capsaicin induces JNK activation in an ROS-dependent manner
SOD↓, (1) inhibition of the activity of antioxidant enzymes SOD, catalase (CAT), and glutathione peroxidase [70];
Catalase↓,
GPx↓,
other↓, (2) inhibition of the activity of mitochondrial complex-I and complex-III in the electron transport chain [70];
SIRT1↓, (3) downregulation of the expression of sirtuin-1, a NAD-dependent deacetylase that regulates the expression of various antioxidant enzymes [69];
NADPH↑, (4) upregulation of the expression of NADPH oxidase 4, which generates superoxide [69];
FOXO3↑, (5) increased expression of FOXO3a, which is a transcription factor that regulates the oxidative stress response [68].

1517- CAP,    Capsaicin Inhibits Multiple Bladder Cancer Cell Phenotypes by Inhibiting Tumor-Associated NADH Oxidase (tNOX) and Sirtuin1 (SIRT1)
- in-vitro, Bladder, TSGH8301 - in-vitro, CRC, T24/HTB-9
ENOX2↓, capsaicin downregulates tNOX expression
TumCCA↑, Capsaicin Downregulates tNOX and Induces Cell Cycle Arrest at G1 Phase
ERK↓, inhibit the activation of ERK
p‑FAK↓,
p‑pax↓,
TumCMig↓,
EMT↓,
SIRT1↓, downregulation of sirtuin 1 (SIRT1) in these tNOX-knockdown cells
Dose∅, 100 and 200 μM effectively reduced tNOX expression in bladder cancer TSGH8301 and T24
ROS↑, capsaicin dose-dependently increased ROS generation
MMP↓,
Bcl-2↓,
Bak↑,
cl‑PARP↑,
Casp3↑,
SIRT1↓, 100 and 200 μM capsaicin decreased SIRT1 expression
ac‑P53↑, concurrently increased p53 acetylation
BIM↑, enhanced the expression level of Bim
p‑RB1↓, downregulation of phosphorylated Rb and cyclin D,
cycD1/CCND1↓,
Dose∅, Interestingly, cell migration was somewhat increased with 10 μM accompanied by up-regulation of tNOX expression
β-catenin/ZEB1↓,
N-cadherin↓,
E-cadherin↑,

1259- CAP,    Capsaicin inhibits HIF-1α accumulation through suppression of mitochondrial respiration in lung cancer cells
- in-vitro, Lung, H1299 - in-vitro, Lung, A549 - in-vitro, Lung, H23 - in-vitro, Lung, H2009
Hif1a↓, Under hypoxic conditions, capsaicin reduced the accumulation of HIF-1α protein
PDK1↓,
GLUT1↓,
ROS↑,
mitResp↓,
ATP↓,

2012- CAP,    Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways
- NA, OS, MG63
AntiTum↑, capsaicin induces apoptosis in various tumor cells as a mechanism of its anti-tumor activity
Apoptosis↑, capsaicin-induced apoptosis and the activation of transient receptor potential receptor vanilloid 1 (TRPV1) in a dose- and time-dependent manner in human osteosarcoma MG63 cells in vitro
TRPV1↑, TRPV1 activation is required for the capsaicin-induced overproduction of ROS and decrease in SOD activity
ROS↑, overproduction of reactive oxygen species (ROS)
SOD↓, decrease in superoxide dismutase (SOD) activity
AMPK↑, capsaicin induced the activation of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK), p53 and C-jun N-terminal kinase (JNK)
P53↑,
JNK↑,
Bcl-2↓, decrease in the level of B-cell lymphoma 2 (Bcl-2)
Cyt‑c↑, increase in the levels of Cytochrome C
cl‑Casp3↑, cleaved-caspase-3
cl‑PARP↑, cleaved polyadenosine diphosphate-ribose polymerase (PARP) in a time-dependent manner following capsaicin treatment in MG63 cells
Ca+2↑, Once the channel is activated, it can enable the rapid increase of intracellular calcium (Ca2+) levels and initiate cell death
MMP↓, several independent studies have demonstrated that capsaicin disrupted MMP (Δψm)

2014- CAP,    Role of Mitochondrial Electron Transport Chain Complexes in Capsaicin Mediated Oxidative Stress Leading to Apoptosis in Pancreatic Cancer Cells
- in-vitro, PC, Bxpc-3 - in-vitro, Nor, HPDE-6 - in-vivo, PC, AsPC-1
ROS↑, ROS was about 4–6 fold more as compared to control and as early as 1 h after capsaicin treatment in BxPC-3 and AsPC-1 cells
*ROS∅, but not in normal HPDE-6 cells
selectivity↑, only small ~1.2fold ROS increase in normal cell
compI↓, capsaicin inhibits about 2.5–9% and 5–20% of complex-I activity
compIII↓, and 8–75% of complex-III activity in BxPC-3 and AsPC-1 cells respectively
eff↑, which was attenuable by SOD, catalase and EUK-134.
selectivity↑, capsaicin treatment failed to inhibit complex-I or complex-III activities in normal HPDE-6 cells
ATP↓, ATP levels were drastically suppressed by capsaicin treatment in both BxPC-3 and AsPC-1 cells
Cyt‑c↑, release of cytochrome c and cleavage of both caspase-9 and caspase-3 due to disruption of mitochondrial membrane potential
Casp9↑,
Casp3↑,
MMP↓,
SOD↓, mice orally fed with 2.5 mg/kg capsaicin show decreased SOD activity and an increase in GSSG/GSH levels as compared to controls
GSH/GSSG↓, mice orally fed with 2.5 mg/kg capsaicin
Apoptosis↑, Capsaicin triggers apoptosis in pancreatic cancer cells but not in normal HPDE-6 cells
*toxicity∅, Capsaicin triggers apoptosis in pancreatic cancer cells but not in normal HPDE-6 cells
GSH↓, Taken together, our results suggest that depletion of GSH level and inhibition of SOD, catalase and GPx by capsaicin disturbs the cellular redox homeostasis resulting in increased oxidative stress.
Catalase↓,
GPx↓,
Dose↝, 13.2 mg dose of capsaicin for a 60 kg person

2018- CAP,  MF,    Capsaicin: Effects on the Pathogenesis of Hepatocellular Carcinoma
- Review, HCC, NA
TRPV1↑, Capsaicin is an agonist for transient receptor potential cation channel subfamily V member 1 (TRPV1)
eff↑, It is noteworthy that capsaicin binding to the TRPV1 receptor may be increased using a static magnetic field (SMF), thus enhancing the anti-cancer effect of capsaicin on HepG2 (human hepatoblastoma cell line) cells through caspase-3 apoptosis
Akt↓, capsaicin can regulate autophagy by inhibiting the Akt/mTOR
mTOR↓,
p‑STAT3↑, Capsaicin can upregulate the activity of the signal transducer and activator of transcription 3 (p-STAT3)
MMP2↑, increase of the expression of MMP-2
ER Stress↑, capsaicin may induce apoptosis through endoplasmic reticulum (ER) stress
Ca+2↑, and the subsequent ER release of Ca2+
ROS↑, Capsaicin-induced ROS generation
selectivity↑, On the other hand, an excess of capsaicin is cytotoxic on HepG2 cells, and normal hepatocytes to a smaller extent, by collapse of the mitochondrial membrane potential with ROS formation
MMP↓,
eff↑, combination of capsaicin and sorafenib demonstrated significant anticarcinogenic properties on LM3 HCC cells, restricting tumor cell growth

2019- CAP,    Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer
- Review, Var, NA
chemoPv↑, Capsaicin has shown significant prospects as an effective chemopreventive agent
Ca+2↑, Capsaicin was shown to cause upstream activation of Ca2+
antiOx↑, Another plausible mechanism implicated in the chemopreventive action of capsaicin is its anti-oxidative effects.
*ROS↓, capsaicin inhibits ROS release and the subsequent mitochondrial membrane potential collapse, cytochrome c expression, chromosome condensation, and caspase-3 activation induced by oxidized low-density lipoprotein in normal human HUVEC cells
*MMP∅,
*Cyt‑c∅,
*Casp3∅,
*eff↑, dietary curcumin and capsaicin concurrent administration in high-fat diet-fed rats were shown to mitigate the testicular and hepatic antioxidant status by increasing GSH levels, glutathione transferase activity, and Cu-ZnSOD expression
*Inflam↓, Anti-inflammation is another mechanism implicated in the chemopreventive action of capsaicin.
*NF-kB↓, inhibition of NF-kB by capsaicin
*COX2↓, compound elicits COX-2 enzyme activity inhibition and downregulation of iNOS
iNOS↓,
TRPV1↑, major pro-apoptotic mechanisms of capsaicin is via the vanilloid receptors, primarily TRPV1
i-Ca+2?, causing a concomitant influx of Ca2+: severe condition of mitochondria calcium overload. at high concentration (> 10 µM), capsaicin induces a slow but persistent increase in intracellular Ca2+
MMP↓, depolarization of mitochondria membrane potential
Cyt‑c↑, release of cytochrome C
Bax:Bcl2↑, activation of Bax and p53 through C-jun N-terminal kinase (JNK) activation
P53↑,
JNK↑,
PI3K↓, blocking the Pi3/Akt/mTOR signalling pathway, capsaicin increases levels of autophagic markers (LC3-II and Atg5)
Akt↓,
mTOR↓,
LC3II↑,
ATG5↑,
p62↑, enhances p62 and Fap-1 degradation and increases caspase-3 activity to induce apoptosis in human nasopharyngeal carcinoma cells
Fap1↓,
Casp3↑,
Apoptosis↑,
ROS↑, generation of ROS in human hepatoma (HepG2 cells)
MMP9↓, inhibition of MMP9 by capsaicin occurs via the suppression of AMPK-NF-κB, EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling pathway
eff↑, capsaicin 8% patch could promote the regeneration and restoration of skin nerve fibres in chemotherapy-induced peripheral neuropathy in addition to pain relief
eff↓, capsaicin has shown several unpleasant side effects, including stomach cramps, skin and gastric irritation, and burning sensation
eff↑, liposomes and micro-emulsion-based drugs have been known to significantly improve oral bioavailability and reduce the irritation of drugs
selectivity↑, In addition, these delivery systems can be surfaced-modified to perform site-directed/cell-specific drug delivery, thereby ensuring increased cell death of cancer cells while sparing non-selective normal cells
eff↑, Furthermore, owing to its antioxidant potential, capsaicin has been applied as a bioreduction and capping agent to synthesize biocompatible silver nanoparticles
ChemoSen↑, capsaicin has been combined with other anticancer therapies for more pronounced anticancer effects

2020- CAP,    Capsaicinoids and Their Effects on Cancer: The “Double-Edged Sword” Postulate from the Molecular Scale
- Review, Var, NA
AntiTum↑, highlighting its antitumor properties mediated by cytotoxicity and immunological adjuvancy against at least 74 varieties of cancer,
selectivity↑, while non-cancer cells tend to have greater tolerance
TRPV1↑, activation or phosphorylation of TRPV1
MMP↓, leads to cell membrane depolarization through the influx of Na2+ and Ca2+,
Ca+2↑,
ER Stress↑, endoplasmic reticulum stress [73], and the inhibition of angiogenesis
angioG↓,
Casp3?, increase in caspase-3 activation, PARP-1 cleavage
cl‑PARP↑,
selectivity↑, oxidative stress threshold reached by these could be potentially higher than that caused in normal cells (tNOX−) when exposed to CAP, possibly also contributing to the selectivity of its effects
ROS↑, increase in the production of reactive oxygen species (ROS),
*ROS∅, Remarkably, in this same work, cells derived from the normal epithelium of human pancreatic ducts (HPDE6-E6E7) showed high tolerance to the same treatment by keeping their ROS levels stable
selectivity↑, In this sense, non-transformed human astrocytes from a primary culture showed greater tolerance to CAP, as they did not experience any of the mentioned effects when exposed to the same treatment

603- Catechins,    Catechins induce oxidative damage to cellular and isolated DNA through the generation of reactive oxygen species
- in-vitro, NA, HL-60
ROS↑,
DNAdam↑,
H2O2↑,

939- Catechins,  5-FU,    Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil
- vitro+vivo, GC, SNU620
lactateProd↓, Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity
ROS↑, induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells.
tumCV↓,
LDHA↓, CA better than EGCG
mt-ROS↑, CA and 5FU significantly enhanced mitochondrial ROS production
proApCas↑,

2653- Cela,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
chemoPv↑, It has been widely studied as chemopreventive and anticancer drug
Catalase↑,
ROS↑, ROS induction has been attributed as the primary mode through which celastrol mediates its anticancer effects.
HSP90↓, celastrol has been reported to inhibit HSP90 function
Sp1/3/4↓, induce suppressor of specificity protein (Sp) repressors [79], activate the PKCzeta–AMPK-p53–PLK 2 signaling axis [73], and activate the JNK pathway [80,81] to induce apoptosis.
AMPK↑,
P53↑,
JNK↑,
ER Stress↑, celastrol induces ER stress [78], mitochondrial dysfunction, specifically disruption of mitochondrial membrane potential [72,78,82], and cell cycle arrest at G2/M phase [76,77] and S phase [75]
MMP↓,
TumCCA↑,
TumAuto↑, Interestingly, at low concentrations (i.e., below the cytotoxic threshold) celastrol was found to induce autophagy in gastric cancer cells through ROS-mediated accumulation of hypoxia-inducible factor 1-α via the transient activation of AKT.
Hif1a↑,
Akt↑,
other↓, (1) inhibition of mitochondrial respiratory chain complex I activity [80];
Prx↓, (2) inhibition of peroxiredoxins, namely peroxiredoxin-1 [76] and peroxiredoxin-2 [78].

4478- Chit,    Chitosan promotes ROS-mediated apoptosis and S phase cell cycle arrest in triple-negative breast cancer cells: evidence for intercalative interaction with genomic DNA
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, BC, T47D
TumCP↓, CS exerts an inhibitory effect on the proliferation of MDA-MB-231, MCF-7 and T47D breast cancer cells in a dose and time-dependent manner while being non-toxic to fibroblast L929 normal cells.
selectivity↑,
MMP↓, Exposure of MDA-MB-231 cells to CS led to depolarization of the mitochondrial membrane, increase in ROS, DNA oxidation, and S phase cell cycle arrest.
ROS↑, MDA-MB-231 cells treated with 70, 145 and 290 μg ml−1 CS for 12 h and 9.29, 13.40 and 20.50% increase in ROS generation was observed respectively
TumCCA↑, CS treated MDA-MB-231 cells exhibit cell cycle arrest in S phase
Apoptosis↑, progressively became apoptotic upon CS exposure
Casp3↑, CS increases caspase-3 activity in MDA-MB-231 cells

4479- Chit,    Chitosan nanoparticles triggered the induction of ROS-mediated cytoprotective autophagy in cancer cells
- in-vitro, Cerv, HeLa - in-vitro, HCC, SMMC-7721 cell
TumAuto↑, CS NPs at nontoxic concentrations ranging from 10–100 μg/mL triggered the induction of autophagy
ROS↑, CS NPs-mediated autophagy was implicated in reactive oxygen species (ROS) generation and the ROS scavenger N-acetylcysteine (NAC) attenuated CS-induced autophagy.
eff↓, (NAC) attenuated CS-induced autophagy.

4481- Chit,    Antioxidant Properties and Redox-Modulating Activity of Chitosan and Its Derivatives: Biomaterials with Application in Cancer Therapy
- Review, Var, NA
*BioAv↑, It is known that chitosan exhibits versatile biological properties, including biodegradability, biocompatibility, and a less toxic nature.
*toxicity↓,
*antiOx↑, Because of its antioxidant, antibacterial, anticancer, anti-inflammatory, and immunostimulatory activities, the biopolymer has been used in a wide variety of pharmaceutical, biomedical, food industry, health, and agricultural applications and has bee
AntiCan↑,
*Inflam↓,
*ROS↓, Many in vitro and in vivo studies have shown that chitosan exhibits redox-regulatory activity due to inhibition of ROS production, prevention of lipid oxidation by significantly reduced serum free fatty acids, and malondialdehyde concentrations
*lipid-P↓,
MDA↓,
selectivity↑, hitosan exerts an inhibitory effect on the proliferation of MDA-MB-231, MCF-7, and T47D breast cancer cells in a dose- and time-dependent manner, while being non-toxic to fibroblast L929 normal cells.
MMP↓, exposure of MDA-MB-231 cells to chitosan led to depolarization of the mitochondrial membrane, increase of ROS generation, DNA oxidation, and S phase cell cycle arrest.
ROS↑,
TumCCA↑,
MDA↑, in vitro, chitosan nanoparticles showed high antitumor activities, which were accompanied with an increase in MDA level and a decrease in GSH level in tumor tissues.
GSH↓,
ChemoSen↑, Possible Mechanism for Sensitizing Cancer Cells Toward Chemotherapeutics

4482- Chit,    Hyaluronic acid-coated chitosan nanoparticles induce ROS-mediated tumor cell apoptosis and enhance antitumor efficiency by targeted drug delivery via CD44
- in-vitro, Lung, A549 - in-vitro, Liver, HepG2
EPR↑, A-coated chitosan NPs enhanced drug accumulation by effectively transporting NPs into CD44-overexpressed tumor cells, and they also resulted in mitochondrial damage induced by the production of reactive oxygen species (ROS).
mtDam↑,
ROS↑,
Apoptosis↑, Compared to free drug and uncoated NPs, HA-coated chitosan NPs exhibited stronger inhibition rates and induced obvious apoptosis in CD44-overexpressed A549 cells.

2801- CHr,    AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells
- in-vitro, Lung, A549
AMPK↑, demonstrated a significant AMPK activation after chrysin treatment in A549 cells
Akt↓, inhibited Akt/mammalian target of rapamycin (mTOR) activation
ChemoSen↑, Chrysin increases doxorubicin-induced AMPK activation to promote A549 cell death and growth inhibition
ROS↑, Recently, studies have confirmed that chrysin is a potent inducer of ROS and in A549 and other cancer cells

2804- CHr,  Rad,    Gamma-Irradiated Chrysin Improves Anticancer Activity in HT-29 Colon Cancer Cells Through Mitochondria-Related Pathway
- in-vitro, CRC, HT29
RadioS↑, enhancement of the anticancer effects of chrysin upon exposure to gamma irradiation
ROS↑, excessive production of included reactive oxygen species, the dissipation of the mitochondrial membrane potential, regulation of the B cell lymphoma-2 family, activation of caspase-9, 3, and cleavage of poly (adenosine diphosphate-ribose) polymerase.
MMP↓,
Casp3↑,
Casp9↑,
cl‑PARP↑,

2806- CHr,  Se,    Selenium-containing chrysin and quercetin derivatives: attractive scaffolds for cancer therapy
- in-vitro, Var, NA
eff↑, SeChry elicited a noteworthy cytotoxic activity with mean IC50 values 18- and 3-fold lower than those observed for chrysin and cisplatin, respectively
selectivity↑, differential behavior toward malignant and nonmalignant cells was observed for SeChry and SePQue, exhibiting higher selectivity indexes
Dose↝, 5 min. of microwave irradiation at 175 W (150 ºC) of an acetonitrile WR and flavonoid solution on a sealed pyrex microwave vial,
TrxR↓, Both compounds were able to decrease cellular TrxR
GSH↓, The results clearly showed that after treatment with both seleno-flavonoids total glutathione concentration (GSH + GSSG) decreased
MMP↓, MMP reduced by up to four times compared to control cells
ROS↑, Both seleno-derivatives were able to increase the oxidant basal production
H2O2↑, ore dramatic decrease of the MMP and a higher ability to increase the hydrogen peroxide basal production,

2781- CHr,  PBG,    Chrysin a promising anticancer agent: recent perspectives
- Review, Var, NA
PI3K↓, It can block Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling in different animals against various cancers
Akt↓,
mTOR↓,
MMP9↑, Chrysin strongly suppresses Matrix metalloproteinase-9 (MMP-9), Urokinase plasminogen activator (uPA) and Vascular endothelial growth factor (VEGF), i.e. factors that can cause cancer
uPA↓,
VEGF↓,
AR↓, Chrysin has the ability to suppress the androgen receptor (AR), a protein necessary for prostate cancer development and metastasis
Casp↑, starts the caspase cascade and blocks protein synthesis to kill lung cancer cells
TumMeta↓, Chrysin significantly decreased lung cancer metastasis i
TumCCA↑, Chrysin induces apoptosis and stops colon cancer cells in the G2/M cell cycle phase
angioG↓, Chrysin prevents tumor growth and cancer spread by blocking blood vessel expansion
BioAv↓, Chrysin’s solubility, accessibility and bioavailability may limit its medical use.
*hepatoP↑, As chrysin reduced oxidative stress and lipid peroxidation in rat liver cells exposed to a toxic chemical agent.
*neuroP↑, Protecting the brain against oxidative stress (GPx) may be aided by increasing levels of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx).
*SOD↑,
*GPx↑,
*ROS↓, A decrease in oxidative stress and an increase in antioxidant capacity may result from chrysin’s anti-inflammatory properties
*Inflam↓,
*Catalase↑, Supplementation with chrysin increased the activity of antioxidant enzymes like SOD and catalase and reduced the levels of oxidative stress markers like malondialdehyde (MDA) in the colon tissue of the rats.
*MDA↓, Antioxidant enzyme activity (SOD, CAT) and oxidative stress marker (MDA) levels were both enhanced by chrysin supplementation in mouse liver tissue
ROS↓, reduction of reactive oxygen species (ROS) and oxidative stress markers in the cancer cells further indicated the antioxidant activity of chrysin
BBB↑, After crossing the blood-brain barrier, it has been shown to accumulate there
Half-Life↓, The half-life of chrysin in rats is predicted to be close to 2 hours.
BioAv↑, Taking chrysin with food may increase the effectiveness of the supplement: increased by a factor of 1.8 when taken with a high-fat meal
ROS↑, In contrast to 5-FU/oxaliplatin, chrysin increases the production of reactive oxygen species (ROS), which in turn causes autophagy by stopping Akt and mTOR from doing their jobs
eff↑, mixture of chrysin and cisplatin caused the SCC-25 and CAL-27 cell lines to make more oxygen free radicals. After treatment with chrysin, cisplatin, or both, the amount of reactive oxygen species (ROS) was found to have gone up.
ROS↑, When reactive oxygen species (ROS) and calcium levels in the cytoplasm rise because of chrysin, OC cells die.
ROS↑, chrysin is the cause of death in both types of prostate cancer cells. It does this by depolarizing mitochondrial membrane potential (MMP), making reactive oxygen species (ROS), and starting lipid peroxidation.
lipid-P↑,
ER Stress↑, when chrysin is present in DU145 and PC-3 cells, the expression of a group of proteins that control ER stress goes up
NOTCH1↑, Chrysin increased the production of Notch 1 and hairy/enhancer of split 1 at the protein and mRNA levels, which stopped cells from dividing
NRF2↓, Not only did chrysin stop Nrf2 and the genes it controls from working, but it also caused MCF-7 breast cancer cells to die via apoptosis.
p‑FAK↓, After 48 hours of treatment with chrysin at amounts between 5 and 15 millimoles, p-FAK and RhoA were greatly lowered
Rho↓,
PCNA↓, Lung histology and immunoblotting studies of PCNA, COX-2, and NF-B showed that adding chrysin stopped the production of these proteins and maintained the balance of cells
COX2↓,
NF-kB↓,
PDK1↓, After the chrysin was injected, the genes PDK1, PDK3, and GLUT1 that are involved in glycolysis had less expression
PDK3↑,
GLUT1↓,
Glycolysis↓, chrysin stops glycolysis
mt-ATP↓, chrysin inhibits complex II and ATPases in the mitochondria of cancer cells
Ki-67↓, the amounts of Ki-67, which is a sign of growth, and c-Myc in the tumor tissues went down
cMyc↓,
ROCK1↓, (ROCK1), transgelin 2 (TAGLN2), and FCH and Mu domain containing endocytic adaptor 2 (FCHO2) were much lower.
TOP1↓, DNA topoisomerases and histone deacetylase were inhibited, along with the synthesis of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and (IL-1 beta), while the activity of protective signaling pathways was increased
TNF-α↓,
IL1β↓,
CycB/CCNB1↓, Chrysin suppressed cyclin B1 and CDK2 production in order to stop cancerous growth.
CDK2↓,
EMT↓, chrysin treatment can also stop EMT
STAT3↓, chrysin block the STAT3 and NF-B pathways, but it also greatly reduced PD-L1 production both in vivo and in vitro.
PD-L1↓,
IL2↑, chrysin increases both the rate of T cell growth and the amount of IL-2

2782- CHr,    Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives
- Review, Var, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, antioxidant, anti-inflammatory, hepatoprotective, neuroprotective
*Inflam↓, inhibitory effect of chrysin on inflammation and oxidative stress is also important in Parkinson’s disease
*hepatoP↑,
*neuroP↑,
*BioAv↓, Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects
*cardioP↑, cardioprotective [69], lipid-lowering effect [70]
*lipidLev↓,
*RenoP↑, Renoprotective
*TNF-α↓, chrysin reduces levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).
*IL2↓,
*PI3K↓, induction of the PI3K/Akt signaling pathway by chrysin contributes to a reduction in oxidative stress and inflammation during cerebral I/R injury
*Akt↓,
*ROS↓,
*cognitive↑, Chrysin (25, 50, and 100 mg/kg) improves cognitive capacity, inflammation, and apoptosis to ameliorate traumatic brain injury
eff↑, chrysin and silibinin is beneficial in suppressing breast cancer malignancy via decreasing cancer proliferation
cycD1/CCND1↓, chrysin and silibinin induced cell cycle arrest via down-regulation of cyclin D1 and hTERT
hTERT/TERT↓,
VEGF↓, Administration of chrysin is associated with the disruption of hypoxia-induced VEGF gene expression
p‑STAT3↓, chrysin is capable of reducing STAT3 phosphorylation in hypoxic conditions without affecting the HIF-1α protein level.
TumMeta↓, chrysin is a potent agent in suppressing metastasis and proliferation of breast cancer cells during hypoxic conditions
TumCP↓,
eff↑, combination therapy of breast cancer cells using chrysin and metformin exerts a synergistic effect and is more efficient compared to chrysin alone
eff↑, combination of quercetin and chrysin reduced levels of pro-inflammatory factors, such as IL-1β, Il-6, TNF-α, and IL-10, via NF-κB down-regulation.
IL1β↓,
IL6↓,
NF-kB↓,
ROS↑, after chrysin administration, an increase occurs in levels of ROS that, subsequently, impairs the integrity of the mitochondrial membrane, leading to cytochrome C release and apoptosis induction
MMP↓,
Cyt‑c↑,
Apoptosis↑,
ER Stress↑, in addition to mitochondria, ER can also participate in apoptosis
Ca+2↑, Upon chrysin administration, an increase occurs in levels of ROS and cytoplasmic Ca2+ that mediate apoptosis induction in OC cells
TET1↑, In MKN45 cells, chrysin promotes the expression of TET1
Let-7↑, Chrysin is capable of promoting the expression of miR-9 and Let-7a as onco-suppressor factors in cancer to inhibit the proliferation of GC cells
Twist↓, Down-regulation of NF-κB, and subsequent decrease in Twist/EMT are mediated by chrysin administration, negatively affecting cervical cancer metastasis
EMT↓,
TumCCA↑, nduction of cell cycle arrest and apoptosis via up-regulation of caspase-3, caspase-9, and Bax are mediated by chrysin
Casp3↑,
Casp9↑,
BAX↑,
HK2↓, Chrysin administration (15, 30, and 60 mM) reduces the expression of HK-2 in hepatocellular carcinoma (HCC) cells to impair glucose uptake and lactate production.
GlucoseCon↓,
lactateProd↓,
Glycolysis↓, In addition to glycolysis metabolism impairment, the inhibitory effect of chrysin on HK-2 leads to apoptosis
SHP1↑, upstream modulator of STAT3 known as SHP-1 is up-regulated by chrysin
N-cadherin↓, Furthermore, N-cadherin and E-cadherin are respectively down-regulated and up-regulated upon chrysin administration in inhibiting melanoma invasion
E-cadherin↑,
UPR↑, chrysin substantially diminishes survival by ER stress induction via stimulating UPR, PERK, ATF4, and elF2α
PERK↑,
ATF4↑,
eIF2α↑,
RadioS↑, Irradiation combined with chrysin exerts a synergistic effect
NOTCH1↑, Irradiation combined with chrysin exerts a synergistic effect
NRF2↓, in reducing Nrf2 expression, chrysin down-regulates the expression of ERK and PI3K/Akt pathways—leading to an increase in the efficiency of doxorubicin in chemotherapy
BioAv↑, chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake
eff↑, Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion

2784- CHr,    Chrysin targets aberrant molecular signatures and pathways in carcinogenesis (Review)
- Review, Var, NA
Apoptosis↑, apoptosis, disrupting the cell cycle and inhibiting migration without generating toxicity or undesired side‑effects in normal cells
TumCMig↓,
*toxicity↝, toxic at higher doses and the recommended dose for chrysin is <3 g/day
ChemoSen↑, chrysin also inhibits multi‑drug resistant proteins and is effective in combination therapy
*BioAv↓, extremely low bioavailability in humans due to rapid quick metabolism, removal and restricted assimilation. The bioavailability of chrysin when taken orally has been estimated to be between 0.003 to 0.02%
Dose↝, safe and effective in various studies where volunteers have taken oral doses ranging from 300 to 625 mg without experiencing any documented effect
neuroP↑, Chrysin has been shown to exert neuroprotective effects via a variety of mechanisms, such as gamma-aminobutyric acid mimetic properties, monoamine oxidase inhibition, antioxidant, anti-inflammatory and anti-apoptotic activities
*P450↓, Chrysin inhibits cytochrome P450 2E1, alcohol dehydrogenase and xanthine oxidase at various dosages (20 and 40 mg/kg body weight) and protects Wistar rats against oxidative stress
*ROS↓,
*HDL↑, ncreased the levels of high-density lipoprotein cholesterol, glutathione S-transferase, superoxide dismutase and catalase
*GSTs↑,
*SOD↑,
*Catalase↑,
*MAPK↓, inactivate the MAPK/JNK pathway and suppress the NF-κB pathways, and at the same time upregulate the expression of PTEN, and activate the VEGF/AKT pathway
*NF-kB↓,
*PTEN↑,
*VEGF↑,
ROS↑, chrysin treatment in ovarian cancer led to the augmented generation of reactive oxygen species, a decrease in MMP and an increase in cytoplasmic Ca2+,
MMP↓,
Ca+2↑,
selectivity↑, It has been found that chrysin has no cytotoxic effect on normal cells, such as fibroblasts
PCNA↓, Chrysin likewise downregulates proliferating cell nuclear antigen (PCNA) expression in cervical carcinoma cells
Twist↓, Chrysin decreases the expression of TWIST 1 and NF-κB and thus suppresses epithelial-mesenchymal transition (EMT) in HeLa cells
EMT↓,
CDKN1C↑, Chrysin administration led to the upregulation of CDKN1 at the transcript and protein leve
p‑STAT3↑, Chrysin decreased the viability of 4T1 breast cancer cells by suppressing hypoxia-induced phosphorylation of STAT3
MMP2↓, chrysin-loaded PGLA/PEG nanoparticles modulated TIMPS and MMP2 and 9, and PI3K expression in a mouse 4T1 breast tumor model
MMP9↓,
eff↑, Chrysin used alone and as an adjuvant with metformin has been found to downregulate cyclin D and hTERT expression in the breast cancer cell line
cycD1/CCND1↓,
hTERT/TERT↓,
CLDN1↓, CLDN1 and CLDN11 expression have been found to be higher in human lung squamous cell carcinoma. Treatment with chrysin treatment reduces both the mRNA and protein expression of these claudin genes
TumVol↓, Treatment with chrysin treatment (1.3 mg/kg body weight) significantly decreases tumor volume, resulting in a 52.6% increase in mouse survival
OS↑,
COX2↓, Chrysin restores the cellular equilibrium of cells subjected to benzopyrene by downregulating the expression of elevated proteins, such as PCNA, NF-κB and COX-2
eff↑, quercetin and chrysin together decreased the levels of pro-inflammatory molecules, such as IL-6, -1 and -10, and the levels of TNF via the NF-κB pathway.
CDK2↓, Chrysin has been shown to inhibit squamous cell carcinoma via the modulation of Rb and by decreasing the expression of CDK2 and CDK4
CDK4↓,
selectivity↑, chrysin selectively exhibits toxicity and induces the self-programed death of human uveal melanoma cells (M17 and SP6.5) without having any effect on normal cells
TumCCA↑, halting the cell cycle at the G2/M or G1/S phases
E-cadherin↑, upregulation of E-cadherin and the downregulation of cadherin
HK2↓, Chrysin decreased expression of HK-2 in mitochondria, and the interaction between HK-2 and VDAC 2 was disrupted,
HDAC↓, Chrysin, a HDAC inhibitor, caused cytotoxicity, and also inhibited migration and invasion.

2785- CHr,    Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin
- Review, Var, NA
*NF-kB↓, suppressed pro-inflammatory cytokine expression and histamine release, downregulated nuclear factor kappa B (NF-kB), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS)
*COX2↓,
*iNOS↓,
angioG↓, upregulated apoptotic pathways [28], inhibited angiogenesis [29] and metastasis formation
TOP1↓, suppressed DNA topoisomerases [31] and histone deacetylase [32], downregulated tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)
HDAC↓,
TNF-α↓,
IL1β↓,
cardioP↑, promoted protective signaling pathways in the heart [34], kidney [35] and brain [8], decreased cholesterol level
RenoP↑,
neuroP↑,
LDL↓,
BioAv↑, bioavailability of chrysin in the oral route of administration was appraised to be 0.003–0.02% [55], the maximum plasma concentration—12–64 nM
eff↑, Chrysin alone and potentially in combination with metformin decreased cyclin D1 and hTERT gene expression in the T47D breast cancer cell line
cycD1/CCND1↓,
hTERT/TERT↓,
MMP-10↓, Chrysin pretreatment inhibited MMP-10 and Akt signaling pathways
Akt↓,
STAT3↓, Chrysin declined hypoxic survival, inhibited activation of STAT3, and reduced VEGF expression in hypoxic cancer cells
VEGF↓,
EGFR↓, chrysin to inhibit EGFR was reported in a breast cancer stem cell model [
Snail↓, chrysin downregulated MMP-10, reduced snail, slug, and vimentin expressions increased E-cadherin expression, and inhibited Akt signaling pathway in TNBC cells, proposing that chrysin possessed a reversal activity on EMT
Slug↓,
Vim↓,
E-cadherin↑,
eff↑, Fabrication of chrysin-attached to silver and gold nanoparticles crossbred reduced graphene oxide nanocomposites led to augmentation of the generation of ROS-induced apoptosis in breast cancer
TET1↑, Chrysin induced augmentation in TET1
ROS↑, Pretreatment with chrysin induced ROS formation, and consecutively, inhibited Akt phosphorylation and mTOR.
mTOR↓,
PPARα↓, Chrysin inhibited mRNA expression of PPARα
ER Stress↑, ROS production by chrysin was the critical mediator behind induction of ER stress, leading to JNK phosphorylation, intracellular Ca2+ release, and activation of the mitochondrial apoptosis pathway
Ca+2↑,
ERK↓, reduced protein expression of p-ERK/ERK
MMP↑, Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c.
Cyt‑c↑,
Casp3↑, Chrysin could elevate caspase-3 activity in the HCC rats group
HK2↓, chrysin declined HK-2 combined with VDAC-1 on mitochondria
NRF2↓, chrysin inhibited the Nrf2 expression and its downstream genes comprising AKR1B10, HO-1, and MRP5 by quenching ERK and PI3K-Akt pathway
HO-1↓,
MMP2↓, Chrysin pretreatment also downregulated MMP2, MMP9, fibronectin, and snail expression
MMP9↓,
Fibronectin↓,
GRP78/BiP↑, chrysin induced GRP78 overexpression, spliced XBP-1, and eIF2-α phosphorylation
XBP-1↓,
p‑eIF2α↑,
*AST↓, Chrysin administration significantly reduced AST, ALT, ALP, LDH and γGT serum activities
ALAT↓,
ALP↓,
LDH↓,
COX2↑, chrysin attenuated COX-2 and NFkB p65 expression, and Bcl-xL and β-arrestin levels
Bcl-xL↓,
IL6↓, Reduction in IL-6 and TNF-α and augmentation in caspases-9 and 3 were observed due to chrysin supplementation.
PGE2↓, Chrysin induced entire suppression NF-kB, COX-2, PG-E2, iNOS as well.
iNOS↓,
DNAdam↑, Chrysin induced apoptosis of cells by causing DNA fragmentation and increasing the proportions of DU145 and PC-3 cells
UPR↑, Also, it induced ER stress via activation of UPR proteins comprising PERK, eIF2α, and GRP78 in DU145 and PC-3 cells.
Hif1a↓, Chrysin increased the ubiquitination and degradation of HIF-1α by increasing its prolyl hydroxylation
EMT↓, chrysin was effective in HeLa cell by inhibiting EMT and CSLC properties, NF-κBp65, and Twist1 expression
Twist↓,
lipid-P↑, Chrysin disrupted intracellular homeostasis by altering MMP, cytosolic Ca (2+) levels, ROS generation, and lipid peroxidation, which plays a role in the death of choriocarcinoma cells.
CLDN1↓, Chrysin decreased CLDN1 and CLDN11 expression in human lung SCC
PDK1↓, Chrysin alleviated p-Akt and inhibited PDK1 and Akt
IL10↓, Chrysin inhibited cytokines release, TNF-α, IL-1β, IL-10, and IL-6 induced by Ni in A549 cells.
TLR4↓, Chrysin suppressed TLR4 and Myd88 mRNA and protein expression.
NOTCH1↑, Chrysin inhibited tumor growth in ATC both in vitro and in vivo through inducing Notch1
PARP↑, Pretreating cells with chrysin increased cleaved PARP, cleaved caspase-3, and declined cyclin D1, Mcl-1, and XIAP.
Mcl-1↓,
XIAP↓,

2790- CHr,    Chrysin: Pharmacological and therapeutic properties
- Review, Var, NA
*hepatoP↑, graphical abstract
*neuroP↓,
*ROS↓,
*cardioP↑,
*Inflam↓,
eff↑, suppression of hTERT and cyclin D1 gene expression in T47D breast cancer cell lines is due to the combined effect of metformin and chrysin
hTERT/TERT↓,
cycD1/CCND1↓,
MMP9↓, nanoparticle-based chrysin in C57B16 mice bearing B16F10 melanoma tumors was markedly presented reductions in the levels of MMP-9, MMP-2, and TERT genes, whereas it enhanced TIMP-2 andTIMP-1 genes expression
MMP2↓,
TIMP1↑,
TIMP2↑,
BioAv↑, nano-encapsulation of chrysin and curcumin improved the delivery of these phytochemicals that significantly inhibited the growth of cancer cells, while it decreased the hTERT gene expression via increased solubility and bioavailability
HK2↓, chrysin treatment restrained tumor growth in HCC xenograft models and significantly reduced HK-2 expression in tumor tissue
ROS↑, showing a significant increase in intracellular reactive oxygen species (ROS), cytotoxicity, mitochondrial membrane potential (MMP) collapse, caspase-3 activation, ADP/ATP ratio, and ultimately apoptosis
MMP↓,
Casp3↑,
ADP:ATP↑,
Apoptosis↑,
ER Stress↑, Likewise, chrysin encouraged endoplasmic reticulum (ER) stress via stimulation of unfolded protein response (UPR
UPR↑,
GRP78/BiP↝, (eIF2α), PRKR-like ER kinase (PERK) and 78 kDa glucose-regulated protein (GRP78).
eff↑, silibinin and chrysin synergistically inhibited growth of T47D BCC and downregulated the hTERT and cyclin D1 level
Ca+2↑, Primarily, increased ROS and cytoplasmic Ca 2+ levels alongside induction of cell death and loss of MMP are involved in inhibition of ovarian cancer through chrysin.

2791- CHr,    Chrysin attenuates progression of ovarian cancer cells by regulating signaling cascades and mitochondrial dysfunction
- in-vitro, Ovarian, OV90
TumCP↓, chrysin inhibited ovarian cancer cell proliferation and induced cell death by increasing reactive oxygen species (ROS) production and cytoplasmic Ca2+ levels as well as inducing loss of mitochondrial membrane potential (MMP).
TumCD↑,
ROS↑,
Ca+2↑,
MMP↓,
MAPK↑, chrysin activated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in ES2 and OV90 cells in concentration-response experiments
PI3K↑, results indicate that the chrysin-induced activation of PI3K and MAPK signaling molecules, which induced apoptosis,
p‑Akt↑, Chrysin stimulated the phosphorylation of AKT and P70S6K proteins in both ES2 and OV90 cells compared to the untreated control cell
PCNA↓, treatment with chrysin attenuated the abundant expression of PCNA protein in both ES2 and OV90 cells
p‑p70S6↑,
p‑ERK↑, chrysin activated the phospho-ERK1/2, p38, and JNK proteins as members of the MAPK pathway in the ovarian cancer cells
p38↑,
JNK↑,
DNAdam↑, stimulates apoptotic events in prostate cancer cells by the accumulation of DNA fragmentation, an increase in the population of cells in the sub-G1 phase of the cell cycle
TumCCA↑,
chemoP↑, combination therapy with chrysin enhances the therapeutic effect of the chemotherapeutic agent, docetaxel, in lung cancer by reducing its adverse effects

2792- CHr,    Chrysin induces death of prostate cancer cells by inducing ROS and ER stress
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
DNAdam↑, chrysin induced apoptosis of cells evidenced by DNA fragmentation and increasing the population of both DU145 and PC-3 cells in the sub-G1 phase of the cell cycle
TumCCA↑,
MMP↓, chrysin induced loss of mitochondria membrane potential (MMP), while increasing production of reactive oxygen species (ROS) and lipid peroxidation in a dose-dependent manner
ROS↑,
lipid-P↑,
ER Stress↑, Also, it induced endoplasmic reticulum (ER) stress through activation of unfolded protein response (UPR) proteins including PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78)
UPR↑,
PERK↑,
eIF2α↑,
GRP78/BiP↑,
PI3K↓, chrysin-mediated intracellular signaling pathways suppressed phosphoinositide 3-kinase (PI3K) and the abundance of AKT, P70S6K, S6, and P90RSK proteins, but stimulated mitogen-activated protein kinases (MAPK) and activation of ERK1/2 and P38 proteins
Akt↓,
p70S6↓,
MAPK↑,

1144- CHr,    8-bromo-7-methoxychrysin-induced apoptosis of hepatocellular carcinoma cells involves ROS and JNK
- in-vitro, HCC, HepG2 - in-vitro, HCC, Bel-7402 - in-vitro, Nor, HL7702
Casp3↑,
*ROS∅, BrMC did not affect ROS generation in L-02 cells
ROS↑,
JNK↑,
*toxicity↓, BrMC had little effect on human embryo liver L-02 cells

1249- CHr,    Chrysin as an Anti-Cancer Agent Exerts Selective Toxicity by Directly Inhibiting Mitochondrial Complex II and V in CLL B-lymphocytes
- in-vitro, CLL, NA
ROS↑,
MMP↓,
ADP:ATP↑,
Casp3↑,
Apoptosis↑,

2315- Citrate,    Why and how citrate may sensitize malignant tumors to immunotherapy
- Review, Var, NA
Bcl-2↓, SCT can induce silent apoptosis by reducing expression of key pro-apoptotic proteins (Bcl-2, surviving, MCL1), and promoting the activation of caspases-3 and −9 and −8, as showed in multiple cancer cell lines
Mcl-1↓,
survivin↓,
Casp3↑,
Casp9↑,
Ferroptosis↑, SCT can also trigger ferroptosis, an iron-dependent form of lytic cell death inducing lipid peroxidation (LPO)
lipid-P↑,
Ca+2↓, citrate lowers mitochondrial Ca2+ concentration by chelation
Akt↓, by chelating cytosolic Ca2+, citrate inhibits the Ca2+/CAMKK2/AKT/mTOR signaling pathway, thereby suppressing HIF1-α dependent glycolysis
mTOR↓,
Hif1a↓,
MCU↓, reduces the activity of the mitochondrial calcium uniporter (MCU), resulting in decreasing ATP production, increasing ROS production
ATP↓,
ROS↑,
eff↑, Of note, ferroptosis can enhance the effectiveness of immunotherapy, as showed in glioma models

1593- Citrate,    Citrate Induces Apoptotic Cell Death: A Promising Way to Treat Gastric Carcinoma?
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901
PFK↓, citrate, a strong physiological inhibitor of phosphofructokinase (PFK)
Glycolysis↓, citrate is a strong inhibitor of glycolysis
tumCV↓, 10 mM citrate led to a nearly complete disappearance of cancer cells, and after 72 h, no cells remained viable whatever the concentration used
cl‑Casp3↑,
cl‑PARP↑,
Apoptosis↑,
ATP↓, depletion of ATP generated by citrate
ChemoSen↑, In the previous study, citrate sensitized the cells to cisplatin, a drug which was poorly efficient by itself on such cells
Mcl-1↓, In the current study, citrate reduced MCL-1 expression in both the gastric cancer lines in a dose-dependent manner, in agreement with previous observations in mesothelioma cells
glucoNG↑, citrate activates neoglucogenesis by enhancing fructose 1,6-bisphosphatase activity
FBPase↑,
OXPHOS↓, When citrate is abundant in cells, this usually means that energy production (ATP) is sufficient, so oxidative phosphorylation (OXPHOS) and the Krebs cycle are slowed down or stopped.
TCA↓, Krebs cycle are slowed down or stopped.
β-oxidation↓, concomitantly inhibits β-oxidation
HK2↓, It may inhibit HK, at least indirectly, by the physiological retroaction of glucose-6-phosphate (G6P) on HK
PDH↓, citrate may inhibit pyruvate dehydrogenase (PDH) (39), the enzyme of the Krebs cycle which links glycolysis and the tricarboxylic cycle
ROS↑, citrate could also promote the formation of reactive oxygen species (ROS) since a sudden elevation of citrate concentration inside the cell might immediately stimulate the Krebs cycle.

1585- Citrate,    Sodium citrate targeting Ca2+/CAMKK2 pathway exhibits anti-tumor activity through inducing apoptosis and ferroptosis in ovarian cancer
- in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, A2780S - in-vitro, Nor, HEK293
Apoptosis↑,
Ferroptosis↑,
Ca+2↓, Sodium citrate chelates intracellular Ca2+
CaMKII ↓, inhibits the CAMKK2/AKT/mTOR/HIF1α-dependent glycolysis pathway, thereby inducing cell apoptosis.
Akt↓,
mTOR↓,
Hif1a↓,
ROS↑, Inactivation of CAMKK2/AMPK pathway reduces Ca2+ level in the mitochondria by inhibiting the activity of the MCU, resulting in excessive ROS production.
ChemoSen↑, Sodium citrate increases the sensitivity of ovarian cancer cells to chemo-drugs
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
Cyt‑c↑, co-localization of cytochrome c and Apaf-1
GlucoseCon↓, glucose consumption, lactate production and pyruvate content were significantly reduced
lactateProd↓,
Pyruv↓,
GLUT1↓, sodium citrate decreased both mRNA and protein expression levels of glycolysis-related proteins such as Glut1, HK2 and PFKP
HK2↓,
PFKP↓,
Glycolysis↓, sodium citrate inhibited glycolysis of SKOV3 and A2780 cells
Hif1a↓, HIF1α expression was decreased significantly after sodium citrate treatment
p‑Akt↓, phosphorylation of AKT and mTOR was notably suppressed after sodium citrate treatment.
p‑mTOR↓,
Iron↑, ovarian cancer cells treated with sodium citrate exhibited higher Fe2+ levels, LPO levels, MDA levels, ROS and mitochondrial H2O2 levels
lipid-P↑,
MDA↑,
ROS↑,
H2O2↑,
mtDam↑, shrunken mitochondria, an increase in mitochondrial membrane density and disruption of mitochondrial cristae
GSH↓, (GSH) levels, GPX activity and expression levels of GPX4 were significantly reduced in SKOV3 and A2780 cells with sodium citrate treatment
GPx↓,
GPx4↓,
NADPH/NADP+↓, significant elevation in the NADP+/NADPH ratio was observed with sodium citrate treatment
eff↓, Fer-1, NAC and NADPH significantly restored the cell viability inhibited by sodium citrate
FTH1↓, decreased expression of FTH1
LC3‑Ⅱ/LC3‑Ⅰ↑, sodium citrate increased the conversion of cytosolic LC3 (LC3-I) to the lipidated form of LC3 (LC3-II)
NCOA4↑, higher levels of NCOA4
eff↓, test whether Ca2+ supplementation could rescue sodium citrate-induced ferroptosis. The results showed that Ca2+ dramatically reversed the enhanced levels of MDA, LPO and ROS triggered by sodium citrate
TumCG↓, sodium citrate inhibited tumor growth by chelation of Ca2+ in vivo

4761- CoQ10,    Elevated levels of mitochondrial CoQ10 induce ROS-mediated apoptosis in pancreatic cancer
- in-vitro, PC, NA - in-vivo, PC, NA
*ETC↝, Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration.
ROS↑, This study demonstrates that delivery of oxidized Coenzyme Q10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model.
*antiOx↑, In addition to its role in ETC function, CoQ10 has phenolic antioxidant activity via its ability to undergo hydrogen abstraction by free radicals6
ROS↑, Paradoxically, CoQ10 also exhibits pro-oxidant activity that occurs either due to a CoQ10 semiquinone reaction5 or due to a reaction with oxygen when CoQ10 is in its oxidized state
OCR↓, Delivery of supraphysiologic levels of ubidecarenone via BPM31510 decreases oxygen consumption rates (OCR) in pancreatic cancer
MMP↓, Ubidecarenone enhances succinate-dependent and glycerol-3-phosphate-dependent ROS generation, mitochondrial membrane depolarization, and regulated cell death
TumCD↑,
TumCG↓, BPM31510 (25 mg/kg, b.i.d) resulted in a significant decrease in tumour growth by day 45 after inoculation compared to saline-treated mice
other↝, NOTE: this is oxidized CoQ10, not the same as CoQ10!!!!!!

4764- CoQ10,  VitE,    Auxiliary effect of trolox on coenzyme Q10 restricts angiogenesis and proliferation of retinoblastoma cells via the ERK/Akt pathway
- in-vitro, RPE, Y79 - in-vitro, Nor, ARPE-19 - in-vivo, NA, NA
tumCV↓, CoQ10, alone and with trolox, reduced Y79 cell viability, induced apoptosis through excess ROS generation, and decreased MMP significantly.
Apoptosis↑,
ROS↑,
MMP↓,
TumCCA↑, Both treatments caused G2/M phase cell arrest.
VEGF↓, The combination of CoQ10 and trolox significantly reduced VEGF-A, ERK, and Akt receptor levels, while CoQ10 alone significantly inhibited ERK and Akt phosphorylation.
ERK↓,
Akt↓,
ChemoSen↑, Several studies thereafter reported a higher therapeutic response rate of CoQ10 when used with other chemotherapeutic agents13, 14 while also improving the tolerability of cancer treatments15,16,17.
chemoP↑,
toxicity↓, CoQ10 + trolox have no adverse effect on ARPE-19 cells
angioG↓, Co-culture of Y79 with human umbilical vein endothelial cells (HUVECs) and the CAM assay results prove that both CoQ10 alone and CoQ10 + trolox are effective in mitigating angiogenic proliferation of cells both in vitro and in vivo

4768- CoQ10,    Role of coenzymes in cancer metabolism
- Review, Var, NA
Risk↓, Deficiency of NADH dehydrogenase ubiquinone 1 subunit (Ndufc2), a subunit of CI, has been found in diabetes, cancer, and stroke
*ROS↓, CoQ10 function as an intracellular antioxidant preventing mitochondrial membrane proteins and phospholipids from free radical-induced oxidative damage
AntiCan↑, CoQ10 supplementation has found beneficial effects in diabetes [137,138], huntington's disease [139], coronary heart disease [140,141], congestive cardiac failure [142], fibromyalgia [143,144], and cancer
TumMeta↓, In addition, they observed that the patients with metastasis had lower CoQ10 levels than those who did not
ROS↑, It has been shown in an in vitro study on C57BL/6 mice that treatment with 100 μM CoQ10 for 72 h. can significantly alleviates pancreatic fibrosis by the ROS-triggered PI3K/AKT/mTOR signaling pathway
TumCG↓, Another in vitro and in vivo study on melanoma cells demonstrated that treatment with CoQ10 inhibit cell growth, induce apoptosis and prevent metastasis through suppression of the Wnt/β-catenin signaling pathway
Apoptosis↑,
TumMeta↓,
Wnt↓,
β-catenin/ZEB1↓,
TumCG↓, CoQ10 significantly lowered the growth of prostate cancer cells without affecting non-cancer prostate cells
selectivity↑,
RadioS↑, human glioblastoma cells with CoQ10 combined with radiation therapy and temozolomide, sensitized cells to radiation-induced DNA damage and potentiates temozolomide cytotoxicity
ChemoSen↑,
H2O2↓, In vitro study suggests that treatment of breast cancer cell lines with CoQ10 significantly decrease intracellular H2O2 content and inhibit MMP-2 activity leading to lower invasion and metastasis
MMP2↓,
cardioP↑, acute reversible depression of myocardial function and a chronic irreversible cardiomyopathy were prevented by different doses of CoQ10
ChemoSen∅, a recent study demonstrated that CoQ10 did not inhibit doxorubicin induced cytotoxicity in breast cancer cell lines [
Dose↝, 59 patients undergoing chemotherapy were enrolled and provided with CoQ10 (30 mg), branch chain amino acids (2500 mg), and carnitine (50 mg) for 21 days.

4772- CoQ10,    The anti-tumor activities of coenzyme Q0 through ROS-mediated autophagic cell death in human triple-negative breast cells
- in-vitro, BC, MDA-MB-468 - in-vitro, BC, MDA-MB-231
TumCP↓, Coenzyme Q0 (CoQ0) inhibits proliferation and colony formation in MDA-MB-468 and 231 cells.
Apoptosis↑, CoQ0 induced apoptosis associated with caspase-3 activation and PARP cleavage
Casp3↑,
cl‑PARP↑,
LC3II↑, CoQ0 induced autophagic cell death is accompanied by LC3-II accumulation and AVO formation
eff↓, Antioxidant NAC prevents CoQ0-induced apoptosis and autophagy.
TumCG↓, CoQ0 (Fig. 1A) suppressed TNBC and Hs578T cell growth, as well as dose-dependently reduced cell growth.
Bax:Bcl2↑, CoQ0 increases Bax/Bcl-2 and Beclin-1/Bcl-2 ratio in both TNBC cell lines
Beclin-1↑,
TumAuto↑, CoQ0 induces autophagy, which ultimately results in cell death TNBC cells
ROS↑, CoQ0 activates intracellular ROS generation in TNBC cells. TNBC cells treated with CoQ0 (5 or 7.5 µM for 0–120 min) showed substantially elevated ROS accumulation

4776- CoQ10,    Antitumor properties of Coenzyme Q0 against human ovarian carcinoma cells via induction of ROS-mediated apoptosis and cytoprotective autophagy
- vitro+vivo, Ovarian, SKOV3
ROS↑, CoQ0 triggered intracellular ROS production, whereas antioxidant N-acetylcysteine prevented CoQ0-induced apoptosis, but not autophagy
eff↓, whereas antioxidant NAC N-acetylcysteine prevented CoQ0-induced apoptosis, but not autophagy
AntiCan↑, Furthermore, CoQ0 treatment to SKOV-3 xenografted nude mice reduced tumor incidence and burden
Apoptosis↑, Our findings emphasize that CoQ0 triggered ROS-mediated apoptosis and cytoprotective autophagy.
tumCV↓, CoQ0 inhibits viability and growth of human ovarian carcinoma cells
TumCG↓, CoQ0 suppresses tumor growth in SKOV-3 xenografted nude mice
TumCCA↑, CoQ0 induces G2/M cell-cycle arrest and reduces cell-cycle proteins in SKOV-3 cells
LC3s↑, CoQ0 promotes LC3 accumulation and AVOs formation in SKOV-3 cells
ERStress↑, CoQ0 triggers apoptotic death of SKOV-3 cells via mitochondrial and ER-stress signals
Beclin-1↑, CoQ0 increases Beclin-1/Bcl-2 and Bax/Bcl-2, and inhibits HER-2/neu/AKT/mTOR signalling in SKOV-3 cells
Bax:Bcl2↑,
HER2/EBBR2↓,
Akt↓,
mTOR↓,

1601- Cu,    The copper (II) complex of salicylate phenanthroline induces immunogenic cell death of colorectal cancer cells through inducing endoplasmic reticulum stress
- in-vitro, CRC, NA
i-CRT↓, Cu(sal)phen induced the release of calreticulin (CRT), adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), the main molecular markers of ICD (immunogenic cell death)
ICD↑,
i-ATP↓,
i-HMGB1↓,
ER Stress↑, accumulation of ROS and inducing ERS
ROS↑,
DCells↑, promoted the maturation of dendritic cells (DCs)
CD8+↑, and activation of CD8+T cells
IL12↑, secretion of interleukin-12 (IL-12) and interferon-γ (IFN-γ)
IFN-γ↑,
TGF-β↓, while downregulating transforming growth factor-β (TGF-β) levels

1639- Cu,  HCAs,    Green synthesis of copper oxide nanoparticles using sinapic acid: an underpinning step towards antiangiogenic therapy for breast cancer
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
angioG↓, confirming its potential to inhibit angiogenesis in cancer
tumCV↓, The CuO NPs showed enhanced toxic effect at both time intervals when compared to that of sinapic acid alone.
Dose↓, The enhanced cytotoxicity observed at much lower concentrations such as 21.5 and 7.5 ug/mL for MCF7 and MDA-MB231
ROS↑, the cancer cells display an elevated level of oxidative stress with increase in the production of reactive oxygen species (ROS).

1604- Cu,    Targeting copper metabolism: a promising strategy for cancer treatment
- Review, NA, NA
eff↓, Cancer cells have been shown to have higher copper levels compared to normal cells. Thus, by reducing the amount of copper available to cancer cells, it is possible to sensitize them to chemotherapy and radiotherapy.
eff↓, copper depletion sensitized ovarian cancer cells to radiation therapy by increasing the production of reactive oxygen species and inducing DNA damage
ROS↑, When CuO NPs enter cancer cell, they can interact with intracellular copper ions and generate ROS, such as hydrogen peroxide (H2O2) and superoxide anion
eff↑, Copper (II) complexes of curcumin have been shown to have enhanced anti-cancer activity compared to curcumin alone due to their ability to induce cancer cell death via multiple mechanisms, including the generation of reactive oxygen species

1603- Cu,  BP,  SDT,    Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response
- in-vitro, BC, 4T1 - in-vivo, NA, NA
GSH↓, Cu2O was incorporated into BP(black phosphorus) to exhaust the overexpressed intracellular GSH
Fenton↑, However, the Cu+-catalyzed Fenton reaction converts H2O2 into OH at a high reaction rate, even in a neutral environment (160 times than that of Fe2+)
ROS↑, BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation,
NO↑,
sonoS↑, Numerous studies have confirmed that BP, as a sonosensitizer, can induce ROS generation in cancer therapy
eff↑, These results indicated that an acidic environment can effectively promote Cu release.
NO↑, massive NO production
*toxicity∅, Additionally, no significant body weight loss or apparent histological abnormalities of the major organs (heart, liver, spleen, lungs, and kidneys) were observed, indicating the negligible organ toxicity
eff?, In vivo studies demonstrated that BCL plus US treatment could significantly inhibit tumor growth

1602- Cu,    A simultaneously GSH-depleted bimetallic Cu(ii) complex for enhanced chemodynamic cancer therapy†
- in-vitro, BC, MCF-7 - in-vitro, BC, 4T1 - in-vitro, Lung, A549 - in-vitro, Liver, HepG2
eff↑, enhanced chemodynamic cancer therapy
GSH↓, glutathione (GSH) depletion properties
H2O2↑, overexpressed H2O2
ROS↑, highly cytotoxic hydroxyl radicals (˙OH) that kill cancer cells
*BioAv↑, complex is quickly taken up by cancer cells and distributed in multiple organelles including mitochondria and the nucleus
selectivity↑, toxicity toward normal cells is significantly lower than that toward cancer cells due to the limited expression of H2O2
TumCCA↑, arrest the cell cycle of the G0/G1 phase
Apoptosis↑, inducing apoptosis rather than necrosis
Fenton↑, Cu+-involved reaction can occur with a highest reaction rate (1x10E4 M-1 s-1) in weakly acidic, which is about 160-fold increase over that of Fe2+
*toxicity?, C50 value of CuL-Cuphen to normal cells COS-7 was about 6.3uM.

1600- Cu,    Cu(II) complex that synergistically potentiates cytotoxicity and an antitumor immune response by targeting cellular redox homeostasis
- Review, NA, NA
ER Stress↑, Endoplasmic reticulum stress, mediated by reactive oxygen species (ROS), is thought to induce an antitumor immune response
ROS↑,
AntiTum↑,
GSH↓, Li and coworkers recently reported that copper-cysteine nanoparticles could contribute to both oxidative •OH production and antioxidant GSH depletion
Ferroptosis↑, ferroptosis-dependent ICD response in cancer cells
selectivity↑, Markedly decreased cytotoxicity against the normal cell line, 293T, was seen
GSH/GSSG↓, GSH/GSSH ratio decreased from ∼9.30 to ∼4.71 after treatment with Cu-1 at its IC50 concentration over the course of 12 h
*ROS∅, only a slight increase was observed in (normal) 293T
eff↑, In sharp contrast, Cu-1 demonstrated a greater in vivo antitumor effect compared to oxaliplatin (Fig. 6 B and D) and did not induce systemic toxicity or body weight loss

1599- Cu,    Copper in tumors and the use of copper-based compounds in cancer treatment
- Review, NA, NA
ROS↑, Copper acts actively in the activation of apoptosis via ROS generation, and this property can be used to eliminate tumor cells
RadioS↑, Copper as a radiotherapy agent

1569- Cu,    Copper Nanoparticles as Therapeutic Anticancer Agents
- Review, NA, NA
Dose∅, 2.5 μg.ml-1 LD50 value for CuI
Dose∅, LD50 value 10 μg.ml-1 for the corresponding Cu(PO4)2 Nps
ROS↑, Both types of NPs cause apoptotic mediated cell death by inducing ROS-mediated DNA damage

1570- Cu,    Development of copper nanoparticles and their prospective uses as antioxidants, antimicrobials, anticancer agents in the pharmaceutical sector
- Review, NA, NA
selectivity↑, specific toxicity towards cancer cells while protecting normal cells
antiOx↑, CuNPs have strong antioxidant properties because they can scavenge reactive oxygen species (ROS) and prevent oxidative damage. CuNPs are potent antioxidants due to their tiny size and wide surface area, which improve their interactions with ROS
ROS↑, Through several processes, such as oxidative stress, DNA damage, and a reduction in cell growth, they can cause cancer cells to die. CuNPs can produce ROS inside cancer cells, resulting in oxidative stress and cell death
eff↑, For improved therapeutic benefits, CuNPs can be utilized alone or with other anti-cancer drugs.
GSH↓, When exposed to CuONPs concentration in a dose-dependent manner (10, 25, 50 μg/ml), the human pulmonary epithelial cells (A549) showed depletion of glutathione and stimulation of lipid peroxidation, catalase and superoxide dismutase.
lipid-P↑,
Catalase↓,
SOD↓,
other↑, CuNPs releasing copper ions may also cause ROS and oxidative stress.

1571- Cu,    Copper in cancer: From pathogenesis to therapy
- Review, NA, NA
*toxicity↝, The toxicity of Cu overload is known to be due, in part, to the release of ROS via the Fenton or Haber-Weiss reaction, causing lipid, protein, DNA, and RNA damage
ROS↑, Cu-induced ROS can induce lipid peroxidation, which raises hydroxynonenal (HNE) levels and causes lipid peroxidation to become toxic.
lipid-P↓,
HNE↑, raises hydroxynonenal (HNE) levels and causes lipid peroxidation to become toxic
MAPK↑, Cu exposure causes an elevation in intracellular ROS levels, which then stimulates the MAPK signaling pathway, increasing JNK/SAPK and p38 homologous activity and phosphorylation levels
JNK↑, Cu-induced ROS continuously activate JNK, promote the production of the AP-1 transcription factor, increase Beclin 1 and Atg7 production, and cause autophagy and apoptosis in tumor cells
AP-1↑,
Beclin-1↑,
ATG7↑,
TumAuto↑,
Apoptosis↑,
HO-1↑, Fang and colleagues consistently found that Cu activates the ROS/heme oxygenase-1 (HO-1)/NAD(P)H quinone oxidoreductase-1 (NQO1) signaling cascade to induce autophagy
NQO1↑,
mt-ROS↑, Cu NPs induce complete autophagy by enhancing mitochondrial ROS production and inducing autophagy
Fenton↑, generating large amounts of ROS and oxygen via a Fenton-like reaction

1572- Cu,    Recent Advances in Cancer Therapeutic Copper-Based Nanomaterials for Antitumor Therapy
- Review, NA, NA
eff↑, generate a large number of reactive oxygen species (ROS) when exposed to light, which could be adopted for photodynamic therapy.
Fenton↑, Cu2+ is vulnerable to the reduction to Cu+, allowing Cu to drive the Fenton reaction and produce hydroxyl radicals (·OH).
ROS↑, increasing Cu ions in cancer tissue makes an antitumor impact that mainly involves OS by triggering the Fenton reaction, which can produce ROS
eff↑, compared with other metals (iron, chromium, cobalt and nickel), the Cu-based Fenton reaction can react in wider pH range
mtDam↑, Excessive Cu can induce the toxic level of ROS that may aggravate the mitochondrial ROS, causing mitochondrial damage
BAX↑, Cu-induced ROS increased Bax (pro-apoptotic protein), while Bcl2 (anti-apoptotic protein) was decreased
Bcl-2↓,
MMP↓,
Cyt‑c↑, releasing CytC that activated Caspase3
Casp3↑,
ER Stress↑, Nano-CuO) triggers OS by ROS, thus stimulating endoplasmic reticulum (ER)-stress
CHOP↑, which thereby enhanced the expression of CHOP
Apoptosis↑, and CHOP-induced apoptosis
selectivity↑, In fact, autophagy induced by copper can either protect cells from death or contribute to cell death, depending on autophagic flux, which is associated with the concentration of copper.
eff↑, combining artemisinin (ART) and copper peroxide nanodots to enhance autophagy and ferroptosis that produced highly cancer toxic reaction
Pyro↑, Copper-Based Pyroptosis
Paraptosis↑, Copper-Based Paraptosis
Cupro↑, Copper-Based Cuproptosis
ChemoSen↑, studies suggested that Cu-MOFs might be a robust nanoplatform for enhancing chemotherapy activity of Cu-organic compounds.
eff↑, CuS NPs had the ability to directly target cancer cells and then induce in nucleus by modification of RGD and TAT peptides, thus heating cancer cell to exhaustive apoptosis through 980 nm NIR irradiation

1595- Cu,    The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy
- Review, NA, NA
eff↑, CuNPs can be used in a variety of therapeutic strategies, such as photothermal therapy combined with immunotherapies, to induce systemic immune responses against tumors
ROS↑, One of the approaches aims at producing excess ROS by exploiting the properties of certain metals, which will lead to the death of cancer cells
eff↓, cancer tumor have higher copper, and feeding them copper may accelerate growth.

1598- Cu,    Targeting copper in cancer therapy: 'Copper That Cancer'
- Review, NA, NA
eff↓, copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes.
eff↑, Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels.
Dose∅, therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties.
eff↑, In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance
angioG↑, These findings unquestionably place copper as a potent inducer of the angiogenic process.
ROS↑, Copper is a redox active metal that can enhance the production of ROS, which subsequently can damage most biomolecules

1597- Cu,    Anticancer potency of copper(II) complexes of thiosemicarbazones
- Review, NA, NA
eff↑, The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic ROS mediated mitochondrial pathway due to excessive production of ROS and hence, are found more active than Ni and Pt complexes.
ROS↑, due to excessive production of ROS

1596- Cu,  CDT,    Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review
- Review, NA, NA
TumCD↑, Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and p
Apoptosis↓,
ROS↑,
angioG↑,
Cupro↑,
Paraptosis↑,
eff↑, copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy.
eff↓, Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes
selectivity↑, Copper nanoparticles also can selectively attack cancer cells and spare healthy cells This selectivity is attributed to the EPR effect, which enables nanoparticles to accumulate in tumor tissue by exploiting leaky blood vessels
DNAdam↑, Copper has been found to induce DNA damage and oxidation through the formation of ROS.
eff↑, Tumor cells suffering from oxygen deficiency often have an increased concentration of CTR-1, which facilitates the transport of copper(I) into the cells
eff↑, The results demonstrate the promising capabilities of 64CuCl2 as a valuable tool for both diagnosis and therapy in various types of cancer
eff↑, nanoparticles have remarkable properties, including a large surface area to volume ratio, excellent compatibility with living organisms, and the ability to generate ROS when exposed to an acidic tumor microenvironment
eff↑, Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy (CDT)
Fenton↑, CDT is a promising treatment strategy for cancer that utilizes the in situ Fenton reaction, which is activated by endogenous substances, such as GSH and H2O2 without the need for external energy input
H2O2↑, Copper-based substrates have been developed that generate H2O2 internally and function effectively in weakly acidic tumor microenvironments (TME)
eff↑, metal peroxide nanomaterials and offers a promising strategy to improve CDT efficacy
eff↑, Copper nanoparticles can also be used in phototherapy
eff↑, Copper nanoparticles have also shown success in destroying cancer tissue by hyperthermia. This method is a local anticancer treatment in which cells are exposed to high temperatures.
RadioS↑, promising results when used in combination with radiotherapy or chemotherapy for various tumor types.
ChemoSen↑,
eff↑, copper nanoparticles are promising in cancer immunotherapy because they enhance immune-based therapies
*toxicity↝, Copper is a necessary trace mineral for the human body, but high concentrations of copper can be toxic
other↑, Extensive research has shown that cancer cells require an increased copper content to support their rapid growth compared to normal cells
eff↑, Copper nanoparticles can be used to generate heat when exposed to certain wavelengths of light or alternating magnetic fields.

1609- CUR,  EA,    Curcumin and Ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells
- in-vitro, Cerv, NA
eff↑, combination of Curcumin and Ellagic acid at various concentrations showed better anticancer properties than either of the drug when used alone as evidenced by MTT assay
Dose∅, IC50 value for Curcumin is calculated as 16.52 mM and for Ellagic acid the IC50 Value is 19.47 mM. The combination of Curcumin and Ellagic acid has IC50 value 10.9 mM.
ROS↑, Curcumin alone increases the ROS level significantly. Similarly the C + E treated cells exhibited a very high magnitude of ROS level.
DNAdam↑, Curcumin and Ellagic acid show mild degree of DNA damage at this concentration but the C + E treated cells shows greater degree of DNA damage
P53↑, C + E treated cells show greater degree of stabilization of p53
P21↑, Elevated expression of p21 in response to Curcumin and C + E treatment
BAX↑, But the C + E treated cells showed higher expression of Bax
Dose∅, Curcumin daily shows detectable levels of Curcumin in plasma and urine and the concentration is close to 11.1 nMol/l

1981- CUR,    Mitochondrial targeted curcumin exhibits anticancer effects through disruption of mitochondrial redox and modulation of TrxR2 activity
- in-vitro, Lung, NA
eff↑, Mitocurcumin, showed 25-50 fold higher efficacy in killing lung cancer cells as compared to curcumin
ROS↑, Mitocurcumin increased the mitochondrial reactive oxygen species (ROS
mt-GSH↓, decreased the mitochondrial glutathione levels
Bax:Bcl2↑, increased BAX to BCL-2 ratio
Cyt‑c↑, cytochrome C release into the cytosol
MMP↓, loss of mitochondrial membrane potential
Casp3↑, increased caspase-3 activity
Trx2↓, mitocurcumin revealed that it binds to the active site of the mitochondrial thioredoxin reductase (TrxR2) with high affinity
TrxR↓, In corroboration with the above finding, mitocurcumin decreased TrxR activity in cell free as well as the cellular system.
mt-DNAdam↑, mitochondrial DNA damage

1980- CUR,  Rad,    Thioredoxin reductase-1 (TxnRd1) mediates curcumin-induced radiosensitization of squamous carcinoma cells
- in-vitro, Cerv, HeLa - in-vitro, Laryn, FaDu
selectivity↑, previously demonstrated that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts
RadioS↑,
TrxR↓, inhibitory activity of curcumin on the anti-oxidant enzyme Thioredoxin Reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells
ROS↑, induced reactive oxygen species
ERK↑, sustained ERK1/2 activation
Dose∅, Curcumin treatment resulted in a dose-dependent decrease in TxnRd activity with an IC50 of approximately 10 µM in both cell lines
cl‑PARP↑, curcumin induced a robust increase in cleaved PARP

1979- CUR,  Rad,    Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase
- in-vitro, Lung, A549
eff↑, As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay.
ROS↑, significant increase in cellular ROS
GSH/GSSG↓, decrease in GSH to GSSG ratio
TrxR↓, inhibition of thioredoxin reductase enzyme by DIMC
selectivity↑, DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system.

1978- CUR,    Curcumin targeting the thioredoxin system elevates oxidative stress in HeLa cells
- in-vitro, Cerv, HeLa
TrxR1↓, curcumin can target the cytosolic/nuclear thioredoxin system to eventually elevate oxidative stress in HeLa cells
ROS↑,
DNA-PK↑, subsequently induces DNA oxidative damage
eff↑, curcumin-pretreated HeLa cells are more sensitive to oxidative stress
Trx↓, down-regulates Trx1 level and decreases Trx activity in HeLa cells
Trx1↓,

1383- CUR,  BBR,  RES,    Regulation of GSK-3 activity by curcumin, berberine and resveratrol: Potential effects on multiple diseases
- Review, NA, NA
GSK‐3β↝,
ROS↑, BBB increased ROS production by decreasing c-MYC expression

1410- CUR,    Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway
- vitro+vivo, OS, MG63
tumCV↓,
Apoptosis↑,
TumCG↓,
NRF2↓, after treatment with curcumin, Nrf2 and GPX4 levels were significantly decreased
GPx4↓,
HO-1↓,
xCT↓, SLC7A11
ROS↑, our results revealed that after treatment with curcumin, ROS and MDA levels were significantly increased while GSH levels were decreased
MDA↑,
GSH↓,

1409- CUR,    Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma
- in-vivo, CCA, Walker256
TumCG↓,
ROS↑,
MMP↓,
STAT3↓,
TumCCA↑, G2/M cell cycle
eff↓, Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells

1408- CUR,    Antiproliferative and ROS Regulation Activity of Photoluminescent Curcumin-Derived Nanodots
- in-vitro, Lung, A549
ROS↓, antioxidation activity at low concentrations (<0.08 mg/mL) with low levels of reactive oxygen species (ROS) generation, i.e., 82% of the ROS level in cells without treatment for A549 cells;
ROS↑, at high concentrations, the nanodots exhibit a pro-oxidant effect on both the cancer cells (A549) and normal cells (EA.hy926) by inducing more ROS generation and dose-dependent cytotoxicity.

3579- CUR,  AgNPs,    Metal–Curcumin Complexes in Therapeutics: An Approach to Enhance Pharmacological Effects of Curcumin
- Review, NA, NA
*IronCh↑, It is well established that curcumin strongly chelates several metal ions, including boron, cobalt, copper, gallium, gadolinium, gold, lanthanum, manganese, nickel, iron, palladium, platinum, ruthenium, silver, vanadium, and zinc.
*BioAv↑, Metal–curcumin complexes increase the solubility, cellular uptake, and bioavailability and improve the antioxidant, anti-inflammatory, antimicrobial, and antiviral effects of curcumin.
*antiOx↑,
*Inflam↓,
*BioAv↑, complexes of curcumin with transition metals may provide another approach to overcome the issues associated with curcumin.
ROS↑, curcumin–metal complexes with liposomes present enhanced cellular uptake and ROS generation in cancer cells and thus cause increased cytotoxicity
*neuroP↑, Since curcumin has the ability to cross the blood–brain barrier due to its hydrophobic nature, it can strongly chelate the metal ions in the brain and prevent metal-induced neurotoxicity.
*eff↑, Curcumin with silver nanoparticle formates also increases the solubility and stability of curcumin in complexes. Curcumin reduces and caps the silver nanoparticles, which increases its stability and solubility in water

2312- CUR,    Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy
- Review, Var, NA
ROS↑,
PKM2↓, ROS accumulation inhibits PKM2

2308- CUR,    Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells
- in-vitro, Liver, HepG2
GlucoseCon↓, Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production
lactateProd↓,
ECAR↓,
NO↓,
ROS↑, Curcumin favors the ROS production in HepG2 cells in normal as well as hyperglycemic conditions. ROS production was detected in cancer cells treated with curcumin, or doxorubicin, or their combinations in NG or HG medium for 24 h
HK2↓, HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, tr
PFK1↓,
GAPDH↓,
PKM2↓,
LDHA↓,
FASN↓,
GLUT1↓, Curcumin treatment was able to significantly decrease the expression of GLUT1, HKII, and HIF-1α in HepG2 cells either incubated in NG or HG medium.
MCT1↓,
MCT4↓,
HCAR1↓,
SDH↑, Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition
ChemoSen↑, Curcumin Prevents High Glucose-Induced Chemoresistance
ROS↑, Treatment of cells with doxorubicin in presence of curcumin was found to cooperatively augment the ROS level in cells of both NG and HG groups.
BioAv↑, Curcumin Favors Drug Accumulation in Cancer Cells
P53↑, An increased expression of p53 in curcumin-treated cells can be suggestive of susceptibility towards cytotoxic action of anticancer drugs
NF-kB↓, curcumin has therapeutic benefits in hyperglycemia-associated pathological manifestations and through NF-κB inhibition
pH↑, Curcumin treatment was found to resist the lowering of pH of culture supernatant both in NG as well in HG medium.

2654- CUR,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
ROS↑, ROS induction has been implicated as one of the mechanisms of the anticancer activity of curcumin and its derivatives in various cancers
Catalase↓, Curcumin induces ROS by inhibiting the activity of various ROS-related metabolic enzymes, such as CAT, SOD1, glyoxalase 1, and NAD(P)H dehydrogenase [quinone] 1 [146,149]
SOD1↓,
GLO-I↓,
NADPH↓,
TumCCA↑, ROS accumulation further mediates G1 or G2/M cell cycle arrest [146,147,150,154], senescence [146], and apoptosis.
Apoptosis↑,
Akt↓, downregulation of AKT phosphorylation [145
ER Stress↑, endoplasmic reticulum stress (namely through the PERK–ATF4–CHOP axis)
JNK↑, activation of the JNK pathway [151],
STAT3↓, and inhibition of STAT3 [155].
BioAv↑, Additionally, the combination of curcumin and piperine, a pro-oxidative phytochemical that drastically increases the bioavailability of curcumin in humans

2688- CUR,    Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs
- Review, Var, NA - Review, AD, NA
*ROS↓, CUR reduced the production of ROS
*SOD↑, CUR also upregulated the expression of superoxide dismutase (SOD) genes
p16↑, The effects of CUR on gene expression in cancer-associated fibroblasts obtained from breast cancer patients has been examined. CUR increased the expression of the p16INK4A and other tumor suppressor proteins
JAK2↓, CUR decreased the activity of the JAK2/STAT3 pathway
STAT3↓,
CXCL12↓, and many molecules involved in cellular growth and metastasis including: stromal cell-derived factor-1 (SDF-1), IL-6, MMP2, MMP9 and TGF-beta
IL6↓,
MMP2↓,
MMP9↓,
TGF-β↓,
α-SMA↓, These effects reduced the levels of alpha-smooth muscle actin (alpha-SMA) which was attributed to decreased migration and invasion of the cells.
LAMs↓, CUR suppressed Lamin B1 and
DNAdam↑, induced DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts in a p16INK4A-dependent manner.
*memory↑, CUR has recently been shown to suppress memory decline by suppressing beta-site amyloid precursor protein cleaving enzyme 1 (BACE1= Beta-secretase 1, an important gene in AD) expression which is implicated in beta-amyoid pathology in 5xFAD transgenic
*cognitive↑, CUR was found to decrease adiposity and improve cognitive function in a similar fashion as CR in 15-month-old mice.
*Inflam↓, The effects of CUR and CR were positively linked with anti-inflammatory or antioxidant actions
*antiOx↑,
*NO↑, CUR treatment increased nNOS expression, acidity and NO concentration
*MDA↓, CUR treatment resulted in decreased levels of MDA
*ROS↓, CUR treatment was determined to cause reduction of ROS in the AMD-RPEs and protected the cells from H2O2-induced cell death by reduction of ROS levels.
DNMT1↓, CUR has been shown to downregulate the expression of DNA methyl transferase I (DNMT1)
ROS↑, induction of ROS and caspase-3-mediated apoptosis
Casp3↑,
Apoptosis↑,
miR-21↓, CUR was determined to decrease both miR-21 and anti-apoptotic protein expression.
LC3II↓, CUR also induced proteins associated with cell death such as LC3-II and other proteins in U251 cells
ChemoSen↑, The combined CUR and temozolomide treatment resulted in enhanced toxicity in U-87 glioblastoma cells.
NF-kB↓, suppression of NF-kappaB activity
CSCs↓, Dendrosomal curcumin increased the expression of miR-145 and decreased the expression of stemness genes including: NANOG, OCT4A, OCT4B1, and SOX2 [113]
Nanog↓,
OCT4↓,
SOX2↓,
eff↑, A synergistic interaction was observed when emodin and CUR were combined in terms of inhibition of cell growth, survival and invasion.
Sp1/3/4↓, CUR inducing ROS which results in suppression of specificity protein expression (SP1, SP3 and SP4) as well as miR-27a.
miR-27a-3p↓,
ZBTB10↑, downregulation of miR-27a by CUR, increased expression of ZBTB10 occurred
SOX9?, This resulted in decreased SOX9 expression.
ChemoSen↑, CUR used in combination with cisplatin resulted in a synergistic cytotoxic effect, while the effects were additive or sub-additive in combination with doxorubicin
VEGF↓, Some of the effects of CUR treatment are inhibition of NF-κB activity and downstream effector proteins, including: VEGF, MMP-9, XIAP, BCL-2 and Cyclin-D1.
XIAP↓,
Bcl-2↓,
cycD1/CCND1↓,
BioAv↑, Piperine is an alkaloid found in the seeds of black pepper (Piper nigrum) and is known to enhance the bioavailability of several therapeutic agents, including CUR
Hif1a↓, CUR inhibits HIF-1 in certain HCC cell lines and in vivo studies with tumor xenografts. CUR also inhibited EMT by suppressing HIF-1alpha activity in HepG2 cells
EMT↓,
BioAv↓, CUR has a poor solubility in aqueous enviroment, and consequently it has a low bioavailability and therefore low concentrations at the target sites.
PTEN↑, CUR treatment has been shown to result in activation of PTEN, which is a target of miR-21.
VEGF↓, CUR treatment resulted in a decrease of VEGF and activated Akt.
Akt↑,
EZH2↓, CUR also suppressed EZH2 expression by induction of miR-let 7c and miR-101.
NOTCH1↓, The expression of NOTCH1 was inhibited upon EZH2 suppression [
TP53↑, CUR has been shown to activate the TP53/miR-192-5p/miR-215/XIAP pathway in NSCLC.
NQO1↑, CUR can also induce the demethylation of the nuclear factor erythroid-2 (NF-E2) related factor-2 (NRT2) gene which in turn activates (NQO1), heme oxygenase-1 (HO1) and an antioxidant stress pathway which can prevent growth in mouse TRAMP-C1 prostate
HO-1↑,

2821- CUR,    Antioxidant curcumin induces oxidative stress to kill tumor cells (Review)
- Review, Var, NA
*antiOx↑, Curcumin is a plant polyphenol in turmeric root and a potent antioxidant
*NRF2↑, regulation by nuclear factor erythroid 2-related factor 2, thereby suppressing reactive oxygen species (ROS) and exerting anti-inflammatory, anti-infective and other pharmacological effects
*ROS↓,
*Inflam↓,
ROS↑, Of note, curcumin induces oxidative stress in tumors. curcumin-induced accumulation of ROS in tumors to kill tumor cells has been noted in several studies
p‑ERK↑, Curcumin promoted ERK/JNK phosphorylation, causing elevated ROS levels and triggering mitochondria-dependent apoptosis
ER Stress↑, Curcumin triggered disturbances in Ca2+ homeostasis, leading to endoplasmic reticulum stress, mitochondrial damage and apoptosis
mtDam↑,
Apoptosis↑,
Akt↓, Curcumin inhibited the AKT/mTOR/p70S6K signaling pathway
mTOR↓,
HO-1↑, Curcumin-induced HO-1 overexpression led to a disturbed intracellular iron distribution and triggered the Fenton reaction
Fenton↑,
GSH↓, Non-small cell lung cancer: Curcumin induced a decrease in GSH and an increase in ROS levels and iron accumulation
Iron↑,
p‑JNK↑, Curcumin causes mitochondrial damage by promoting phosphorylation of ERK and JNK, resulting in the increased release of ROS and cytochrome c into the cytoplasm, thereby triggering a mitochondrion-dependent pathway of apoptosis
Cyt‑c↑,
ATF6↑, thyroid cancer with curcumin, both activating transcription factor (ATF) 6 and the ER stress marker C/EBP homologous protein (CHOP) were activated by curcumin and Ca2+-ATPase activity was also affected.
CHOP↑,

2980- CUR,    Inhibition of NF B and Pancreatic Cancer Cell and Tumor Growth by Curcumin Is Dependent on Specificity Protein Down-regulation
- in-vivo, PC, NA
TumCG↓, curcumin inhibits Panc28 and L3.6pL pancreatic cancer cell and tumor growth in nude mice bearing L3.6pL cells as xenografts
p50↓, curcumin decreased expression of p50 and p65 proteins and NFkappaB-dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factor
p65↓,
NF-kB↓,
Sp1/3/4↓,
MMP↓, Curcumin also decreased mitochondrial membrane potential and induced reactive oxygen species in pancreatic cancer cell
ROS↑,

2978- CUR,    N-acetyl cysteine mitigates curcumin-mediated telomerase inhibition through rescuing of Sp1 reduction in A549 cells
- in-vitro, Lung, A549
ROS↑, ROS induced by curcumin in A549 cells was detected by flow cytometry
hTERT/TERT↓, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin
Sp1/3/4↓, curcumin decreases the expression of Sp1 through proteasome pathway
eff↓, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin.

872- CUR,  RES,    New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects
- in-vitro, BC, TUBO - in-vitro, BC, SALTO
TumCP↓,
tumCV↓,
p62↓, reduced by Cur
p62↑, accumulated by Res
TumAuto↑, Cur only
TumAuto↓, Res only
ROS↑, increased ROS with Res
ROS↓, decreased ROS with Cur or combination
CHOP↑, strongly upregulated by the curcumin/resveratrol combination

462- CUR,    Curcumin promotes cancer-associated fibroblasts apoptosis via ROS-mediated endoplasmic reticulum stress
- in-vitro, Pca, PC3
Bcl-2↓,
MMP↓,
cl‑Casp3↑,
BAX↑,
BIM↑,
p‑PARP↑,
PUMA↑,
p‑P53↑,
ROS↑,
p‑ERK↑,
p‑eIF2α↑,
CHOP↑,
ATF4↑,

405- CUR,  5-FU,    Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis
- vitro+vivo, CRC, HCT116
Apoptosis↑, more pronounced increase in apoptosis in p53-deficient when compared to p53-proficient cells
TumCMig↓,
NRF2↑,
ROS↑, antioxidant N-acetylcysteine suppressed the induction of apoptosis by curcumin
MET↑, Curcumin induces MET and inhibits lung-metastases formation via inducing miR-34a
miR-34a↑, Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner.

407- CUR,    Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress
- in-vitro, Melanoma, A375
Apoptosis↑,
ROS↑,
GSH↓,
MMP↓, wreaking

410- CUR,    Nrf2 depletion enhanced curcumin therapy effect in gastric cancer by inducing the excessive accumulation of ROS
- vitro+vivo, GC, AGS - vitro+vivo, GC, HGC27
ROS↑,
NRF2↑, add knockdown of NRF2 enchances CUR efficacy

412- CUR,    Curcumin and Its New Derivatives: Correlation between Cytotoxicity against Breast Cancer Cell Lines, Degradation of PTP1B Phosphatase and ROS Generation
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
ROS↑, 25uM
PTP1B↓,

477- CUR,    Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells
- in-vitro, Cerv, SiHa
TumCP↓,
TumCCA↑, Inducing G2/M cell cycle arrest
Apoptosis↑,
TumAuto↑,
CycB/CCNB1↓, cyclins B1
CDC25↓,
ROS↑,
p62↑,
LC3‑Ⅱ/LC3‑Ⅰ↑,
cl‑Casp3↑,
cl‑PARP↑,
P53↑,
P21↑,

414- CUR,    Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
Ferroptosis↑,
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
GSH↓,
HO-1↑, Curcumin upregulates a variety of ferroptosis target genes related to redox regulation, especially heme oxygenase-1 (HO-1).
NRF2↑,
GPx↓,
ROS↑,
Iron↑, curcumin caused marked accumulation of intracellular iron
GPx4↓,
HSP70/HSPA5↑,
ATFs↑, ATF4
CHOP↑, DDIT3
MDA↑,
FTL↑, Curcumin upregulated FTL (encoding ferritin light chain), FTH1
FTH1↑,
BACH1↑,
REL↑, v-rel reticuloendotheliosis viral oncogene homolog A
USF1↑,
NFE2L2↑,

424- CUR,    Curcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-κB signaling and polyamine metabolism in breast cancer cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
Src↓,
p‑STAT1↓, pSTAT-1
p‑Akt↓,
p‑p44↓, p-p44
p‑p42↓, p-p42
RAS↓,
Raf↓, c-RAF
Vim↓,
β-catenin/ZEB1↓,
P53↓,
Bcl-2↓,
Mcl-1↓,
PIAS-3↑,
SOCS-3↑,
SOCS1↑,
ROS↑,
NF-kB↓, NF-kB inactivation, ROS generation and PA depletion in MCF-7, MDA-MB-453 and MDA-MB-231 breast can- cer cells
PAO↑,
SSAT↑,
P21↑,
Bak↑,

426- CUR,    Use of cancer chemopreventive phytochemicals as antineoplastic agents
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, CAL51
Bcl-2↓,
ROS↑,
BAX↑,
RAD51↑,
γH2AX↑,

454- CUR,    Curcumin-Induced DNA Demethylation in Human Gastric Cancer Cells Is Mediated by the DNA-Damage Response Pathway
- in-vitro, GC, MGC803
TumCMig↓,
TumCP↓,
ROS↑,
mtDam↑,
DNAdam↑,
Apoptosis↑,
ATR↑,
P21↑,
p‑P53↑,
GADD45A↑,
p‑γH2AX↑,

448- CUR,    Heat shock protein 27 influences the anti-cancer effect of curcumin in colon cancer cells through ROS production and autophagy activation
- in-vitro, CRC, HT-29
Apoptosis↑,
TumCCA↑, G2/M cell cycle arrest
p‑Akt↓,
Akt↓,
Bcl-2↓,
p‑BAD↓,
BAD↑,
cl‑PARP↑,
ROS↑,
HSP27↑,
Beclin-1↑,
p62↑,
GPx1↓,
GPx4↓,

440- CUR,    Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells
- vitro+vivo, CRC, SW480 - vitro+vivo, CRC, HT-29
NNMT↓,
p‑STAT3↓,
TumCP↓,
TumCCA↑, G2/M phase cell cycle arrest
ROS↑,

143- CUR,    Nonautophagic cytoplasmic vacuolation death induction in human PC-3M prostate cancer by curcumin through reactive oxygen species -mediated endoplasmic reticulum stress
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145 - in-vitro, Pca, PC3
ER Stress↑, curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II.
CHOP↑,
GRP78/BiP↑,
ROS↑, curcumin induced ER stress by triggering ROS generation
LC3II↑,
eff↓, treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death.
tumCV↓, Curcumin treatment results in reduced cell viability and altered morphology of prostate cancer cells

161- CUR,  MeSA,    Enhanced apoptotic effects by the combination of curcumin and methylseleninic acid: potential role of Mcl-1 and FAK
- in-vitro, BC, MDA-MB-231 - in-vitro, Pca, DU145
Mcl-1↑, CUR alone
Mcl-1↓, CUR+MeSA
MPT↑,
AIF↑, An Enhanced AIF Nuclear Translocation Was Detected in the Combination-Treated MDA-MB-231 Cells
chemoPv↑, Curcumin and methylseleninic acid (MSeA) are well-documented dietary chemopreventive agents.
Apoptosis↑, Combining MSeA With Curcumin Resulted in a Significantly Enhanced Apoptotic Effect in MDA-MB-231 and DU145 Cells
ROS↑, a significantly increased ROS generation was detected in curcumin-treated cells, whereas no change was observed in MSeA-treated cells at both 3 and 6 h posttreatment.
FAK↓, Curcumin-induced FAK inhibition
STAT3↓, Previous studies showed that curcumin was capable of inhibiting activity of STAT3 and NF kB [37]. Indeed, we confirmed these effects in MDA-MB-231 cells
NF-kB↓,

117- CUR,    Increased Intracellular Reactive Oxygen Species Mediates the Anti-Cancer Effects of WZ35 via Activating Mitochondrial Apoptosis Pathway in Prostate Cancer Cells
- in-vivo, Pca, RM-1 - in-vivo, Pca, DU145
ROS↑, WZ35 Increased Reactive Oxygen Species (ROS) Accumulation in RM-1 Cells
tumCV↓, Our results showed that WZ35 treatment induced loss of cell viability, cell apoptosis, and G2/M cycle arrest in both RM-1 and DU145 cells, coupled with ROS overproduction, intracellular calcium surge, and activation of mitochondrial apoptosis
Apoptosis↑,
TumCCA↑,
Ca+2↑,
eff↓, ROS also mediated cell cycle arrest in G2/M phase evidenced by the fact that pretreatment with NAC significantly decreased cell accumulation in G2/M phase and CDC2/cyclin B1 protein level in WZ35-treated cells
ER Stress↑, Thus, ER stress may be involved in the anti-prostate cancer effects of WZ35

118- CUR,    Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
ROS↑, WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells.
Bcl-2↓,
PARP↑,
cDC2↓, decreased expression of CDC2, cyclinB1, and MDM2
CycB/CCNB1↓,
MDM2↓,
eff↓, Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis,
eIF2α↑, WZ35 treatment also induced a constant increase in the level of phosphorylated eIF2α 3 to 12 h after WZ35 treatment
ATF4↑, ATF4 expression also increased in a similar manner with p-eIF2α
CHOP↑, CHOP protein expression apparently increased 9-24 h after WZ35 treatment and peaked at 12 h
ER Stress↑, results suggest that WZ35 can induce ER stress in prostate cancer cells
TumCCA↑, WZ35 induced cell cycle arrest in G2/M phase in PC-3 cells

134- CUR,  RES,  MEL,  SIL,    Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3
Apoptosis↑,
ROS↑, curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3.
Trx1↓, Melatonin and silibinin did not change the basal redox state in LNCaP and these compounds even caused a further TRX1 reduction in PC-3 cells.
TumCG↓, Melatonin and silibinin inhibit cell growth while curcumin and resveratrol induce apoptosis in prostate cancer cell
eff↓, NAC prevents curcumin-induced apoptosis
TXNIP↑, Resveratrol decreases TRX1 by increasing TXNIP mRNA levels in PC-3 cells.

132- CUR,    Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells
- in-vitro, Pca, PC3
TumCCA↑, inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.
ROS↑, correlating with the upregulation of reactive oxygen species
TumAuto↑,
UPR↑, The upregulation of eIF2α in curcumin-treated cells, suggests activation of the UPR-associated PERK pathway
ER Stress↑,
Casp3↑, Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase.
Casp9↑,
Casp12↑,
PARP↑,
other↝, Curcumin-treated PC3 cells expressed 146 upregulated and 184 downregulated proteins when compared with control PC3 cells (treated with DMSO).
GRP78/BiP↑, GRP78 and the PDI family were upregulated by 1.69 and ≥1.25-fold respectively
PDI↑,
eIF2α↑, other upregulated proteins related to ER stress figure eukaryotic translation initiation factor 2A (EIF2A), with a significant fold change of 1.25,
other↝, downregulated antioxidant markers such as peroxiredoxin 6 (PRDX6) and protein DJ-1 (PARK7) with significant fold changes of –1.39 and –1.51, respectively

159- CUR,    Crosstalk from survival to necrotic death coexists in DU-145 cells by curcumin treatment
- in-vitro, Pca, DU145
ROS↑, at higher concentrations
p‑Jun↑, phosphorylation
p‑p38↑, Moreover, increased p38 phosphorylation was decreased soon after 4 h of curcumin treatment
TumAuto↑, curcumin-induced autophagy was related to caspase-dependent apoptotic cell death,
Casp8↑, Necrotic cell death by autophagy-induced caspase 8/9 degradation lasts until late stages of cell death after curcumin treatmen
Casp9↑,
Akt↓, decreased activities of Akt, ERK, and p38 after curcumin treatment (
ERK↓,
p38↓,

4829- CUR,    Dual Action of Curcumin as an Anti- and Pro-Oxidant from a Biophysical Perspective
- Review, Var, NA
*antiOx↑, therapeutic effects against different disorders, mostly due to its anti-oxidant properties.
ROS↑, However, curcumin can act as a pro-oxidant when blue light is applied, since upon illumination it can generate singlet oxygen
*lipid-P↓, In addition to inhibiting lipid peroxidation, curcumin appears to reduce induciblenitric oxide (NO) synthase (iNOS) activity.
*iNOS↓,
*BioAv↓, poor bioavailability is the key to curcumin’s health-promoting effects,

4830- CUR,    Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions
- in-vitro, Var, NA
eff↑, intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation.
ROS↑, Apoptosis of Cancer Cells Induced by Curcumin Is Mediated by ROS
DNAdam↑,
TumCG↓, Curcumin Inhibits Growth and Induces Apoptosis in Different Types of Cancer Cells
Apoptosis↑,
eff↓, Curcumin-Induced Antiproliferation and Apoptosis in Cancer Cells Are Inhibited by a Cuprous Chelator but Not by Iron and Zinc Chelators
Fenton↑, Generation of superoxide anions may spontaneously result in the synthesis of H2O2, which in turn results in the formation of hydroxyl radicals via oxidation of reduced copper (Fenton reaction)
eff↑, Copper Supplementation Increases the Sensitivity of Normal Breast Epithelial Cells to the Antiproliferative Effects of Curcumin

4831- CUR,    The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity
- in-vitro, NA, NA
*NRF2↑, We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation.
*P53↓,
*NF-kB↓, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation
ROS↑, In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one
Inflam↓,
ChemoSen↑, Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation.

4826- CUR,    The Bright Side of Curcumin: A Narrative Review of Its Therapeutic Potential in Cancer Management
- Review, Var, NA
*antiOx↑, Curcumin demonstrates strong antioxidant and anti-inflammatory properties, contributing to its ability to neutralize free radicals and inhibit inflammatory mediators
*Inflam↑,
*ROS↓,
Apoptosis↑, Its anticancer effects are mediated by inducing apoptosis, inhibiting cell proliferation, and interfering with tumor growth pathways in various colon, pancreatic, and breast cancers
TumCP↓,
BioAv↓, application is limited by its poor bioavailability due to its rapid metabolism and low absorption.
Half-Life↓,
eff↑, curcumin-loaded hydrogels and nanoparticles, have shown promise in improving curcumin bioavailability and therapeutic efficacy.
TumCCA↑, Studies have demonstrated that curcumin can suppress the proliferation of cancer cells by interfering with the cell cycle [21,22]
BAX↑, Curcumin enhances the expression of pro-apoptotic proteins such as Bax, Bak, PUMA, Bim, and Noxa and death receptors such as TRAIL-R1/DR4 and TRAIL-R2/DR5
Bak↑,
PUMA↑,
BIM↑,
NOXA↑,
TRAIL↑,
Bcl-2↓, curcumin decreases the levels of anti-apoptotic proteins like Bcl-2, Bcl-XL, survin, and XIAP
Bcl-xL↓,
survivin↓,
XIAP↓,
cMyc↓, This shift in the balance of apoptotic regulators facilitates the release of cytochrome c from mitochondria [33,35] and activates caspases
Casp↑,
NF-kB↓, Curcumin suppresses the activity of key transcription factors like NF-κB, STAT3, and AP-1 and interferes with critical signal transduction pathways such as PI3K/Akt/mTOR and MAPK/ERK.
STAT3↓,
AP-1↓,
angioG↓, curcumin inhibits angiogenesis and metastasis by downregulating VEGF, VEGFR2, and matrix metalloproteinases (MMPs).
TumMeta↑,
VEGF↓,
MMPs↓,
DNMTs↓, Epigenetic modifications through the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) further contribute to its anticancer properties.
HDAC↓,
ROS↑, curcumin-loaded nanoparticles showed significant cytotoxicity in the SCC25, MDA-MB-231, and A549 cell lines, with a decrease in tumor cell proliferation, an increase in ROS, and an increase in apoptosis.

4828- CUR,    Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)
- Review, Var, NA
*NF-kB↓, TNF-mediated NF-κB activation was inhibited by curcumin
ROS↑, curcumin induced the production of reactive oxygen species and modulated intracellular GSH levels.

1875- DCA,    Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells
- in-vitro, neuroblastoma, NA - in-vivo, NA, NA
selectivity↑, acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells.
AntiCan↑, DCA exhibits an unexpected anticancer effect on NB tumor cells
TumVol↓, growth inhibition became statistically significant when mice were treated with 25 mg/kg/dose of DCA (55% of reduction compared with control group)
PDKs↓, effects of DCA are related to PDK inhibition, mitochondrial oxidative phosphorylation activation and specific mitochondrial hyperpolarization reduction,
mt-OXPHOS↑,
MMP↓,
Glycolysis↓, shifting cellular metabolism from glycolysis to glucose oxidation, without any deleterious effect on normal cells.
toxicity↓, Indeed, more than 40 clinical trials of DCA report that the most significant adverse effect of long-term DCA administration is a reversible peripherical neuropathy.
Warburg↓, indeed, DCA is able to reverse the Warburg effect by inhibiting PDK, restoring mitochondrial membrane potential and increasing ROS production.
ROS↑,
eff↑, DCA was celebrated as the magic bullet against cancer, even if it is currently not yet approved for cancer treatment.

1864- DCA,  MET,    Dichloroacetate Enhances Apoptotic Cell Death via Oxidative Damage and Attenuates Lactate Production in Metformin-Treated Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, T47D - in-vitro, Nor, MCF10
PDKs↓, Dichloroacetate (DCA) is a well-established drug used in the treatment of lactic acidosis which functions through inhibition of pyruvate dehydrogenase kinase (PDK) promoting mitochondrial metabolism
eff↑, DCA and metformin are used in combination, synergistic induction of apoptosis of breast cancer cells occurs.
ROS↑, Metformin-induced oxidative damage is enhanced by DCA through PDK1 inhibition which also diminishes metformin promoted lactate production.
PDK1↓,
lactateProd↓, also diminishes metformin promoted lactate production.
p‑PDH↑, DCA is an inhibitor of pyruvate dehydrogenase kinase (PDK) which phosphorylates pyruvate dehydrogenase (PDH), rendering it inactive
Dose∅, DCA (2.5 mM) and metformin (1 mM)
OCR↑, DCA treated cells had a significantly higher oxygen consumption rate compared to control cells.
DNA-PK↑,
γH2AX↑, phosphorylatoin of histone H2AX (p-H2AX), which is a useful surrogate marker of such DNA damage
cl‑PARP↑, large increase of cleaved PARP
selectivity↑, Importantly, we also show that this combination of drugs does not kill non-transformed breast epithelial cells MCF10A under the same conditions in which the drugs kill cancer cells.
*toxicity∅, does not kill non-transformed breast epithelial cells MCF10A under the same conditions in which the drugs kill cancer cells.

1873- DCA,    Dual-targeting of aberrant glucose metabolism in glioblastoma
- in-vitro, GBM, U87MG - in-vitro, GBM, U251
PDKs↓, dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor.
eff↑, By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells)
selectivity↑,
MMP↓, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis
ROS↑,
Apoptosis↑,
Warburg↓, Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor that reverses the Warburg effect
eff↑, DCA has been demonstrated to sensitize cancer cells towards apoptosis and enhance the effects of several anti-cancer agents, including arsenic trioxide [20], cisplatin [22,23] and metformin [24].
Dose∅, IC50 values of DCA were at suprapharmacological millimolar level
toxicity∅, whilst the IC50 values of DCA for non-cancerous cells were not reached (DCA concentration in this study was tested up to 50 mM)

1872- DCA,    Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment
- in-vitro, Oral, HSC2 - in-vitro, Oral, HSC3
PDKs↓, Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate.
ROS↑, enhanced production of reactive oxygen species
OCR↑, DCA - a mildly cytotoxic concentration - caused, indeed, an increase of the resting endogenous OCR in all the three OSCC cell lines
other↑, Consequently, the OxPhos/Glycolysis flux ratio increased largely in HSC-2 and scantly in PE15 with an intermediate value for HSC-3

1869- DCA,    Dichloroacetate induces autophagy in colorectal cancer cells and tumours
- in-vitro, CRC, HT-29 - in-vitro, CRC, HCT116 - in-vitro, Pca, PC3 - in-vitro, CRC, HT-29
LC3II↑, Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo
ROS↑, increased production of reactive oxygen species (ROS)
mTOR↓, mTOR inhibition
MCT1↓, DCA is a possible competitive MCT-1 inhibitor
NADH:NAD↓, increased NAD+/NADH ratios
NAD↑,
TumAuto↑, DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced kPL and increased NAD+/NADH ratio.
lactateProd↓, DCA treatment reduces lactate excretion with no change in glucose uptake
LDH↑, Increased LDH activity

1885- DCA,    Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW-620 - in-vitro, CRC, HT-29
SMCT1∅, SLC5A8 transports dichloroacetate very effectively with high affinity. This transporter is expressed in normal cells, but the expression is silenced in tumor cells via epigenetic mechanisms.
eff↓, lack of the SLC5A8 transporter makes tumor cells resistant to the antitumor activity of dichloroacetate.
eff↑, However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells, and prostate cancer cells.
eff↑, our findings suggest that combining dichloroacetate with a DNA methylation inhibitor would offer a means to reduce the doses of dichloroacetate to avoid detrimental effects associated with high doses but without compromising antitumor activity.
PDKs↓, Dichloroacetate is an inhibitor of pyruvate dehydrogenase kinase (PDK), which phosphorylates the E1α subunit of PDC and inactivates the complex
MMP↓, depolarization of the mitochondrial membrane,
Glycolysis↓, suppression of glycolysis
mitResp↑, enhancement of mitochondrial oxidation
ROS↑, production of reactive oxygen species,
eff↑, In control cells, which did not express the transporter, dichloroacetate did not have any significant effect. However, under identical conditions, SLC5A8-expressing cells underwent apoptosis to a marked extent. This phenomenon was seen in all three c

5194- DCA,    Metabolic modulation of glioblastoma with dichloroacetate
- vitro+vivo, GBM, NA
MMP↓, Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA.
mt-ROS↑, DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo.
Apoptosis↑,
CSCs↓,
Hif1a↓, DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro.
P53↑,
angioG↓,
toxicity↓, and there was no hematologic, hepatic, renal, or cardiac toxicity.
PDKs↓, sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas.

5195- DCA,  Rad,    Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells
- in-vitro, BC, 4T1 - in-vitro, BC, EMT6
PDKs↑, Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production.
ROS↑, Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells
p‑PDH↓, hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production.
ECAR↓,
lactateProd↓,
selectivity↓, Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells
RadioS↑, Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged.

5196- DCA,    Dichloroacetate induces apoptosis in endometrial cancer cells
- in-vitro, Var, NA
selectivity↑, Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on non-cancerous 293T cells.
MMP↓, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism.
survivin↓,
Ca+2↓, DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway.
P53↑, DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism.
PDK1↓, DCA binds to PDK and attenuates inhibition of PDH activity.
PDH↑,
Glycolysis↓, The increased PDH activity shifts metabolism from glycolysis to glucose oxidation and decreases mitochondrial membrane potential (MMP) hyperpolarization
OXPHOS↑,
ROS↑, translocation of reactive oxygen species (ROS) and cytochrome c from the mitochondria to the cytoplasm, subsequently inducing apoptosis through the activation of caspases
Cyt‑c↑,
Apoptosis↑,
Casp↑,
tumCV↓, DCA Reduces Endometrial Cancer Cell Viability in a Dose-Dependent Manner
PUMA↑, DCA Increases PUMA Expression

4901- DCA,  Sal,    Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer
- Review, NSCLC, NA
Glycolysis↓, DCA redirects mitochondrial metabolism away from glycolysis to OXPHOS by the inhibition of PDKs
OXPHOS↑,
PDKs↓,
ROS↑, DCA increases reactive oxygen species (ROS), which induce downstream changes in mitochondrial function, causing the selective apoptosis of cancer cells.
Apoptosis↑,
GlucoseCon↓, treatment with DCA decreased glucose consumption and lactate production in vitro in a manner that was statistically significant compared to the controls
lactateProd↓,
RadioS↑, it enhanced the sensitivity of A549 and H1299 cells to X-ray-induced cell killing
TumAuto↑, DCA has been shown to induce autophagy instead of inhibiting it.
mTOR↓, The DCA-induced induction of autophagy was found to be mediated by the generation of ROS, the inhibition of the mammalian targets of rapamycin (mTOR),
LC3s↓, Lu and colleagues found that LC3 decreased while p62 levels increased, both of which are hallmarks of autophagy inhibition
p62↑,
TumCG↓, In vivo studies have demonstrated that DCA inhibits the growth of A549 and H1975 tumor xenografts and enhances the survival of tumor-bearing nude mice
OS↑,
toxicity↝, the most clinically limiting side effect of DCA is peripheral neuropathy
ChemoSen↑, DCA exerts synergistic potential with the most widely used chemotherapy agent, paclitaxel, on NSCLC cells.
eff↑, DCA has also been shown to have anticancer synergies with various non-traditional agents, the most prominent of which is metformin.
eff↑, Another compound that DCA has been shown to have a strong synergism with is ivermectin.
Ferritin↓, SAL and its derivatives prevent the movement of iron from the lumen to the cytosol, triggering an iron-depletion reaction that is characterized by the rapid degradation of ferritin
CSCs↓, SAL has been shown to selectively target CSCs in vitro and in vivo, but its mode of action is not fully understood.
EMT↓, SAL has also been shown to suppress the epithelial–mesenchymal transition (EMT) as well as transforming growth factors (TGFs). EMT is a process that is pivotal to metastasis.
ROS↑, SAL triggers apoptosis by elevating intracellular ROS levels, leading to the translocation of Bax protein to the mitochondria, cytochrome c (Cytc) release, and the activation of caspase-3
Cyt‑c↑,
Casp3↑,
ER Stress↑, SAL was observed to upregulate ER stress-related proteins in a time-/dose-dependent manner
selectivity↑, SAL induced cell death in multiple apoptosis-resistant cancer cell lines, but not in normal healthy human cells
eff↑, Skeberdytė and colleagues were among the first to recognize that DCA had synergistic potential with SAL.
TumCG↓, DCA and SAL were found to significantly suppress tumor growth in vivo in the mice.

4456- DFE,    Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells
- in-vitro, Pca, PC3
TumCD↑, MTT assay showed the strong inhibitory effect of EAFAD on PC3 cells.
MMP↓, Loss of mitochondrial membrane potential and increased oxidative stress were observed in EAFAD treated cells, which suggested mitochondrial involvement in apoptosis.
mt-ROS↑,
Apoptosis↑,
TumCCA↑, arrest the cell cycle in S phase.

4454- DFE,    Cytostatic and Anti-tumor Potential of Ajwa Date Pulp against Human Hepatocellular Carcinoma HepG2 Cells
- in-vitro, Liver, HepG2
ROS↑, ADP extract increased the reactive oxygen species level and decreased the mitochondrial membrane potential in treated HCC cells
MMP↓,
TumCCA↑, ADP extract induced elevation of S and G2/M phases of cell cycle.
Apoptosis↑, ADP extract induced apoptosis in HCC cells
selectivity↑, ADP extract did not display any significant effect on normal cell line Vero.
MMP↓, Results suggested that treatment of HepG2 cells with ADP extract resulted in a dose-dependent decrease in the percent MMP level in treated HCC cells.
TumCCA↑, ADP extract induced S and G2/M phase arrest

1844- dietFMD,    Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment
- Review, NA, NA
Risk↓, CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients.
AMPK↑, the increased AMP levels activate AMPK
Akt↓, This activation results in the inhibition of AKT and mTOR pathways
mTOR↓,
SIRT1↑, energy deficit also activates the SIRT pathways, which downregulates HIF1α, and the Nrf2 pathway
Hif1a↓,
NRF2↓,
SOD↑, enhances antioxidant defenses (e.g., superoxide dismutase SOD1 and SOD2)
ROS↑, Additionally, in prostate cancer (PC) [55] and triple-negative breast cancer (TNBC) [56] cell lines glucose restriction (GR) has been shown to trigger an increase in ROS, leading to cell death.
IGF-1↓, CR decreases poor prognosis markers such as IGF1, pAKT, and PI3K
p‑Akt↓,
PI3K↑,
GutMicro↑, induces changes in the gut microbiome linked to anti-tumor effects
OS↑, Incorporating a nutraceutical regimen like CR or KD with CT has reduced tumor growth and relapse and improved the survival rate
eff↝, type of dietary intervention, with FMD being the first option, followed by KD and CR last. FMD has been considered the most cost-effective and applicable because it does not completely restrict food intake.
ROS↑, findings consistently indicating that dietary restrictions render highly proliferative tumor cells more susceptible to oxidative damage
TumCCA↑, CR has been reported to induce cell cycle arrest in the G0/G1 phases , enabling cells to undergo DNA repair more efficiently and diminishing DNA damage by CRT
*DNArepair↑,
DNAdam↑, In contrast, tumoral cells, which have an altered cell cycle, are unable to repair DNA, leading to cell death

1863- dietFMD,  Chemo,    Effect of fasting on cancer: A narrative review of scientific evidence
- Review, Var, NA
eff↑, recommend combining prolonged periodic fasting with a standard conventional therapeutic approach to promote cancer‐free survival, treatment efficacy, and reduce side effects in cancer patients.
ChemoSideEff↓, lowered levels of IGF1 and insulin have the potential to protect healthy cells from side effects
ChemoSen↑,
Insulin↓, causes insulin levels to drop and glucagon levels to rise
HDAC↓, Histone deacetylases are inhibited by ketone bodies, which may slow tumor development.
IGF-1↓, FGF21 rises during intermittent fasting, and it plays a vital role in lowering IGF1 levels by inhibiting phosphorylated STAT5 in the liver
STAT5↓,
BG↓, Fasting suppresses glucose, IGF1, insulin, the MAPK pathway, and heme oxygenase 1
MAPK↓,
HO-1↓,
ATG3↑, while increasing many autophagy‐regulating components (Atgs, LC3, Beclin1, p62, Sirt1, and LAMP2).
Beclin-1↑,
p62↑,
SIRT1↑,
LAMP2↑,
OXPHOS↑, Fasting causes cancer cells to release oxidative phosphorylation (OXPHOS) through aerobic glycolysis
ROS↑, which leads to an increase in reactive oxygen species (ROS), p53 activation, DNA damage, and cell death in response to chemotherapy.
P53↑,
DNAdam↑,
TumCD↑,
ATP↑, and causes extracellular ATP accumulation, which inhibits Treg cells and the M2 phenotype while activating CD8+ cytotoxic T cells.
Treg lymp↓,
M2 MC↓,
CD8+↑,
Glycolysis↓, By lowering glucose intake and boosting fatty acid oxidation, fasting can induce a transition from aerobic glycolysis to mitochondrial oxidative phosphorylation in cancerous cells, resulting in increased ROS
GutMicro↑, Fasting has been shown to have a direct impact on the gut microbial community's constitution, function, and interaction with the host, which is the complex and diverse microbial population that lives in the intestine
GutMicro↑, Fasting also reduces the number of potentially harmful Proteobacteria while boosting the levels of Akkermansia muciniphila.
Warburg↓, Fasting generates an anti‐Warburg effect in colon cancer models, which increases oxygen demand but decreases ATP production, indicating an increase in mitochondrial uncoupling.
Dose↝, Those patients fasted for 36 h before treatment and 24 h thereafter, having a total of 350 calories per day. Within 8 days of chemotherapy, no substantial weight loss was recorded, although there was an improvement in quality of life and weariness.

1847- dietFMD,  VitC,    Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers
- in-vitro, PC, PANC1
TumCG↓, Fasting-mimicking diets delay tumor progression
ChemoSen↑, sensitize a wide range of tumors to chemotherapy
eff↑, vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1
HO-1↓, FMD reverses the effect of vitamin C on HO-1(downregulating HO-1)
Ferritin↓,
Iron↑, consequently increasing reactive iron, oxygen species, and cell death
ROS↑, Vitamin C’s pro-oxidant action is strictly dependent on metal-ion redox chemistry. In particular, free iron was shown to be a key player in vitamin C-induced cytotoxic effects
TumCD↑,
IGF-1↓, effects on the insulin-like growth factor 1 (IGF-1)
eff↓, When cancer cells were grown under STS conditions before and during treatment, vitamin C-mediated toxicity was strongly enhanced
eff↓, Conversely, KRAS-wild-type CRC (SW48, HT29), prostate cancer (PC-3), ovarian cancer (COV362) cell lines and a normal colon cell line (CCD841CoN) were resistant to vitamin C when used both as a single agent and in combination with STS

1851- dietFMD,  Chemo,    Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy
- in-vitro, GBM, LN229 - in-vitro, neuroblastoma, SH-SY5Y
selectivity↑, Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2
selectivity↑, Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide
ROS↑, promote oxidative stress and DNA damage
DNAdam↑,
BG↓, blood glucose level for both mice and humans is ≈1.0 g/liter but can reach 0.5 g/liter after starvation.

1852- dietFMD,  Chemo,    Starvation Based Differential Chemotherapy: 
A Novel Approach for Cancer Treatment
- Review, Var, NA
ChemoSideEff↓, Ten volunteers with different types of cancers were starved for 48–140 hours before chemotherapy and five–56 hours after. Overall, all patients showed decreased side effects of chemotherapy.
*toxicity↓, A case report showed that short-term starvation of up to five days followed by chemotherapy is not only safe and feasible, but also helps to ameliorate chemotherapy related side-effects.3
mTOR↓, reduction in mTOR activity
IGF-1↓, Studies reveal that starvation reduces levels of IGF-1 significantly. Short-term starvation of 72 hours reduces circulating IGF-1 by 70%
IGFBP1↑, and increases the level of IGF binding protein (IGFBP-1) an IGF-1 inhibitor, by 11-fold
BG↓, glucose levels were reduced by 41%
ROS↑, Increased metabolic rate as a result of DR causes increased ROS production

1846- dietFMD,  VitC,    A fasting-mimicking diet and vitamin C: turning anti-aging strategies against cancer
- Study, Var, NA
TumCG↓, FMDs delay tumor progression
ChemoSen↑, potentiate chemotherapy efficacy
ChemoSideEff↓, while protecting healthy tissues from chemo-associated side effects in different cancer models
ROS↑, presence of metals, and particularly iron, high dose of vitamin C exerts a pro-oxidant action by generating hydrogen peroxide and hydroxyl radicals via Fenton chemistry
Fenton↑,
H2O2↑,
eff↑, we show that FMD cycles potentiate high-dose vitamin C anti-cancer effects in a range of cancer types
HO-1↓, KRAS-mutant cancer cells respond to vitamin C treatment by up-regulating HO-1, and consequently limiting vitamin C pro-oxidant action. FMD is able to revert HO-1 up-regulation
DNAdam↑, increase in free reactive iron and oxygen species causing DNA damage and cell death
eff↑, we found that the nontoxic FMD + vitamin C combination therapy is as effective as oxaliplatin + vitamin C in delaying tumor progression while the triple FMD, vitamin C and chemotherapy combination treatment is the most effective.

1854- dietFMD,    How Far Are We from Prescribing Fasting as Anticancer Medicine?
- Review, Var, NA
ChemoSideEff↓, ample nonclinical evidence indicating that fasting can mitigate the toxicity of chemotherapy and/or increase the efficacy of chemotherapy.
ChemoSen↑, Fasting-Induced Increase of the Efficacy of Chemotherapy
IGF-1↓,
IGFBP1↑, biological activity of IGF-1 is further compromised due to increased levels of insulin-like growth factor binding protein 1 (IGFBP1)
adiP↑, increased levels of adiponectin stimulate the fatty acid breakdown.
glyC↓, After depletion of stored glycogen, which occurs usually 24 h after initiation of fasting, the fatty acids serve as the main fuels for most tissues
E-cadherin↑, upregulation of E-cadherin expression via activation of c-Src kinase
MMPs↓, decrease of cytokines, chemokines, metalloproteinases, growth factors
Casp3↑, increase of level of activated caspase-3
ROS↑, it is postulated that the beneficial effects of fasting are ascribed to rapid metabolic and immunological response, triggered by a temporary increase in oxidative free radical production
ATP↓, Glucose deprivation leads to ATP depletion, resulting in ROS accumulation
AMPK↑, Additionally, ROS activate AMPK
mTOR↓, Under conditions of glucose deprivation, AMPK inhibits mTORC1
ROS↑, Beyond glucose deprivation, another mechanism increasing ROS levels is the AA (amino acids) starvation
Glycolysis↓, Indeed, in cancer cells, limited glucose sources impair glycolysis, decrease glycolysis-based NADPH production due to reduced utilization of the pentose phosphate pathway [88,89,90,91],
NADPH↓,
OXPHOS↝, and shift the metabolism from glycolysis to oxidative phosphorylation (OXPHOS) (“anti-Warburg effect”), leading to ROS overload [92,93,94,95].
eff↑, Fasting compared to long-term CR causes a more profound decrease in insulin (90% versus 40%, respectively) and blood glucose (50% versus 25%, respectively).
eff↑, FMD have been demonstrated to result in alterations of the serum levels of IGF-I, IGFBP1, glucose, and ketone bodies reminiscent of those observed in fasting
*RAS↓, A plausible explanation of the differential protective effect of fasting against chemotherapy is the attenuation of the Ras/MAPK and PI3K/Akt pathways downstream of decreased IGF-1 in normal cells
*MAPK↓,
*PI3K↓,
*Akt↓,
eff↑, Starvation combined with cisplatin has been shown in vitro to protect normal cells, promoting complete arrest of cellular proliferation mediated by p53/p21 activation in AMPK-dependent and ATM-independent manner
ROS↑, generation of ROS due to paradoxical activation of the AKT/S6K, partially via the AMPK-mTORC1 energy-sensing pathways malignant cells
Akt↑, cancer cells
Casp3↑, combination of fasting and chemotherapy was in part ascribed to enhanced apoptosis due to activation of caspase 3

1860- dietFMD,  Chemo,    Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape
- in-vitro, BC, SUM159 - in-vitro, BC, 4T1
PI3K↑, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression.
Akt↑,
mTOR↑,
CDK4↑,
CDK6↑,
hyperG↓, FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs.
TumCG↓, cycles of FMD significantly slowed down tumor growth, reduced tumor size, and caused an increased expression of intratumor Caspase3
TumVol↓,
Casp3↑,
BG↓, confirming our hypothesis that lowering intracellular glucose levels (through reduced extracellular levels or reduced uptake) reduces CSC survival
eff↑, 2DG potentiated the effect of FMD both in terms of delaying tumor progression and in decreasing the number of mammospheres derived by tumor masses,
eff∅, metformin did not show any additive or synergistic antitumor effect when combined with the FMD, thus suggesting that FMD and metformin have redundant effects on blood glucose levels
PKA↓, We have previously shown that prolonged fasting reduces the activity of protein kinase A (PKA) in different types of normal cells
KLF5↓, PKA inhibition resulted in the downregulation of KLF5, a potential therapeutic target for TNBC
p‑GSK‐3β↑, (GSK3β) phosphorylation
Nanog↓, stemness-associated genes NANOG and OCT4, and KLF2 and TBX3,
OCT4↓,
KLF2↓,
eff↑, Combining FMD cycles with PI3K/AKT/mTOR inhibitors results in long-term animal survival and reduces treatment-induced side effects
ROS↑, FMD resulted in an increased expression of pro-apoptotic molecules, such as BIM, and ASK1, a critical cellular stress sensor frequently activated by ROS, whose production was previously shown to be increased by the FMD
BIM↑,
ASK1↑,
PI3K↑, FMD cycles upregulate PI3K-AKT and mTOR pathways and downregulate CCNB-CDK1 while upregulating CCND-CDK4/6 signaling axes
Akt↑,
mTOR↑,
CDK1↓,
CDK4↑,
CDK6↑,
eff↑, combining STS with pictilisib, ipatasertib, and rapamycin, selective inhibitors for PI3K, AKT, and mTOR, respectively, resulted in enhanced cancer cell death and reduction of mammosphere numbers in SUM159 cells

1861- dietFMD,  Chemo,    Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models
- in-vitro, Colon, CT26 - in-vivo, NA, NA
selectivity↑, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy
ChemoSen↑, STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.
BG↓, glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect
AminoA↓,
Warburg↓,
OCR↑, characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.
ATP↓,
ROS↑, a significant increase in O2consumption rate (OCR), indicative of an increased oxidative metabolism, was observed
Apoptosis↑,
GlucoseCon↓, STS was as effective as oxaliplatin (OXP) in reducing the average tumor glucose consumption
PI3K↓, STS and in particular STS+OXP down-regulated the expression of PI3K
PTEN↑, and up-regulated PTEN expression
GLUT1↓, STS induced a profound reduction in GLUT1 , GLUT2 , HKII , PFK1, PK
GLUT2↓,
HK2↓,
PFK1↓,
PKA↓,
ATP:AMP↓, Accordingly, the ATP/AMP ratio, a good indicator of cellular energy charge, was dramatically reduced by the two STS settings
Glycolysis↓, results strongly support the effect of STS on reducing glycolysis and lactate production and increasing respiration at Complexes I-IV resulting in superoxide production/oxidative stress but in reduced ATP generation.
lactateProd↓,

1810- dietKeto,  Oxy,    The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer
- in-vivo, Var, NA
BG↓, KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer.
TumCG↓,
OS↑,
eff↑, While HBO2T alone did not influence cancer progression, combining the KD with HBO2T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls.
Dose∅, Mice undergoing HBO2T received 100% O2 for 90 minutes at 1.5 ATM gauge (2.5 ATM absolute) three times per week (M, W, F) in a hyperbaric chamber (Model 1300B, Sechrist Industries, Anaheim, CA).
KeyT↑, only the KD+HBO2T animals showed significantly increased ketones compared to controls
eff↑, we hypothesized that combining these non-toxic treatments would provide a powerful, synergistic anti-cancer effect.
cachexia↓, While low carbohydrate or ketogenic diets promote weight loss in overweight individuals, they are also known to spare muscle wasting during conditions of energy restriction and starvation
ChemoSen↑, KD improves quality of life and enhances the efficacy of chemotherapy treatment in the clinic
*ROS↓, ketone body metabolism protects cells from oxidative damage by decreasing ROS production. cancer cells are unable to effectively metabolize ketone bodies; we do not expect that ketones would confer the same protective effects onto the cancer cells
ROS↑, HBO2T increases ROS production within the cell which can lead to membrane lipid peroxidation and cell death
lipid-P↑,
selectivity↑, KD weakens cancer cells by glucose restriction and the inherent anti-cancer effects of ketone bodies while simultaneously conferring a protective advantage to the healthy tissue capable of ketone metabolism.
toxicity∅, HBO2T should be considered a safe treatment for patients with varying malignancies and that there is no convincing evidence its use promotes cancer progression or recurrence

2273- dietMet,    Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vivo, NA, NA
ROS↑, Met-Cys double deprivation had synergistic action on elevating ROS level, decreased GSH level and inhibition of glioma cell proliferation.
GSH↓,
TumCP↓,
TumAuto↑, triggered autophagy of glioma cells both in vitro and in vivo
LC3II↑, Met-Cys deprivation strongly gave rise to the formation of the autophagosome and increased LC3-II protein expression, both of which are autophagy related indicators

2272- dietMet,    Methionine restriction - Association with redox homeostasis and implications on aging and diseases
- Review, Nor, NA
*OS↑, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models
*mt-ROS↓, Mitochondrial ROS reduction by methionine restriction (MR) maintains redox balance
*H2S↑, MR ameliorates oxidative stress by autophagy activation and hepatic H2S generation.
*FGF21↑, MR impact on cognition by upregulation of FGF21 and alterations of gut microbiome.
*cognitive↑,
*GutMicro↑,
*IGF-1↓, long-term, low-fat, whole-food vegan diet may increase life expectancy in humans by down-regulating IGF-I activity
*mTOR↓, Suppression of the mTOR pathway by MR can also lead to increased H2S production,
*GSH↑, 80% MR increases the GSH content in erythrocytes of rats,
*SOD↑, A diet restricting methionine to 80% (0.17% Met) significantly increases plasma SOD and decreases MDA levels while increasing mRNA expression of Nrf2, HO-1, and NQO-1 in the heart of HFD-fed mice with cardiovascular impairment
*MDA↓,
*NRF2↑,
*HO-1↑,
*NQO1↑,
*GLUT4↑, In skeletal muscle, MR improved expression and transport of GLUT4 and glycogen levels and increased the expression of glycolysis-related genes (HK2, PFK, PKM) in HFD-fed mice
*Glycolysis↑,
*HK2↑,
*PFK↑,
*PKM2↑,
*GlucoseCon↑, promoting glucose uptake and glycogen synthesis, glycolysis, and aerobic oxidation in skeletal muscle.
*ATF4↑, MR can increase the expression of hepatic FGF21 by activating GCN2/ATF4/PPARα signaling in liver cells, thereby improving insulin sensitivity, accelerating energy expenditure, and promoting fat oxidation and glucose metabolism
*PPARα↑,
GSH↓, MR was able to decrease GSH in HepG2 cells, thereby regulating the activation state of protein tyrosine phosphatases such as PTEN.
GSTs↑, decrease of GSH by MR also triggers upregulation of glutathione S-transferase
ROS↑, Double deprivation of methionine and cystine both in vitro and in vivo resulted in a decrease in GSH content, an increase in ROS levels, and an induction of autophagy in glioma cells
*neuroP↑, A neuroprotective role of FGF21

2264- dietMet,    Methionine restriction for cancer therapy: From preclinical studies to clinical trials
- Review, Var, NA
TumCP↓, methionine restriction (MR) reduces cancer cell proliferation via different mechanisms
*ROS?, MR lowers sulfur-containing metabolite levels, reduces oxidative stress, and enhances the immune response
ChemoSen↑, may sensitize tumors to chemo/radiotherapy
RadioS↑,
eff↑, therapeutic potential of MR lies in its ability to synergize with other therapies, enhancing overall antitumor efficacy.
ROS↑, increases ROS, weaking cancer cell defense (from graphical abstract). In colon cancer, MR increases oxidative stress, induces cell cycle arrest, and promotes the apoptosis of p53(Tumor Protein 53)-deleted cells
selectivity↑, methionine-depleted media significantly impaired the growth of malignant cells while leaving normal cell growth unchanged.
TS↓, MR also targets thymidylate synthase (TS), a key enzyme in nucleotide synthesis, enhancing the chemotherapeutic efficacy of 5-FU by lowering TS activity and expression
eff↑, duration of methionine deprivation can significantly affect the tumor cell response. Intermittent methionine deprivation appears particularly beneficial, enhancing tumor cell sensitivity to CD8+ T cell-mediated cytotoxicity

2267- dietMet,    Role of amino acids in regulation of ROS balance in cancer
- Review, Var, NA
TumCG↓, Indeed, restriction of methionine, which is an essential amino-acid, decreases tumor-growth in patient-derived xenograft mouse models of colorectal cancer by affecting the 1-C metabolism.
GSH↓, Interestingly, methionine restriction leads to a decrease in GSH pool and consequently to a ROS imbalance that affects tumor cell proliferation and can be alleviated by antioxidant treatment.
ROS↑,

2155- dietP,    Transepithelial Anti-Neuroblastoma Response to Kale among Four Vegetable Juices Using In Vitro Model Co-Culture System
- in-vivo, neuroblastoma, Caco-2 - NA, NA, SH-SY5Y
AntiCan↑, Juicing vegetables is thought to be an anticancer treatment. Support exists for a rank order of anticancer greens (kale > dandelion > lettuce > spinach) based on degrees of bioavailability of different phytochemicals
ROS↑, Kale juice uniquely induced reactive oxygen species and S-phase cell cycle arrest in SH-SY5Y. no differentiation agents were added to SH-SY5Ys, leaving them fully metastatic
eff↑, Fermentation enhances some
eff↑, By and large, most phytochemicals are best prepared for human consumption by fresh juicing
eff↑, kale’s abundant and diverse phytochemical flavonoids (Scheme 1B), also found in other Brassica such as cauliflower, broccoli, Brussel sprouts, and cabbages

1626- dietSTF,  dietFMD,    When less may be more: calorie restriction and response to cancer therapy
- Review, Var, NA
CRM↑,
ChemoSen↑, CR mimetics as adjuvant therapies to enhance the efficacy of chemotherapy, radiation therapy, and novel immunotherapies.
RadioS↑,
eff↑, CR mimetics as adjuvant therapies to enhance the efficacy of chemotherapy, radiation therapy, and novel immunotherapies.
eff↑, Intermittent fasting has been shown to enhance treatment with both chemotherapy and radiation therapy.
IGF-1↓, Exposure to an energy restricted diet results in reduced systemic glucose and growth factors such as IGF-1
TumCG↓, reduction of IGF-1 levels in CR results in decreased tumor growth and progression
AMPK↑, CR also induces activation of AMP-activated protein kinase (AMPK), (working in opposition to IGF-1)
eff↑, Recent research in our lab showed that combining autophagy inhibition with a CR regimen reduced tumor growth more than either treatment alone [20].
ChemoSen↑, Short-term fasting has been shown to improve chemotherapeutic treatment with etoposide [40], mitoxantrone, oxaliplatin [41], cisplatin, cyclophosphamide, and doxorubicin [42] in transgenic and transplant mouse models
RadioS↑, Alternate day fasting has also been shown to improve the radiosensitivity of mammary tumors in mice
ROS↑, improve the radiosensitivity: likely due to enhanced oxidative stress and DNA damage during short-term fasting on cancer cells.
DNAdam↑,
eff↑, fasting-mimicking diet, in which mice are fed the same amount of food as control mice, albeit with a severely reduced caloric density, showed a similar reduction in tumor growth as short-term starvation
HO-1↓, fasting-mimicking diet were associated with increased autophagy in the cancer cells and reduced heme oxygenase-1 (HO-1) in the microenvironment

5068- dietSTF,    mTOR-autophagy axis regulation by intermittent fasting promotes skeletal muscle growth and differentiation
- in-vivo, Nor, NA
*glucose↓, Following short-term fasting, blood glucose levels in the sMF and sSF groups were significantly lower than those in the ND group
ROS↑, reactive oxygen species (ROS) levels were significantly higher in the sSF group compared to the sMF and ND groups
LC3B↑, sSF groups exhibited a significant upregulation of LC3B protein levels
p62↓, Conversely, p62 levels (1.00 ± 0.08, 0.58 ± 0.09 & 0.28 ± 0.05, P < 0.01) and the phosphorylation ratio of mTOR (p-mTOR/mTOR) (1.00 ± 0.04, 0.70 ± 0.10 & 0.35 ± 0.03, P < 0.01) were significantly reduced.
p‑mTOR↓,
p‑AMPK↑, IMF group exhibited a significant increase in the LC3B-II/I ratio and the phosphorylation ratio of AMPK (p-AMPK/AMPK)

5069- dietSTF,    The Role of Intermittent Fasting in the Activation of Autophagy Processes in the Context of Cancer Diseases
- Review, Var, NA
Risk↓, IF has shown potential for reducing cancer risk and enhancing therapeutic efficacy by sensitizing tumor cells to chemotherapy and radiotherapy.
ChemoSen↑, intermittent fasting (IF) may enhance the effectiveness of chemotherapy and targeted therapies by activating autophagy. IF enhances the effectiveness of chemotherapy, including drugs such as cisplatin, cyclophosphamide, and doxorubicin
RadioS↑, disease stabilization, improved response to radiotherapy patients with glioma
*Dose↝, 16:8—16 h of fasting with an 8 h eating window;
*Dose↝, 5:2—consuming a standard number of calories for 5 days and reducing intake to 25% of daily requirements for 2 days;
*Dose↝, Eat–Stop–Eat—complete fasting for 24–48 h.
*LDL↓, IF during Ramadan (approximately 18 h of fasting for 29–30 days) reduces LDL cholesterol levels and increases HDL cholesterol in women, as well as reducing inflammatory markers such as CRP and TNF-α
*CRP↓,
*TNF-α↓,
TumAuto↓, Intermittent fasting activates autophagy as an adaptive mechanism to nutrient deprivation, which may modulate tumor development and treatment
GLUT1↓, fasting reduces the expression of glucose transporters GLUT1/2, which slow down cancer metabolism and increase the susceptibility of cancer cells to oxidative stress
GLUT2↓,
glucose↓, studies on cell and animal models have shown that intermittent fasting reduces glucose and insulin-like growth factor (IGF-1) levels [103], as well as insulin [104,105], resulting in the inhibition of the mTOR kinase pathway (PI3K/Akt/mTOR), suppress
IGF-1↓,
Insulin↓,
mTOR↓,
mTORC1↓, suppression of mTORC1 [22], and activation of AMPK through increased ADP/ATP ratio in cells, which supports autophagy and induces apoptosis
AMPK↑,
Warburg↓, Moreover, IF counteracts the Warburg effect by promoting oxidative phosphorylation, leading to an increase in the production of reactive oxygen species (ROS) and enhanced oxidative stress in cancer cells [106,108], causing DNA damage and the activati
OXPHOS↑,
ROS↑,
DNAdam↑,
JAK1↓, fasting reduces the production of adenosine by cancer cells, inhibiting the activation of the JAK1/STAT pathway, thereby reducing cancer cell proliferation
STAT↓,
TumCP↓,
QoL↑, reduction in IGF-1 levels, improved quality of life patients with multiple cancer types

5386- docx,  AsP,    Co-delivery of docetaxel and palmitoyl ascorbate by liposome for enhanced synergistic antitumor efficacy
- vitro+vivo, Liver, HepG2 - in-vitro, BC, MCF-7 - in-vitro, Pca, PC3
Dose↝, The average diameters of the liposomes ranged from 140 to 170 nm. Negative zeta potential values were observed for all systems, ranged from −40 mV to −56 mV
ROS↑, Further, fluorescent microscopy using ROS-sensitive markers confirmed the generation of ROS after treatment of cells with PA-liposomes.
eff↑, The synergistic antitumor effect of co-delivery liposomes was also evaluated both in vitro and in vivo.
eff↑, combined use of PA and DOC at a weight ratio of 200:1 had the highest synergistic effect in HepG2, MCF-7 and PC-3 lines

4913- DSF,    Anticancer effects of disulfiram: a systematic review of in vitro, animal, and human studies
- Review, Var, NA
Apoptosis↑, Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis
tumCV↑, DSF was associated with enhanced apoptosis and tumor inhibition rates,
eff↑, The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule
toxicity↓, noticeable body weight loss after DSF treatment, which indicated that there was no major toxicity of DSF.
antiNeop↑, antineoplastic activity of DSF was first recorded in 1977
ChemoSen↑, The synergistic effect of Cis, DOX, TMZ, PTX, Gy, and DSF in induced apoptosis was significantly higher than that of DSF or Cis or DOX or TMZ or Gy alone
RadioS↑, Tumor cell growth was significantly inhibited when DSF, chemotherapy, and radiation therapy were used simultaneously, as shown in the examined in vivo studies
OS↑, All three studies show that DSF is safe and seems to prolong survival of cancer patients
ROS↑, Metabolites of DSF chelate with metal ions, leading to alterations in the intracellular levels of metal ions, enhancement of oxidative stress, inhibition of the activities of superoxide dismutase or matrix metalloproteinases,
SOD↓,
MMP1↓,
eff↑, observation that the combination of DSF with metal ions (Cu, Ag) leads to enhanced anticancer effectiveness is in accordance with the observations of in vitro and animal experiments
Half-Life↓, At the pH of 7.4, the half-life of DSF is 1–1.5 min

4914- DSF,  immuno,    Disulfiram and cancer immunotherapy: Advanced nano-delivery systems and potential therapeutic strategies
- Review, Var, NA
AntiTum↑, potential as an anti-tumor agent and even as an enhancer of cancer immunotherapy
eff↑, Targeted delivery: through nanotechnology, specific delivery of disulfiram to tumor sites can be achieved to minimize damage to normal tissues and increase drug accumulation in tumor cells
ALDH↓, It works by inhibiting an enzyme called Aldehyde Dehydrogenase (ALDH).
Dose↝, DSF is not only affordable at $20–40 for a daily dose of 250 mg taken orally in the USA, but it is also considered to be safe, allowing for long-term treatment at the same dosage.
RadioS↑, DSF/Cu can enhance the effects of ionizing radiation and induce ICD in breast cancer
angioG↓, inhibition of angiogenesis and metastasis, make it a versatile agent in combating cancer
TumMeta↓,
BioAv↝, limitations associated with its delivery, solubility, and off-target toxicity have prompted the development of innovative strategies to improve its clinical efficacy
ROS↑, DSF effectively treats tumors. Such as increasing the production of ROS, causing DNA damage, and impeding enzyme activity.
DNAdam↑,
P-gp↓, DSF can target P-glycoprotein (P-gp) dysfunction, cancer stem cells (CSCs), and hinder the process of epithelial-mesenchymal transition (EMT).
CSCs↓,
EMT↓,
Imm↑, DSF stimulates the immune system
SOD↓, generation of ROS, inhibition of the superoxide dismutase activity and activation of the mitogen-activated protein kinase (MAPK)
MAPK↓,
NF-kB↓, NF-κB inhibiting activity of DSF could be attributed to their inhibition of the proteasome and degradation other regulatory redox-sensitive proteins.
ChemoSen↑, therapeutic effect of combining DSF with conventional cancer drugs like cisplatin and doxorubicin (DOX) has been proven to be enhanced.
eff↑, combination use of DSF with immunotherapy has shown remarkable success in preclinical and clinical studies.
toxicity↝, The administration of disulfiram necessitates the complete abstinence from alcohol
BioAv↑, researchers use lipid nanoparticles as carriers for disulfiram and used to improve its bioavailability and reduce side effects.
*Inflam↓, DSF has the ability to inhibit inflammation, which has potential applications in treating various inflammatory diseases,
Sepsis↓, Mice with sepsis experienced reduced mortality when administered with DSF-loaded lactoferrin nanoparticles,

4916- DSF,  Cu,    The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics
- Review, Var, NA
TumCP↓, inhibits proliferation, migration, and invasion of malignant tumor cells.
TumCMig↓,
TumCI↓,
eff↑, divalent copper ions can enhance the antitumor effects of DSF
Imm↑, immunomodulatory properties of DSF
ROS↑, Elevated production of reactive oxygen species (ROS) and suppression of the ROS/NF-κB signaling pathway
NF-kB↓,
chemoP↑, DSF has been shown to effectively inhibit NF-κB pathway activity and augment the apoptotic impact of 5-fluorouracil (5-FU) on colorectal cancer cells when administered in conjunction with 5-FU
JNK↑, Activate the JNK signaling pathway
FOXO↑, In acute myeloid leukemia, DSF/Cu2+ enhances the expression of the oncogene FOXO and inhibits the expression of the oncogene MYC, inducing G0/G1 cell cycle arrest and tumor cell apoptosis
Myc↑,
TumCCA↑,
Apoptosis↑,
RadioS↑, DSF/Cu2+ enhances the efficacy of conventional chemotherapy and chemoradiation, while remaining cost-effective
PD-L1↑, DSF can upregulate PD-L1 expression by promoting DNMT1-mediated hypomethylation of IRF7
eff↑, DSF was found to markedly enhance the efficacy of anti-PD-1 antibody treatment
CSCs↓, Inhibition of cancer stem cells
Dose↝, DSF's oral dosage form is ineffective for cancer treatment due to its instability in the gastric environment and rapid degradation in the body
Half-Life↑, DSF encapsulated PEG-PLGA NPs have been shown to improve tumor site delivery and prolong systemic circulation half-life.

4915- DSF,  Cu,    Disulfiram: A novel repurposed drug for cancer therapy
- Review, Var, NA
ROS↑, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF
TumCD↑,
NF-kB↓,
CSCs↓, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs),
ChemoSen↑, becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients.
RadioS↑,
eff↑, no doubt that the combination of DSF and Cu2+ achieves a better antitumor effect than DSF alone.
selectivity↑, DSF facilitates increased Cu uptake into cancer cells, enabling DSF to specifically target cancer cells while sparing normal cells
Proteasome?, DSF on proteasome inhibition

5009- DSF,  Cu,    Activation of Oxidative Stress and Down-Regulation of Nuclear Factor Erythroid 2-Related Factor May Be Responsible for Disulfiram/Copper Complex Induced Apoptosis in Lymphoid Malignancy Cell Lines
- vitro+vivo, lymphoma, NA
AntiTum↑, Disulfiram (DS), an antialcoholism drug, demonstrates strong antitumor activity in a copper (Cu)-dependent manner.
ROS↑, DS/Cu induces reactive oxidative stress (ROS) which activates stress related signaling pathway (c-Jun-amino-terminal kinase, JNK).
JNK↑,
NRF2↓, Nrf2 expression was increased when Raji cells were treated for less than 12h and decreased after 18h or 24h treatment
eff↓, N-acetyl-L-cysteine (NAC), an antioxidant, can partially attenuate DS/Cu complex-induced apoptosis
TumCD↑, Therefore the DS/Cu induced ROS may be higher than that antioxidant factors could protect and thus the Nrf2-mediated cellular survival mechanism was disabled through down regulation of Nrf2 to allow initiation of death process.

5012- DSF,  Cu,    Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems
ROS↑, DSF’s anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins
ALDH↓,
TumCP↓, DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis.
CSCs↓,
angioG↓,
TumMeta↓,
DNAdam↑, anti-cancer mechanism of DSF/Cu (II) may be mediated by the regulation of reactive oxygen species (ROS), enzyme activity regulation, induction of DNA damage, proteasome inhibition, and transcription factors
Proteasome↓,
SOD1↓, The complex of DSF and Cu (II)has been reported to inhibit the enzyme superoxide dismutase 1 (SOD1), one of the major enzymesthat mitigates oxidative damage in melanoma cells
GSR↓, The inhibition of Glutathione reductase (GSR) inhibition by DSF disrupts glutathione GSH redox cycling, producing an accumulation of oxidized glutathione (GSSG) and a lower GSH/GSSG ratio, producing an increase in ROS level
ox-GSSG↑,
GSH/GSSG↓,
MMP↓, DSF induces the disruption of the mitochondrial membrane potential and cause apoptosis in human melanoma cell lines
Akt↓, induced the apoptosis of erbB2-positive breast cancer cells by inhibiting AKT, cyclin D1, and NFκB signaling
cycD1/CCND1↓,
NF-kB↓,
CSCs↓, In hepatocellular carcinoma, DSF decreases CSCs by inhibiting the p38 mitogen-activated protein kinase (MAPK) pathway [118].
MAPK↓,
angioG↓, Thus, the inhibition of DSF/Cu (II) in CSCs decrease angiogenesis.
DrugR↓, DSF/Cu (II) overcomes drug resistance via targeting the proteasome, epithelial–mesenchymal transition (EMT), P-gp, CSC activity
EMT↓,
Vim↓, By downregulating associated proteins such as Vimentin, DSF/Cu (II) inhibits the EMT, which consequently overcomes the paclitaxel resistance of prostate and lung cancer
BioAv↑, The use of these nanoparticle-based formulations can increase the accumulation of DSF at the target site, thereby reducing the toxic effects on healthy tissues and improving the therapeutic index.
eff↑, In clinical trials, DSF is provided orally, but Cu (II) is critical for the efficacy of DSF

5006- DSF,  Cu,    Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition
- vitro+vivo, lymphoma, NA
TumCD↑, n combination with a low concentration (1 μM) of Cu2+, DS induced cytotoxicity in Raji cells with an IC50 of 0.085 ± 0.015 μM and in Molt4 cells with an IC50 of 0.435 ± 0.109 μM.
TumCP↑, DS/Cu inhibits the proliferation of Raji cells in vivo.
Apoptosis↑, After exposure to DS (3.3 μM)/Cu (1 μM) for 24 hours, apoptosis was detected in 81.03 ± 7.91% of Raji cells
NRF2↓, After 24 h exposure, DS/Cu inhibits Nrf2 expression.
ROS↑, DS/Cu induced ROS generation.
p‑JNK↑, DS/Cu induced phosphorylation of JNK and inhibits p65 expression as well as Nrf2 expression both in vitro and in vivo.
p65↓,
eff↓, N-acetyl-L-cysteine (NAC), an antioxidant, can partially attenuate DS/Cu complex-induced apoptosis and block JNK activation in vitro.
NF-kB↓, Moreover, ROS-related activation of JNK pathway and inhibition of NF-κB and Nrf2 may also contribute to the DS/Cu induced apoptosis.

4832- EA,    Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid
*antiOx↑, Ellagic acid (EA) is a naturally occurring polyphenolic compound endowed with strong antioxidant and anticancer properties that is present in high quantity in a variety of berries, pomegranates, and dried fruits.
*AntiCan↑,
TumCMig↓, Moreover, EA can inhibit tumour cell migration, extra-cellular matrix invasion and angiogenesis,
angioG↓,
ChemoSen↑, EA may increase tumour sensitivity to chemotherapy and radiotherapy.
RadioS↑,
*chemoP↑, EA oral administration as supportive therapy to standard chemotherapy has been recently evaluated in small clinical studies with colorectal or prostate cancer patients.
*BioAv↓, Overall, EA shows a low bioavailability (0.1–0.4 mmol/L, equivalent to 30–120 ng/mL, with respect to 0.5–18.6 mmol/L, equivalent to 0.1–4 mg/mL for Uro)
eff↓, that hampers its beneficial effects to human health after in vivo oral administration.
selectivity↑, induced apoptosis in colon cancer Caco-2 cells but did not show any toxic effect in normal human lung fibroblasts.
MMP2↓, decreased levels of pro-matrix metalloproteinase-2 (pro-MMP-2 or gelatinase), pro-MMP-9 (or gelatinase B) and vascular endothelial growth factor
MMP9↓,
VEGF↓,
TumCCA↑, Similar results were obtained with HCT-15 and HCT-116 cell lines, where EA exposure promoted cell cycle arrest, induced apoptosis and increased the production of reactive oxygen intermediates
Apoptosis↑,
ROS↑,
BioAv↑, To overcome EA poor water solubility and oral bio-availability EA-encapsulated chitosan nanoparticles were produced

1607- EA,    Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions
- Review, GC, NA
STAT3↓, EA inhibits STAT3 signaling
TumCP↓, EA inhibits cell proliferation, induces apoptosis
Apoptosis↑,
NF-kB↓, inhibiting nuclear factor-kappa B
EMT↓, suppressing epithelial–mesenchymal transition
RadioS↑, In liver cancer, EA exhibits radio-sensitizing effects
antiOx↑, As a potential antioxidant agent,
COX1↓, EA suppresses the expression of several factors, including COX1, COX2, c-myc, snail, and twist1
COX2↓,
cMyc↓,
Snail↓,
Twist↓,
MMP2↓, significantly decreased MMP-2 and MMP-9 expression and activity.
P90RSK↓,
CDK8↓, downregulate CDK8 expression and activity
PI3K↓, inactivating PI3K/Akt signaling
Akt↓,
TumCCA↑, promote cell cycle arrest
Casp8↑, ctivating caspase-8, and lowering proliferating cell nuclear antigen (PCNA) expression,
PCNA↓,
TGF-β↓,
Shh↓, suppression of the Akt, Shh, and Notch pathways, EA can prevent the growth, angiogenesis, and metastasis of pancreatic cancer
NOTCH↓,
IL6↓,
ALAT↓, decreasing liver injury biomarkers such as alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST)
ALP↓,
AST↓,
VEGF↓,
P21↑,
*toxicity∅, no toxicity was found for a 50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day
*Inflam↓, ncluding anti-inflammatory [10], anti-oxidant [11], anti-allergic [12], and anti-mutagenic [13] properties, as well as potential health advantages like gastroprotective [14], cardioprotective [15], neuroprotective [16, 17], and hepatoprotective [18,
*cardioP↑,
*neuroP↑,
*hepatoP↑,
ROS↑, Exposure to EAs induced apoptosis, accelerated cell cycle arrest, and elevated the generation of reactive oxygen intermediates [59].
*NRF2↓, As a potential antioxidant agent, it scavenges reactive oxygen species (ROS), and by upregulating of Nrf2,
*GSH↑, Moreover, EA increases reduced glutathione (GSH), which is critical for cellular defense against oxidative stress and liver damage,

1605- EA,    Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence
- Review, Var, NA
*BioAv↓, Within the gastrointestinal tract, EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility.
antiOx↓, strong antioxidant properties [12,13], anti-inflammatory effects
Inflam↓,
TumCP↓, numerous studies indicate that EA possesses properties that can inhibit cell proliferation
TumCCA↑, achieved this by causing cell cycle arrest at the G1 phase
cycD1/CCND1↓, reduction of cyclin D1 and E levels, as well as to the upregulation of p53 and p21 proteins
cycE/CCNE↓,
P53↑,
P21↑,
COX2↓, notable reduction in the protein expression of COX-2 and NF-κB as a result of this treatment
NF-kB↓,
Akt↑, suppressing Akt and Notch signaling pathways
NOTCH↓,
CDK2↓,
CDK6↓,
JAK↓, suppression of the JAK/STAT3 pathway
STAT3↓,
EGFR↓, decreased expression of epidermal growth factor receptor (EGFR)
p‑ERK↓, downregulated the expression of phosphorylated ERK1/2, AKT, and STAT3
p‑Akt↓,
p‑STAT3↓,
TGF-β↓, downregulation of the TGF-β/Smad3
SMAD3↓,
CDK6↓, EA demonstrated the capacity to bind to CDK6 and effectively inhibit its activity
Wnt/(β-catenin)↓, ability of EA to inhibit phosphorylation of EGFR
Myc↓, Myc, cyclin D1, and survivin, exhibited decreased levels
survivin↓,
CDK8↓, diminished CDK8 level
PKCδ↓, EA has demonstrated a notable downregulatory impact on the expression of classical isoenzymes of the PKC family (PKCα, PKCβ, and PKCγ).
tumCV↓, EA decreased cell viability
RadioS↑, further intensified when EA was combined with gamma irradiation.
eff↑, EA additionally potentiated the impact of quercetin in promoting the phosphorylation of p53 at Ser 15 and increasing p21 protein levels in the human leukemia cell line (MOLT-4)
MDM2↓, finding points to the ability of reduced MDM2 levels
XIAP↓, downregulation of X-linked inhibitor of apoptosis protein (XIAP).
p‑RB1↓, EA exerted a decrease in phosphorylation of pRB
PTEN↑, EA enhances the protein phosphatase activity of PTEN in melanoma cells (B16F10)
p‑FAK↓, reduced phosphorylation of focal adhesion kinase (FAK)
Bax:Bcl2↑, EA significantly increases the Bax/Bcl-2 rati
Bcl-xL↓, downregulates Bcl-xL and Mcl-1
Mcl-1↓,
PUMA↑, EA also increases the expression of Bcl-2 inhibitory proapoptotic proteins PUMA and Noxa in prostate cancer cells
NOXA↑,
MMP↓, addition to the reduction in MMP, the release of cytochrome c into the cytosol occurs in pancreatic cancer cells
Cyt‑c↑,
ROS↑, induction of ROS production
Ca+2↝, changes in intracellular calcium concentration, leading to increased levels of EndoG, Smac/DIABLO, AIF, cytochrome c, and APAF1 in the cytosol
Endoglin↑,
Diablo↑,
AIF↑,
iNOS↓, decreased expression of Bcl-2, NF-кB, and iNOS were observed after exposure to EA at concentrations of 15 and 30 µg/mL
Casp9↑, increase in caspase 9 activity in EA-treated pancreatic cancer cells PANC-1
Casp3↑, EA-induced caspase 3 activation and PARP cleavage in a dose-dependent manner (10–100 µmol/L)
cl‑PARP↑,
RadioS↑, EA sensitizes and reduces the resistance of breast cancer MCF-7 cells to apoptosis induced by γ-radiation
Hif1a↓, EA reduced the expression of HIF-1α
HO-1↓, EA significantly reduced the levels of two isoforms of this enzyme, HO-1, and HO-2, and increased the levels of sEH (Soluble epoxide hydrolase) in LnCap
HO-2↓,
SIRT1↓, EA-induced apoptosis was associated with reduced expression of HuR and Sirt1
selectivity↑, A significant advantage of EA as a potential chemopreventive, anti-tumor, or adjuvant therapeutic agent in cancer treatment is its relative selectivity
Dose∅, EA significantly reduced the viability of cancer cells at a concentration of 10 µmol/L, while in healthy cells, this effect was observed only at a concentration of 200 µmol/L
NHE1↓, EA had the capacity to regulate cytosolic pH by downregulating the expression of the Na+/H+ exchanger (NHE1)
Glycolysis↓, led to intracellular acidification with subsequent impairment of glycolysis
GlucoseCon↓, associated with a decrease in the cellular uptake of glucose
lactateProd↓, notable reduction in lactate levels in supernatant
PDK1?, inhibit pyruvate dehydrogenase kinase (PDK) -bind and inhibit PDK3
PDK1?,
ECAR↝, EA has been shown to influence extracellular acidosis
COX1↓, downregulation of cancer-related genes, including COX1, COX2, snail, twist1, and c-Myc.
Snail↓,
Twist↓,
cMyc↓,
Telomerase↓, EA, might dose-dependently inhibit telomerase activity
angioG↓, EA may inhibit angiogenesis
MMP2↓, EA demonstrated a notable reduction in the secretion of matrix metalloproteinase (MMP)-2 and MMP-9.
MMP9↓,
VEGF↓, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
Dose↝, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
PD-L1↓, EA downregulated the expression of the immune checkpoint PD-L1 in tumor cells
eff↑, EA might potentially enhance the efficacy of anti-PD-L1 treatment
SIRT6↑, EA exhibited statistically significant upregulation of sirtuin 6 at the protein level in Caco2 cells
DNAdam↓, increase in DNA damage

1621- EA,    The multifaceted mechanisms of ellagic acid in the treatment of tumors: State-of-the-art
- Review, Var, NA
AntiCan↑, Studies have shown its anti-tumor effect in gastric cancer, liver cancer, pancreatic cancer, breast cancer, colorectal cancer, lung cancer and other malignant tumors
Apoptosis↑,
TumCP↓,
TumMeta↓,
TumCI↓,
TumAuto↑,
VEGFR2↓, inhibition of VEGFR-2 signaling
MAPK↓, MAPK and PI3K/Akt pathways
PI3K↓,
Akt↓,
PD-1↓, Downregulation of VEGFR-2 and PD-1 expression
NOTCH↓, Inhibition of Akt and Notch
PCNA↓, regulation of the expression of proliferation-related proteins PCNA, Ki67, CyclinD1, CDK-2, and CDK-6
Ki-67↓,
cycD1/CCND1↓,
CDK2↑,
CDK6↓,
Bcl-2↓,
cl‑PARP↑, up-regulated the expression of cleaved PARP, Bax, Active Caspase3, DR4, and DR5
BAX↑,
Casp3↑,
DR4↑,
DR5↑,
Snail↓, down-regulated the expression of Snail, MMP-2, and MMP-9
MMP2↓,
MMP9↓,
TGF-β↑, up-regulation of TGF-β1
PKCδ↓, Inhibition of PKC signaling
β-catenin/ZEB1↓, decreases the expression level of β-catenin
SIRT1↓, down-regulates the expression of anti-apoptotic protein, SIRT1, HuR, and HO-1 protein
HO-1↓,
ROS↑, up-regulates ROS
CHOP↑, activating the CHOP signaling pathway to induce apoptosis
Cyt‑c↑, releases cytochrome c
MMP↓, decreases mitochondrial membrane potential and oxygen consumption,
OCR↓,
AMPK↑, activates AMPK, and downregulates HIF-1α expression
Hif1a↓,
NF-kB↓, inhibition of NF-κB pathway
E-cadherin↑, Upregulates E-cadherin, downregulates vimentin and then blocks EMT progression
Vim↓,
EMT↓,
LC3II↑, Up-regulation of LC3 – II expression and down-regulation of CIP2A
CIP2A↓,
GLUT1↓, regulation of glycolysis-related gene GLUT1 and downstream protein PDH expression
PDH↝,
MAD↓, Downregulation of MAD, LDH, GR, GST, and GSH-Px related protein expressio
LDH↓,
GSTs↑,
NOTCH↓, inhibited the expression of Akt and Notch protein
survivin↓, survivin and XIAP was also significantly down-regulated
XIAP↓,
ER Stress↑, through ER stress
ChemoSideEff↓, could improve cisplatin-induced hepatotoxicity in colorectal cancer cells
ChemoSen↑, Enhancing chemosensitivity

1620- EA,  Rad,    Radiosensitizing effect of ellagic acid on growth of Hepatocellular carcinoma cells: an in vitro study
- in-vitro, Liver, HepG2
ROS↑, Treatment of HepG2 cells with EA and gamma radiation showed increased reactive oxygen species generation
P53↑, up regulation of p53 protein expression
TumCCA↑, combination treatment increased G2/M phase cell population
IL6↓, decreased IL-6, COX–2 and TNF-α expression
COX2↓,
TNF-α↓,
MMP↓, caused a loss in mitochondrial membrane potential
angioG↓, decreased level of angiogenesis marker MMP-9
MMP9↓,
BAX↑,
Casp3↑,
Apoptosis↑,
RadioS↑,
TBARS↑, EA increased TBARS level in HepG2 cells after irradiation
GSH↓, EA decreased the reduced glutathione content in HepG2 cells after irradiation
Bax:Bcl2↑, Combination treatment increased the Bax/Bcl2 ratio
p‑NF-kB↓, EA along with radiation decreased p-NF-κB level in tumour cells
p‑STAT3↓, Radiation and EA combination treatment decreased p-STAT3 level in tumour cells

1606- EA,    Ellagic acid inhibits proliferation and induced apoptosis via the Akt signaling pathway in HCT-15 colon adenocarcinoma cells
- in-vitro, Colon, HCT15
TumCP↓,
cycD1/CCND1↓,
Apoptosis↑,
PI3K↓, strong inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway by EA
Akt↓,
ROS↑, production of reactive oxygen intermediates, which were examined by 2,7-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time, after treatment with EA
Casp3↑, EA promoted the expression of Bax, caspase-3, and cytochrome c, and suppression of Bcl-2 activity in HCT-15 cells
Cyt‑c↑,
Bcl-2↓,
TumCCA↑, induces G2/M phase cell cycle arrest in HCT-15 cells
Dose∅, since 60 lM of the drug concentration could cause attentional loss of cells (60 and 45 % were viable in 12 and 24 h treatment, respectively) for crucial experiments, we used this dosage to assess the effect of EA in killing HCT-15 cells
ALP↓, significant decrease in the activity of ALP at 60 lM concentration of EA for the 12 h treatment
LDH↓, decrease in the activity of LDH in cells was proportional to increase in the incubation time with EA.
PCNA↓, EA down-regulated the expressions of PCNA and cyclin D1
P53↑, EA promoted p53 gene expression
Bax:Bcl2↑, increase in the Bcl-2/Bax ratio

1608- EA,    Ellagic Acid from Hull Blackberries: Extraction, Purification, and Potential Anticancer Activity
- in-vitro, Cerv, HeLa - in-vitro, Liver, HepG2 - in-vitro, BC, MCF-7 - in-vitro, Lung, A549 - in-vitro, Nor, HUVECs
eff↑, Hull blackberry fruits into five growth periods according to color and determined the EA content in the fruits in each period. The EA content in the green fruit stage was the highest at 5.67 mg/g FW
Dose∅, EA inhibited HeLa cells with an IC50 of 35 μg/mL
*BioAv↑, EA is not sensitive to high temperatures and is not highly soluble in many solvents.
selectivity↑, selectivity index varied from 7.4 for Hela to about 1 for A549
TumCP↓, EA reduced the proliferation of human cervical cancer HeLa, SiHa, and C33A cells in a dose- and time-dependent manner, and the inhibitory effect was significantly more pronounced in HeLa cells than in SiHa and C33A cells
Casp↑, EA reduced the proliferation of human cervical cancer HeLa, SiHa, and C33A cells in a dose- and time-dependent manner, and the inhibitory effect was significantly more pronounced in HeLa cells than in SiHa and C33A cells
PTEN↑,
TSC1↑,
mTOR⇅,
Akt↓, AKT, PDK1 expression were down-regulated
PDK1↓,
E6↓, mRNA levels of E6/E7 were determined to decrease gradually with the increase in EA incubation time and concentration
E7↓,
DNAdam↑, When DNA damage is introduced into cells from exogenous or endogenous sources there is an increase in the amount of intracellular reactive oxygen species (ROS)
ROS↑,
*BioAv↓, EA cannot be exploited for in vivo therapeutic applications in the current situation because of its poor water solubility and accordingly low bioavailability.
*BioEnh↑, As Lei [52] reported that EA in pomegranate leaf is rapidly absorbed and distributed as well as eliminated in rats
*Half-Life∅, blood concentration peaked at 0.5 h with Cmax = 7.29 μg/mL, and the drug concentration decreased to half of the original after 57 min of administration

1610- EA,    Anticancer Effect of Pomegranate Peel Polyphenols against Cervical Cancer
- Review, Cerv, NA
TumCCA↑, EA had a dose-dependent apoptotic effect on HeLa cells caused by cell cycle arrest in the G1 phase via the regulation of STAT3
STAT3↓,
P21↑, increase in the expression of both p21 mRNA and protein
IGFBP7↑, increase in igfb7
Akt↓, inhibition of the Akt/mTOR signaling
mTOR↓,
ROS↑, increase in the production of ROS and DNA damage
DNAdam↑,
P53↑, restored activity of p53 and p21 genes and
P21↑,
BAX↑, increased expression of the Bax

1611- EA,    Targeting Myeloperoxidase Activity and Neutrophil ROS Production to Modulate Redox Process: Effect of Ellagic Acid and Analogues
- in-vitro, Mal, NA
*BioAv↓, ellagic acid is widely studied due to its antioxidant and parasite-inhibiting properties. However, its low oral bioavailability remains a concern
eff↑, very effective inhibitor of Plasmodium falciparum, showing an in vitro activity ranging from 100 to 300 nM
*BioAv↓, ellagic acid remains its very low oral bioavailability (<30% in mice), which impedes its use as an oral antimalarial drug and was partially linked to its low hydrosolubility.
ROS↑, when in contact with the parasite environment, could become pro-oxidant and efficient

1613- EA,    Ellagitannins in Cancer Chemoprevention and Therapy
- Review, Var, NA
ROS↑, pomegranate ET inhibit pro-inflammatory pathways including, but not limited to, the NF-κB pathway, whose activation leads to immune reactions, inflammation, and the transcription of genes involved in cell survival, such as Bclx and inhibitors of apop
angioG↓, ET to inhibit angiogenesis
ChemoSen↑, ET could also be utilized to increase the sensitivity of tumor cells to standard chemotherapeutic drugs
BAX↑, induction of pro-apoptotic mediators (Bax and Bak), downregulation of Bcl-2 and Bcl-XL, and reduced expression of cyclin-dependent kinases 2, 4, 6, and cyclins D1, D2, and E
Bak↑,
Bcl-2↓,
Bcl-xL↓,
CDK2↓,
CDK4↓,
CDK6↓,
cycD1/CCND1↓,
cycE1↓,
TumCG↓, reduced LNCaP prostate cancer xenograft size, tumor vessel density, VEGF peptide levels and HIF-α expression after four weeks of treatment in severe combined immunodeficient mice
VEGF↓,
Hif1a↓,
eff↑, Oenothein B, a macrocyclic ET, and quercetin-3-O-glucuronide from Epilobium sp. herbs—used in traditional medicine to treat benign prostatic hyperplasia and prostatic adenoma—have been proven to strongly inhibit the proliferation of human prostate ca
COX2↓, pomegranate ET (i.e., punicalagin and ellagic acid) have been shown to suppress cyclooxygenase-2 (COX-2) protein expression in human colon cancer (HT-29) cells
TumCCA↑, pomegranate ET and their metabolites, i.e., urolithins A and C, inhibit HT-29 cells proliferation via G0/G1 and G2/M arrest
selectivity↑, interestingly, normal human breast epithelial cells (MCF-10A) were far less sensitive to the inhibitory effect of polyphenol-rich fractions.
Wnt/(β-catenin)↓, suppression of Wnt/β-catenin
*toxicity∅, LD50 of a standardized pomegranate fruit extract containing 30% punicalagin in Wistar rats was >5 g/kg b.w.,

20- EGCG,    Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer
- in-vivo, Liver, NA - in-vivo, Tong, NA
HH↓,
Gli1↓,
Smo↓,
TNF-α↓,
COX2↓, EGCG inhibits cyclooxygenase-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3
*antiOx↑, EGCG is a well-known antioxidant and it scavenges most free radicals, such as ROS and RNS
Hif1a↓,
NF-kB↓,
VEGF↓,
STAT3↓,
Bcl-2↓,
P53↑, EGCG activates p53 in human prostate cancer cells
Akt↓,
p‑Akt↓,
p‑mTOR↓,
EGFR↓,
AP-1↓,
BAX↑,
ROS↑, apoptosis was convoyed by ROS production and caspase-3 cleavage
Casp3↑,
Apoptosis↑,
NRF2↑, pancreatic cancer cells via inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling
*H2O2↓, EGCG plays a role in the inhibition of H2O2 and NO production in human skin [10].
*NO↓, EGCG plays a role in the inhibition of H2O2 and NO production in human skin [10].
*SOD↑, fig 2
*Catalase↑, fig 2
*GPx↑, fig 2
*ROS↓, fig 2

642- EGCG,    Prooxidant Effects of Epigallocatechin-3-Gallate in Health Benefits and Potential Adverse Effect
ROS↑, under high-dose conditions. Autooxidation of EGCG generates substantial ROS
H2O2↑, One EGCG molecule could produce more than two H2O2 molecules
Apoptosis↑,
Trx↓, High concentration of EGCG inactivated Trx/TrxR via the formation of EGCG-Trx1 and EGCG-TrxR conjugates
TrxR↓, High concentration of EGCG inactivated Trx/TrxR via the formation of EGCG-Trx1 and EGCG-TrxR conjugates
JNK↑,
HO-1↑,
Fenton↑,

641- EGCG,  Se,    Antioxidant effects of green tea
ROS↑, Concentration is a factor that could determine whether green tea polyphenols act as antioxidants or pro-oxidants. EGC and EGCG, both generate hydrogen peroxide at concentrations greater than 10 μM
H2O2↑, Adding milk to green tea decreases formation of hydrogen peroxide,
ROS⇅, Selenium could enhance anticancer activity of green tea [29], possibly by enhancing antioxidant activity [30, 31], or even its pro-oxidant activity [32].

668- EGCG,    The Potential Role of Epigallocatechin-3-Gallate (EGCG) in Breast Cancer Treatment
- Review, BC, MCF-7 - Review, BC, MDA-MB-231
HER2/EBBR2↓,
EGFR↓,
mtDam↑,
ROS↑,
PI3K/Akt↓,
P53↑,
P21↑,
Casp3↑,
Casp9↑,
BAX↑,
PTEN↑,
Bcl-2↓,
hTERT/TERT↓,
STAT3↓,
TumCCA↑, EGCG causes cell cycle arrest by preventing cyclin accumulation D1
Hif1a↓,

663- EGCG,    EGCG-coated silver nanoparticles self-assemble with selenium nanowires for treatment of drug-resistant bacterial infections by generating ROS and disrupting biofilms
- in-vitro, NA, NA
ROS↑, Bacteria

651- EGCG,    Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications
ROS↑, mounting evidence that EGCG can stimulate ROS production, which in turn leads to the phosphorylation and activation of AMPK
p‑AMPK↑,
mTOR↓,
FAK↓,
Smo↓,
Gli1↓,
HH↓,
TumCMig↓,
TumCI↓,
NOTCH↓,
JAK↓,
STAT↓,
Bcl-2↓,
Bcl-xL↓,
BAX↑,
Casp9↑,

695- EGCG,  TFdiG,    The antioxidant and pro-oxidant activities of green tea polyphenols: a role in cancer prevention
- in-vitro, NA, HL-60
ROS↑,
IronCh↑,
Apoptosis↑,

694- EGCG,    Matcha green tea (MGT) inhibits the propagation of cancer stem cells (CSCs), by targeting mitochondrial metabolism, glycolysis and multiple cell signalling pathways
- in-vitro, BC, MCF-7
Glycolysis↓, MGT might similarly act as a glycolysis inhibitor
GAPDH↓,
ROS↑, Tea cathechins may act both as anti-oxidant and as pro-oxidants
OCR↓,
ECAR↓,
mTOR↓,
OXPHOS↓,

692- EGCG,    EGCG: The antioxidant powerhouse in lung cancer management and chemotherapy enhancement
- Review, NA, NA
ROS↑,
Apoptosis↑,
DNAdam↑,
CTR1↑,
JWA↑,
β-catenin/ZEB1↓, downregulation of the Wnt/β-catenin pathway interferes with CSC traits
P53↑,
Vim↓,
VEGF↓,
p‑Akt↓,
Hif1a↓,
COX2↓,
ERK↓,
NF-kB↓,
Akt↓,
Bcl-xL↓,
miR-210↓,

676- EGCG,  Chemo,    The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review
- Review, NA, NA
PI3k/Akt/mTOR↓,
Apoptosis↑,
ROS↑,
TumAuto↑,

3223- EGCG,    The Effects of Green Tea Catechins in Hematological Malignancies
- Review, AML, NA
Prx↓, In IM9 multiple myeloma cells, EGCG reduced the protein levels of peroxiredoxin V (Prdx V, which catalyzes the reduction in hydrogen peroxide), inducing ROS accumulation and cell death
ROS↑,

3219- EGCG,    Nano-chemotherapeutic efficacy of (−) -epigallocatechin 3-gallate mediating apoptosis in A549 cells: Involvement of reactive oxygen species mediated Nrf2/Keap1signaling
- in-vitro, Lung, A549
ROS↑, Nano EGCG exhibited increased ROS/RNS levels and decreased mitochondrial membrane potential
RNS↓,
MMP↓,
NRF2↑, EGCG exhibited an increased expression of Nrf2 and Keap1 that could regulate apoptosis in A549 cells.
Keap1↓,

3238- EGCG,    Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications
- Review, Var, NA
Telomerase↓, EGCG stimulates telomere fragmentation through inhibiting telomerase activity.
DNMTs↓, EGCG reduced DNMTs,
cycD1/CCND1↓, EGCG also reduced the protein expression of cyclin D1, cyclin E, CDK2, CDK4, and CDK6. EGCG also inhibited the activity of CDK2 and CDK4, and caused Rb hypophosphorylation
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
HATs↓, EGCG can inhibit certain biomedically important molecular targets such as DNMTs, HATs, and HDACs
HDAC↓,
selectivity↑, EGCG has shown higher cytotoxicity in cancer cells than in their normal counterparts.
uPA↓, EGCG blocks urokinase, an enzyme which is essential for cancer growth and metastasis
NF-kB↓, EGCG inhibits NFκB and expression of TNF-α, reduces cancer promotion
TNF-α↓,
*ROS↓, It acts as strong ROS scavenger and antioxidant,
*antiOx↑,
Hif1a↓, ↓ HIF-1α; ↓ VEGF; ↓ VEGFR1;
VEGF↓,
MMP2↓, ↓ MMP-2; ↓ MMP-9; ↓ FAK;
MMP9↓,
FAK↓,
TIMP2↑, TIMP-2; ↑
Mcl-1↓, ↓ Mcl-1; ↓ survivin; ↓ XIAP
survivin↓,
XIAP↓,
PCNA↓, ↓ PCNA; ↑ 16; ↑ p18; ↑ p21; ↑ p27; ↑ pRb; ↑ p53; ↑ mdm2
p16↑,
P21↑,
p27↑,
pRB↑,
P53↑,
MDM2↑,
ROS↑, ↑ ROS; ↑ caspase-3; ↑ caspase-8; ↑ caspase-9; ↑ cytochrome c; ↑ Smac/DIABLO; ↓↑ Bax; Z Bak; ↓ cleaved PPAR;
Casp3↑,
Casp8↑,
Casp9↑,
Cyt‑c↑,
Diablo↑,
BAX⇅,
cl‑PPARα↓,
PDGF↓, ↓ PDGF; ↓ PDGFRb; ↓ EGFR;
EGFR↓,
FOXO↑, activated FOXO transcription factors
AP-1↓, The inhibition of AP-1 activity by EGCG was associated with inhibition of JNK activation but not ERK activation.
JNK↓,
COX2↓, EGCG reduces the activity of COX-2 following interleukin-1A stimulation of human chondrocytes
angioG↓, EGCG inhibits angiogenesis by enhancing FOXO transcriptional activity

3215- EGCG,    Epigallocatechin gallate modulates ferroptosis through downregulation of tsRNA-13502 in non-small cell lung cancer
- in-vitro, NSCLC, A549 - in-vitro, NSCLC, H1299
TumCP↓, EGCG resulted in a notable suppression of cell proliferation, as evidenced by a reduction in Ki67 immunofluorescence staining
Ki-67↓,
GPx4↓, EGCG treatment led to a decrease in the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while increasing the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4).
ACSL4↑,
Iron↑, accompanied by an increase in intracellular iron, malondialdehyde (MDA), and reactive oxygen species (ROS), alongside ultrastructural alterations characteristic of ferroptosis.
MDA↑,
ROS↑,
Ferroptosis↑,
eff↑, The cooperative effect of metformin and EGCG-activated Nrf2/HO-1 signaling pathway, facilitated by SIRT1-mediated Nrf2 deacetylation, enhances the susceptibility of NSCLC to EGCG modulation by promoting reactive oxygen species (ROS) generation and a
NRF2↑,
HO-1↑,

3203- EGCG,    (-)- Epigallocatechin-3-gallate induces GRP78 accumulation in the ER and shifts mesothelioma constitutive UPR into proapoptotic ER stress
- NA, MM, NA
ROS↑, We have previously shown that (-)-epigallocatechin-3-gallate (EGCG) enhances ROS production and alters Ca2+ homeostasis in cell lines deriving from therapy-recalcitrant malignant mesothelioma (MMe).
Ca+2↝,
GRP78/BiP↑, Exposure to EGCG further increased GRP78 in the ER, and induced ATF4, spliced XBP1, CHOP, and EDEM expressions, combined with a reduction of cell surface GRP78 and a rise in caspase 3 and 8 activities.
ATF4↑,
XBP-1↑,
CHOP↑,
Casp3↑,
Casp8↑,
*GRP78/BiP↓, n non-cancer mouse retinal pigment epithelial cells,EGCG has been found to downregulate GRP78 and UPR signaling (Karthikeyan et al., 2017).
*UPR↓,
UPR↑, However, if ER homeostasiscannot be re-established, the UPR switches its signaling toward irreversible ER stress with the activation of apoptosis (

3205- EGCG,    The Role of Epigallocatechin-3-Gallate in Autophagy and Endoplasmic Reticulum Stress (ERS)-Induced Apoptosis of Human Diseas
- Review, Var, NA - Review, AD, NA
Beclin-1↑, EGCG not only regulates autophagy via increasing Beclin-1 expression and reactive oxygen species generation,
ROS↑,
Apoptosis↑, Apoptosis is a common cell function in biology and is induced by endoplasmic reticulum stress (ERS)
ER Stress↑,
*Inflam↓, EGCG has health benefits including anti-tumor [15], anti-inflammatory [16], anti-diabetes [17], anti-myocardial infarction [18], anti-cardiac hypertrophy [19], anti-atherosclerosis [20], and antioxidant
*cardioP↑,
*antiOx↑,
*LDL↓, These effects are mainly related to (LDL) cholesterol inhibition, NF-κB inhibition, MPO activity inhibition, decreased levels of glucose and glycated hemoglobin in plasma, decreased inflammatory markers, and reduced ROS generation
*NF-kB↓,
*MPO↓,
*glucose↓,
*ROS↓,
ATG5↑, EGCG induced autophagy by enhancing Beclin-1, ATG5, and LC3B and promoted mitochondrial depolarization in breast cancer cells.
LC3B↑,
MMP↑,
lactateProd↓, 20 mg kg−1 EGCG significantly decreased glucose, lactic acid, and vascular endothelial growth factor (VEGF) levels
VEGF↓,
Zeb1↑, (20 uM) inhibited the proliferation through activating autophagy via upregulating ZEB1, WNT11, IGF1R, FAS, BAK, and BAD genes and inhibiting TP53, MYC, and CASP8 genes in SSC-4 human oral squamous cells [
Wnt↑,
IGF-1R↑,
Fas↑,
Bak↑,
BAD↑,
TP53↓,
Myc↓,
Casp8↓,
LC3II↑, increasing the LC3-II expression levels and induced apoptosis via inducing ROS in mesothelioma cell lines,
NOTCH3↓, but also could reduce partially Notch3/DLL3 to reduce drug-resistance and the stemness of tumor cells
eff↑, In combination therapies, low-intensity pulsed electric field (PEF) can improve EGCG to affect tumor cells; ultrasound (US) with tumor cells is the application of physical stimulation in cancer therapy.
p‑Akt↓, 20 μM EGCG increased intracellular ROS levels and LC3-II, and inhibited p-Akt in PANC-1 cells
PARP↑, 100 μM EGCG increased LC3-II, activated caspase-3 and PARP, and reduced p-Akt in HepG2
*Cyt‑c↓, EGCG protected neuronal cells against human viruses by inhibiting cytochrome c and Bax translocations, and reducing autophagy with increased LC3-II expression and decreased p62 expression
*BAX↓,
*memory↑, EGCG restored autophagy in the mTOR/p70S6K pathway to weaken memory and learning disorders induced by CUMS
*neuroP↑, Finally, EGCG increased the neurological scores through inhibiting cell death
*Ca+2?, EGCG treatment, [Ca2+]m and [Ca2+]i expressions were reduced and oxyhemoglobin-induced mitochondrial dysfunction lessened.
GRP78/BiP↑, MMe cells with EGCG treatment improved GRP78 expression in the endoplasmic reticulum, and induced EDEM, CHOP, XBP1, and ATF4 expressions, and increased the activity of caspase-3 and caspase-8.
CHOP↑, GRP78 accumulation converted UPR of MMe cells into pro-apoptotic ERS
ATF4↑,
Casp3↑,
Casp8↑,
UPR↑,

3214- EGCG,    EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway
- in-vitro, Nor, MRC-5 - in-vitro, Cerv, HeLa - in-vitro, Nor, HEK293 - in-vitro, BC, MDA-MB-231 - in-vitro, CRC, HCT116
mTOR↓, In contrast, EGCG treatment in HeLa cells led to AMPK-induced mTOR inactivation
AMPK↑, via AMPK activation,
selectivity↑, EGCG was previously reported to differentially induce ROS production in normal and cancer cells, resulting in the preferential perturbation of the redox homeostasis of cancer cells via increased ROS levels, especially H2O2, in cancer cells
ROS↑,
selectivity↑, EGCG-induced selective death of cancer cells is accomplished by the positive and negative regulation of the p62-KEAP1-NRF2-HO-1 antioxidant survival pathway between normal cells and cancer cells, respectively,
HO-1↓, HO-1 expression decreased significantly with increasing EGCG concentration in all six different cancer cells
*NRF2↑, According to our findings, EGCG increased the protein level of NRF2 in normal cells but decreased them in cancer cells even though its mRNA levels were more or less equal in both cell types
NRF2↓,
*HO-1↑, upregulates HO-1 through the prolonged stability of NRF2 in MRC5 cells, whereas it downregulates HO-1 through the increased degradation of NRF2 by ubiquitination in HeLa and HCT116 cells.

1975- EGCG,    Molecular bases of thioredoxin and thioredoxin reductase-mediated prooxidant actions of (-)-epigallocatechin-3-gallate
- in-vitro, Cerv, HeLa
TrxR↓, EGCG-induced inactivation of TrxR and decreased cell survival, revealing TrxR as a new target of EGCG.
Trx↓,
ROS↑, EGCG induced inactivation of Trx/TrxR in parallel with increased ROS levels in HeLa cells.
Dose↑, Statistics indicated that ROS levels were significantly higher within a range of 50-200uM EGCG than that at 25 uM EGCG, but there were no significant differences in ROS levels between 50 uM vs 100 uM,

1976- EGCG,    Epigallocatechin-3-gallate exhibits anti-tumor effect by perturbing redox homeostasis, modulating the release of pro-inflammatory mediators and decreasing the invasiveness of glioblastoma cells
- in-vitro, GBM, U87MG
ROS↑, Polyphenol epigallocatechin-3-gallate (EGCG) induced apoptosis in glioma cells by elevating oxidative stress through increased reactive oxygen species (ROS) generation. Signs of apoptosis included altered mitochondrial membrane potential and elevated
MMP↓, altered mitochondrial membrane potential
Casp3↑, elevated expression of caspase-3 (5fold) and cytochrome c
Cyt‑c↑,
Trx1↓, The increase in ROS was concomitant with the decrease in expression of thioredoxin (TRX-1)
Ceru↓, and ceruloplasmin (CP)
IL6↓, EGCG downregulated the levels of pro-inflammatory cytokine interleukin (IL)-6 and chemokines IL-8, monocyte-chemoattractant protein (MCP)-1 and RANTES
IL8↓,
MCP1↓,
RANTES?,
uPA↝, 40-50% decrease in uPa activity was observed in glioma cells upon treatment with 50 and 100 uM of EGCG
ROS↑, ROS production, a significant 1.7- and 2-fold (p<0.05) increase in ROS production was observed in cells treated with 50 and 100 uM EGCG respectively,

1303- EGCG,    (-)-Epigallocatechin-3-gallate induces apoptosis in human endometrial adenocarcinoma cells via ROS generation and p38 MAP kinase activation
- in-vitro, EC, NA
TumCP↓,
ER-α36↓,
cycD1/CCND1↓,
ERK↑,
Jun↓,
BAX↑,
Bcl-2↓,
cl‑Casp3↑,
ROS↑,
p38↑,

2309- EGCG,  Chemo,    Targeting Glycolysis with Epigallocatechin-3-Gallate Enhances the Efficacy of Chemotherapeutics in Pancreatic Cancer Cells and Xenografts
- in-vitro, PC, MIA PaCa-2 - in-vitro, Nor, HPNE - in-vitro, PC, PANC1 - in-vivo, NA, NA
TumCG↓, EGCG reduced pancreatic cancer cell growth in a concentration-dependent manner
eff↑, and the growth inhibition effect was further enhanced under glucose deprivation conditions.
ROS↑, EGCG at 40 µM increased ROS levels by 1.4- and 1.6-fold in Panc-1 and MIA PaCa-2 cells, respectively
ECAR↓, EGCG affected glycolysis by suppressing the extracellular acidification rate through the reduction of the activity and levels of the glycolytic enzymes phosphofructokinase and pyruvate kinase.
ChemoSen↑, EGCG sensitized gemcitabine to inhibit pancreatic cancer cell growth in vitro and in vivo.
selectivity↑, EGCG at 80 µM for 72 h had significantly less effect on the HPNE cells, reducing cell growth by only 24%
Glycolysis↓, EGCG Inhibits Glycolysis through Suppressing Rate-Limiting Enzymes. EGCG Plus Gemcitabine Further Inhibits Glycolysis
PFK↓, EGCG treatment reduced both the activity and expression levels of phosphofructokinase (PFK) and pyruvate kinase (PK) in Panc-1 and MIA PaCa-2 cells
PKA↓,
HK2∅, EGCG failed to reduce hexokinases II (HK2) and lactate dehydrogenase A (LDHA) protein expression levels
LDHA∅,
PFKP↓, EGCG reduced the levels of PFKP and PKM2 (p < 0.01 for both) in pancreatic tumor xenograft homogenates, obtained from mice treated with EGCG
PKM2↓,
H2O2↑, EGCG at 40 µM increased H2O2 levels by 1.5- and 1.9-fold in Panc-1 and MIA PaCa-2 cells
TumW↓, EGCG and gemcitabine, given as single agents, reduced tumor weight by 40% and 52%, respectively, compared to vehicle-treated controls (p < 0.05 and p < 0.01). In combination, EGCG plus gemcitabine reduced tumor weight by 67%,

2310- EGCG,    Epigallocatechin-3-gallate downregulates PDHA1 interfering the metabolic pathways in human herpesvirus 8 harboring primary effusion lymphoma cells
- in-vitro, lymphoma, PEL
GLUT3↑, EGCG increased GLUT3 and decreased PDHA1 and GDH1 expression to disrupt glycolysis and glutaminolysis in PEL cells
PDHA1↓,
GDH↓,
ROS↑, Previously we have demonstrated that EGCG induces ROS generation and cell death in HHV8 harboring PEL cells
Glycolysis↓, EGCG induced PEL cell death may due to suppresses both the aerobic glycolysis and oxidative phosphorylation
OXPHOS↓,

2563- EGCG,    Cardioprotective effect of epigallocatechin gallate in myocardial ischemia/reperfusion injury and myocardial infarction: a meta-analysis in preclinical animal studies
- Review, NA, NA
cardioP↑, EGCG significantly improves cardiac function, serum myocardial injury enzyme, and oxidative stress levels in MIRI animal models
ROS↑,
AntiAg↑, EGCG can inhibit platelet aggregation induced by U46619, collagen, arachidonic acid, and toxic carotenoids and shear force-induced platelet adhesion dose-dependently by suppressing PLCγ2 and tyrosine phosphorylation
eff↑, What’s more, its combination with common antiplatelet therapeutic agents, aspirin (ASA), clopidogrel (CPD), and tiglitazarol (TCG), did not further inhibit platelet aggregation resulting in bleeding complications
COX1↓, EGCG inhibits platelet activation by inhibiting microsomal cyclooxygenase-1 activity in platelets

988- EMD,    Emodin Induced Necroptosis and Inhibited Glycolysis in the Renal Cancer Cells by Enhancing ROS
- in-vitro, RCC, NA
Necroptosis↑, emodin induces necroptosis, but not apoptosis, in renal cancer cells
p‑RIP1↑,
MLKL↑,
ROS↑, levels of ROS increased upon emodin treatment in a dose-dependent manner
Glycolysis↓,
GLUT1↓,
PI3K↓,
Akt↓,

1332- EMD,    Induction of Apoptosis in HepaRG Cell Line by Aloe-Emodin through Generation of Reactive Oxygen Species and the Mitochondrial Pathway
- in-vivo, Nor, HepaRG
*tumCV↓,
*ROS↑,
*MMP↓,
*Fas↑,
*P53↑,
*P21↑,
*Bax:Bcl2↑,
*Casp3↑,
*Casp8↑,
*Casp9↑,
*cl‑PARP↑,
*TumCCA↑, S-phase cell cycle arrest
*P21↑,
*cycE/CCNE↑,
*cycA1/CCNA1↓,
*CDK2↓,

1327- EMD,    Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway
- in-vitro, Lung, A549
Cyt‑c↑, pronounced release of cytochrome c
Casp2↑,
Casp3↑,
Casp9↑,
ERK↓,
Akt↓,
ROS↑, free radical scavenger ascorbic acid and N-acetylcysteine attenuated emodin-mediated ROS production, ERK and AKT inactivation, mitochondrial dysfunction, Bcl-2/Bax modulation, and apoptosis
MMP↓,
Bcl-2↓,
BAX↑,

1322- EMD,    The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers
- Review, Var, NA
Apoptosis↑,
TumCP↓,
ROS↑,
TumAuto↑,
EMT↓,
TGF-β↓,
DNAdam↑,
ER Stress↑,
TumCCA↑,
ATP↓,
NF-kB↓,
CYP1A1↑,
STAC2↓,
JAK↓,
PI3K↓,
Akt↓,
MAPK↓,
FASN↓,
HER2/EBBR2↓,
ChemoSen↑, DOX combined with emodin can improve the sensitivity of MDA-MB-231 and MCF-7 cells to chemotherapy
eff↑, emodin was reported to increase the anti-proliferative effect of an EGFR inhibitor (afatinib) against PC through downregulation of EGFR by promoting STAT3
ChemoSen↑, gemcitabine combined with emodin increased cell death
angioG↓,
VEGF↓,
MMP2↓,
eNOS↓,
FOXD3↑,
MMP9↓,
TIMP1↑,

1323- EMD,    Anticancer action of naturally occurring emodin for the controlling of cervical cancer
- Review, Cerv, NA
TumCCA↑, cell cycle arrest in the G2/M phase
DNAdam↑,
mTOR↓,
Casp3↑,
Casp8↑,
Casp9↑,
TGF-β↑,
SMAD3↓,
p‑SMAD4↓,
ROS↑,
MMP↓,
CXCR4↓,
HER2/EBBR2↓,
ER Stress↓,
TumAuto↑, can increase the level of autophagy in A549 lung cancer cells, but did not affect autophagy in healthy non-cancerous Ha CaT cells
NOTCH1↓,

1324- EMD,    Is Emodin with Anticancer Effects Completely Innocent? Two Sides of the Coin
- Review, Var, NA
*toxicity↑, however, it is known that emodin, which shows toxicity to cancer cells, may cause kidney toxicity, hepatotoxicity, and reproductive toxicity especially at high doses and long-term use.
*BioAv↓, poor oral bioavailability
Akt↓,
ERK↓,
ROS↑, pretreatment of cells with ascorbic acid prevented the induction of ROS by emodin and inhibited the upregulation of p53
MMP↓,
Bcl-2↓,
BAX↑,
TumCCA↑, increasing the percentage of both S and G2/M phase cells

1321- EMD,    Antitumor effects of emodin on LS1034 human colon cancer cells in vitro and in vivo: roles of apoptotic cell death and LS1034 tumor xenografts model
- in-vitro, CRC, LS1034 - in-vivo, NA, NA
tumCV↓,
TumCCA↑, induced G2/M phase arrest
ROS↑,
Ca+2↑,
MMP↓,
Apoptosis↑,
Cyt‑c↑,
Casp9↑,
Bax:Bcl2↑,

1318- EMD,    Aloe-emodin Induces Apoptosis in Human Liver HL-7702 Cells through Fas Death Pathway and the Mitochondrial Pathway by Generating Reactive Oxygen Species
- in-vitro, Nor, HL7702
*TumCCA↑, induced S and G2/M phase cell cycle arrest
*ROS↑,
*MMP↓,
*Fas↑,
*P53↑,
*P21↓,
*Bax:Bcl2↑,
*cl‑Casp3↑,
*cl‑Casp8↑,
*cl‑Casp9↑,
*cl‑PARP↑,

1326- EMD,    Emodin induces a reactive oxygen species-dependent and ATM-p53-Bax mediated cytotoxicity in lung cancer cells
- in-vitro, Lung, A549
Apoptosis↑,
ROS↑,
P53↑,
BAX↑,
ATM↑,

1328- EMD,    Emodin induces apoptosis of human tongue squamous cancer SCC-4 cells through reactive oxygen species and mitochondria-dependent pathways
- in-vitro, Tong, SCC4
TumCCA↑, G2/M arrest
P21↑,
Chk2↑,
CycB/CCNB1↓,
cDC2↓,
Apoptosis↑,
Cyt‑c↑, release of cytochrome c from mitochondria
Casp9↑,
Casp3↑,
ROS↑,
MMP↓,
Bax:Bcl2↑,
ER Stress↑,

1331- EMD,    Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway
- in-vitro, NPC, NA
TumCCA↑, induced G(2)/M phase arrest
CycB/CCNB1↑,
DNAdam↑,
Casp3↑,
cl‑PARP↑,
MMP↓,
Ca+2↑,
ROS↑,

1245- EMD,    Emodin Exhibits Strong Cytotoxic Effect in Cervical Cancer Cells by Activating Intrinsic Pathway of Apoptosis
- in-vitro, Cerv, HeLa
TumCG↓, emodin strongly inhibited the HeLa cell growth and proliferatio
TumCP↓,
Apoptosis↑,
ROS↑, observed significant ROS generation and caspases activation
Casp3↑,
Casp9↑,
MMP↓,
DNAdam↑,
GSH↓,

5521- EP,    Nanosecond Pulsed Electric Fields (nsPEFs) Modulate Electron Transport in the Plasma Membrane and the Mitochondria
- in-vitro, BC, 4T1 - in-vitro, Nor, H9c2
ETC↓, NsPEFs attenuates ET in the mitochondrial electron transport system (ETS) at Complex I.
ROS↑, NsPEFs increase ROS more in cytosol of cancer cells.
*mt-ROS↑, NsPEFs increase ROS more in mitochondria in non-cancer cells.

5529- EP,    Effects of nsPEFs on Electron Transport and Mitochondrial Structures and Functions
- Review, Var, NA
ETC↓, NsPEFs attenuated electron transport (ET) (O2 consumption) in the electron transport chain (ETC) of intact and permeabilized cells
OCR↓,
CellMemb↑,
mt-ROS↑, Effects of nsPEFs on increases in mROS were synergistic with the complex I inhibitor rotenone
MMP↓, dissipating the ΔΨm

5494- EP,    An Overview of Subnanosecond Pulsed Electric Field Biological Effects: Toward Contactless Technologies for Cancer Treatment
- Review, Var, NA
other↝, Figure 1, equivalent electrical circuit
ROS↑, Another aspect to consider is the fact that PEF application has been shown to result in reactive oxygen species (ROS) production not only in cells71,72 but also in the medium surrounding the cells
Temp∅, Provided the number of pulses and the PRF are not too high, allowing for interpulse heat dissipation, in most cases, thermal effects can even be neglected.
CellMemb↑, he main primary effect of nsPEFs is the permeabilization of both the cell membrane82 and organelle membranes, followed by calcium entry,83 loss of resting membrane potential,62,84 increased cellular K+ efflux,84 activation of VGCC ion channels
Ca+2↑, In addition to apoptosis, nsPEFs are known to trigger calcium mobilization.
Apoptosis↑, The apoptosis is characterized by several morphological changes in the cell, due to energy-dependent biochemical mechanisms, leading to cell death
TumCD↑,
MMP↓, , while the dissipation of ψ (mitochondria membrane potential) occurs at a higher level (around 40 kV/cm)
necrosis↑, A severe dysregulation of Ca2+ stimulates a cell death by necrosis, while a milder dysregulation provokes a cell death by apoptosis.103
TumVol↓, As a result, tumor shrinkage of 90% could be observed within 2 weeks, and the repetition of a second treatment at that time could result in complete regressions.
Remission↑,

5495- EP,    Irreversible electroporation in focal therapy for prostate cancer: current status and future directions
- Review, Pca, NA
Ca+2↑, Ca2+ overload→ATP depletion→mitochondrial dysfunction
ATP↓,
mtDam↑,
ROS↑, ROS generation from mitochondrial leakage disrupts cell homeostasis.
CellMemb↑, EP: membrane permeabilization→drug uptake↑;

5526- EP,    Nanosecond Pulsed Electric Field Modulates Electron Transport and Mitochondrial Structure and Function
- Review, Var, NA
CellMemb↑, In this work, nsPEF treatment is used to demonstrate changes that affect viability, plasma membrane permeability ROS (Reactive Oxygen Species) in the cytosol and mitochondria, and Electron Transport Chain (ETC) in cell cultures.
ROS↑, nsPEF and rotenone synergistically enhanced ROS production in intact cells suggesting that nsPEF and rotenone act at different Complex I sites.
ETC↝, A reduced cellular oxygen consumption after nsPEFs treatment indicates an alteration of the ETC at Complex I in intact and permeabilized cells as well as in isolated hepatocyte mitochondria
OCR↓,
MMP↓, collapse the mitochondrial membrane potential and cause cell death.

5525- EP,    Cell responses without receptors and ligands, using nanosecond pulsed electric fields (nsPEFs)
- Review, Var, NA
CellMemb↑, Over 30 years ago, electric fields were shown to transiently permeabilize plasma membranes and to introduce deoxyribonucleic acid (DNA) into cells by electroporation.
Ca+2↑, NsPEFs have been shown to breach intracellular granules,9 to mobilize Ca2+ from the ER and through plasma membranes,18–20 and to modulate intracellular Ca2+ levels in chromaffin cells
ER Stress↑,
ROS↑, NsPEFs induce calcium-dependent reactive oxygen species, which appear to require calcium entry through the plasma membrane pores.
MMP↓, NsPEFs also cause a rapid time- and electric field-dependent dissipation of the mitochondria membrane potential (∆Ψm).
VGCC↓, It has been shown that nsPEFs inhibit voltage-gated Na+ and Ca2+ channels,35
VGSC↓,
Dose↝, What seems clear is that when used at low repetition rates (1–2 Hz), nsPEF-induced cell death is not thermal nor immediate, but somewhat calculated and finally, default-driven.

5519- EP,    Nanosecond Pulsed Electric Fields (nsPEFs) for Precision Intracellular Oncotherapy: Recent Advances and Emerging Directions
- Review, Var, NA
MMP↓, nsPEF bypasses plasma-membrane shielding to porate organelles, collapse mitochondrial potential, perturb ER calcium, and transiently open the nuclear envelope.
Ca+2↑,
eff↑, synergy with checkpoint blockade.
ER Stress↑, capacity to directly target organelles such as mitochondria, endoplasmic reticulum (ER),
selectivity↑, selectively ablate solid tumors, suppress metastatic spread, and prime systemic anti-tumor immunity while sparing adjacent normal tissue [7,9,10,11,12,13,14,15].
CSCs↓, Preclinical investigations have demonstrated that nsPEFs significantly reduce CSC-associated subpopulations, including CD44+/CD24− cells in breast cancer xenografts and CD133+ glioma stem-like cells
CD44↓,
CD133↓,
ROS↑, nsPEFs release Ca2+ from the ER, disrupt mitochondrial membrane potential, induce reactive oxygen species (ROS) generation, and perturb nuclear chromatin structure within nanoseconds
Imm↑, nsPEFs not only eliminate local tumor cells but also convert the tumor into an in situ vaccine, amplifying their therapeutic relevance in the era of immunotherapy
DNAdam↑, figure 2
MOMP↑, induce mitochondrial outer membrane permeabilization (MOMP)
Cyt‑c↑,
Casp9↑, Subsequent release of cytochrome c enables apoptosome assembly, caspase-9 activation, and downstream activation of caspases-3/7, culminating in cell death
Casp3↑,
Casp9↑,
TumCD↑,
Fas↑, In certain cell types, nsEP can also activate the extrinsic pathway, where Fas receptor clustering stimulates caspase-8.
UPR↑, This rapid surge triggers ER stress pathways, activates unfolded protein response (UPR) signaling, and promotes cross-talk with mitochondria through mitochondria-associated membranes (MAMs)
Dose↝, longer ns pulses (100–300 ns) generate sustained plasma membrane charging, resulting in robust Ca2+ influx, osmotic imbalance, and apoptotic priming.
Dose↝, A critical threshold of 10–20 kV/cm is generally required to initiate pore formation in malignant cells, with higher amplitudes (>30–40 kV/cm) producing more extensive permeabilization [100].
Dose↓, Low pulse counts (<100) frequently produce reversible stress responses, such as transient mitochondrial depolarization or ER Ca2+ release, without committing cells to apoptosis. I
Dose↑, In contrast, higher pulse counts (500–1000) lead to irreversible apoptosis, caspase activation, and release of DAMPs that initiate ICD [80,106].
HMGB1↓, ICD after nsPEF is characterized by surface exposure of calreticulin, extracellular ATP release, and HMGB1 emission
eff↑, The integration of nsPEFs with NP-based systems thus represents a synergistic platform where physical membrane poration and molecular targeting cooperate to maximize therapeutic efficacy.
EPR↑, demonstrates that PEF + AuNPs enhanced membrane permeabilization compared with PEF alone,
ChemoSen↑, The superior efficacy of delayed drug administration following nsPEF exposure can be attributed to transient biophysical and biochemical changes that persist after pulsing.
ETC↝, study demonstrated that nsPEFs dynamically alter trans-plasma membrane electron transport (tPMET) and mitochondrial electron transport chain activity, resulting in differential ROS generation in cancer versus non-cancer cells (Figure 9).
*AntiAge↑, Mechanistically, nsPEFs upregulated HIF-1α and SIRT1, mediators of mitochondrial retrograde signaling, thereby reversing hallmarks of aging
*Hif1a↑,
*SIRT1↑,

2455- erastin,    Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments
- in-vitro, Cerv, HeLa
xCT↓, targeted inhibitors have been developed, such as erastin
GSH↓, erastin significantly reduced intracellular GSH levels in HeLa cells
ROS↑, erastin significantly increased intracellular ROS levels in HeLa cells
TumCMig↓, erastin significantly inhibited the migration activity of HeLa cells,

2204- erastin,    Regulation of ferroptotic cancer cell death by GPX4
- in-vitro, fibroS, HT1080
GSH↓, Erastin Depletes Glutathione to Trigger Selective Ferroptosis
Ferroptosis↑,
ROS↑, erastin induces the formation of ROS, causing an oxidative cell death.
GPx↓, GSH Depletion Inactivates GPX Enzymes to Induce Ferroptosis
GPx4↓, RSL3 Binds to and Inactivates GPX4
lipid-P↑, lipid oxidation is common to both erastin-induced and RSL3-induced ferroptotic cell death
eff↓, Although erastin displayed synthetic lethality in the engineered cells, it did not show selective lethality in RAS-mutated cancer cell lines over RAS wild-type counterparts
eff↑, DLBCLs were more sensitive to erastin than AML and MM cells.

5046- erastin,  SAS,    The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis
- Study, Var, NA
xCT↓, reduced by the system xc– inhibitors, erastin and sulfasalazine
ROS↑, moreover, inhibiting xCT impairs cystine uptake, causing an accumulation of ROS and suppressing tumor growth.
TumCG↓,
GSH↓, Erastin functions by inhibiting the import of cystine, thereby depleting intracellular glutathione (GSH), which serves as a necessary cofactor for the enzyme glutathione peroxidase 4 (GPX4) in eliminating lipid peroxides
Ferroptosis↑, erastin is commonly used to induce ferroptosis, particularly in cultured cells.

5055- Ex,    Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes
- Review, Var, NA
OS↑, In 2008, a cohort study of breast cancer survivors identified that patients who consistently exercised for greater than 2.5 hours per week following diagnosis had a greater than 60% reduction in the risk of all deaths compared with patients who were
IGF-1↓, Table 1, IGF1 Decreased levels, IGFBP3 Increased levels
IGFBP3↑,
BRCA1↑, BRCA1 Increased expression
BRCA2↑, BRCA2 Increased expression
RAS↓, RAS family oncogenes Suppressed activity
P53↑, P53 Enhanced activity
HSPs↑, Heat shock proteins Enhanced activity
Leptin↓, Leptin Reduced activity
Irisin↓, Irisin Enhanced activity
Resistin↓, Resistin Reduced activity
NK cell↑, NK cells Enhanced activity
CRP↓, C-reactive protein, interleukin-6, TNFα Reduced activity
IL6↓,
TNF-α↓,
PGE1↓, Prostaglandins Reduced activity
COX2↓, Cox-2 Reduced activity
*GSH↑, Glutathione, Catalase and Superoxide dismutase Increased activity
*Catalase↑,
*SOD↑,
*monoA↑, Monoamines Higher levels
*EndoR↑, Endorphins Increased release
*testos↑, testosterone increases immediately after vigorous exercise in some but not all studies. lasting for 20–60 minutes post-exercise
ROS↑, Physical activity, especially if strenuous, produces reactive oxidative species (ROS)
QoL↑, Adverse cancer-related symptoms, which have been shown to be alleviated by exercise, include fatigue, muscle weakness, thromboembolism, weight gain, loss of bone density, quality of life (QOL), psychological distress, incontinence and sexual dysfunct
BMD↑, the rate of decline in BMD was significantly less in the resistance exercise group, with a greater benefit seen in the aerobic exercise group
BowelM↑, Exercise reduces bowel transit time and ameliorates constipation and its associated abdominal cramps

1654- FA,    Molecular mechanism of ferulic acid and its derivatives in tumor progression
- Review, Var, NA
AntiCan↑, FA has anti-inflammatory, analgesic, anti-radiation, and immune-enhancing effects and also shows anticancer activity,
Inflam↓,
RadioS↑,
ROS↑, FA can cause mitochondrial apoptosis by inducing the generation of intracellular reactive oxygen species (ROS)
Apoptosis↑,
TumCCA↑, G0/G1 phase
TumCMig↑, inducing autophagy; inhibiting cell migration, invasion, and angiogenesis
TumCI↓,
angioG↓,
ChemoSen↑, synergistically improving the efficacy of chemotherapy drugs and reducing adverse reactions.
ChemoSideEff↓,
P53↑, FA could increase the expression level of p53 in MIA PaCa-2 pancreatic cancer cells
cycD1/CCND1↓, while reducing the expression levels of cyclin D1 and cyclin-dependent kinase (CDK) 4/6.
CDK4↓,
CDK6↓,
TumW↓, FA treatment was found to reduce tumor weight in a dose-dependent manner, increase miR-34a expression, downregulate Bcl-2 protein expression, and upregulate caspase-3 protein expression
miR-34a↑,
Bcl-2↓,
Casp3↑,
BAX↑,
β-catenin/ZEB1↓, isoferulic acid dose-dependently downregulated the expression of β-catenin and MYC proto-oncogene (c-Myc), inducing apoptosis
cMyc↓,
Bax:Bcl2↑, FXS-3 can inhibit the activity of A549 cells by upregulating the Bax/Bcl-2 ratio
SOD↓, After treatment with FA, Cao et al. [40] observed an increase in ROS production and a decrease in superoxide dismutase activity and glutathione content in EC-1 and TE-4 oesophageal cancer cells
GSH↓,
LDH↓, FA could promote the release of lactate dehydrogenase (LDH)
ERK↑, A can activate the ERK1/2 pathway
eff↑, conjugated zinc oxide nanoparticles with FA (ZnONPs-FA) to act on hepatoma Huh-7 and HepG2 cells. The results showed that ZnONPs-FA could induce oxidative DNA damage and apoptosis by inducing ROS production.
JAK2↓, by inhibiting the JAK2/STAT6 immune signaling pathway
STAT6↓,
NF-kB↓, thus inhibiting the activation of NF-κB
PYCR1↓, FA can target PYCR1 and inhibit its enzyme activity in a concentration-dependent manner.
PI3K↓, FA inhibits the activation of the PI3K/AKT pathway
Akt↓,
mTOR↓, FA could significantly reduce the expression level of mTOR mRNA and Ki-67 protein in A549 lung cancer graft tissue
Ki-67↓,
VEGF↓,
FGFR1↓, FA is a novel FGFR1 inhibitor
EMT↓, FA can inhibit EMT
CAIX↓, selectively inhibit CAIX
LC3II↑, Autophagy vacuoles and increased LC3-II and p62 autophagy proteins were observed after treatment with this compound
p62↑,
PKM2↓, FA could inhibit the expression of PKM2 and block aerobic glycolysis
Glycolysis↓,
*BioAv↓, FA has poor solubility in water and a poor ability to pass through biological barriers [118]; therefore, the extent to which it is metabolized in vivo after oral administration is largely unknown

1656- FA,    Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling
- Review, Var, NA
tyrosinase↓,
CK2↓,
TumCP↓,
TumCMig↓,
FGF↓,
FGFR1↓,
PI3K↓,
Akt↓,
VEGF↓,
FGFR1↓,
FGFR2↓,
PDGF↓,
ALAT↓,
AST↓,
TumCCA↑, G0/G1 phase arrest
CDK2↓,
CDK4↓,
CDK6↓,
BAX↓,
Bcl-2↓,
MMP2↓,
MMP9↓,
P53↑,
PARP↑,
PUMA↑,
NOXA↑,
Casp3↑,
Casp9↑,
TIMP1↑,
lipid-P↑,
mtDam↑,
EMT↓,
Vim↓,
E-cadherin↓,
p‑STAT3↓,
COX2↓,
CDC25↓,
RadioS↑,
ROS↑,
DNAdam↑,
γH2AX↑,
PTEN↑,
LC3II↓,
Beclin-1↓,
SOD↓,
Catalase↓,
GPx↓,
Fas↑,
*BioAv↓, ferulic acid stability and limited solubility in aqueous media continue to be key obstacles to its bioavailability, preclinical efficacy, and clinical use.
cMyc↓,
Beclin-1↑, ferulic acid by elevating the levels of the apoptosis and autophagy biomarkers, including beclin-1, Light chain (LC3-I/LC3-II), PTEN-induced putative kinase 1 (PINK-1), and Parkin
LC3‑Ⅱ/LC3‑Ⅰ↓,

2496- Fenb,    Impairment of the Ubiquitin-Proteasome Pathway by Methyl N-(6-Phenylsulfanyl-1H-benzimidazol-2-yl)carbamate Leads to a Potent Cytotoxic Effect in Tumor Cells
- in-vitro, NSCLC, A549 - in-vitro, NSCLC, H460
TumCG↓, We report that fenbendazole (FZ) (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl)carbamate) exhibits a potent growth-inhibitory activity against cancer cell lines but not normal cells.
selectivity↑, but not normal cells
P53↑, A number of apoptosis regulatory proteins that are normally degraded by the ubiquitin-proteasome pathway like cyclins, p53, and IκBα were found to be accumulated in FZ-treated cells.
IKKα↑,
ER Stress↑, FZ induced distinct ER stress-associated genes like GRP78, GADD153, ATF3, IRE1α, and NOXA in these cells.
GRP78/BiP↑,
CHOP↑,
ATF3↑,
IRE1↑,
NOXA↑,
ROS↑, fenbendazole induced endoplasmic reticulum stress, reactive oxygen species production, decreased mitochondrial membrane potential, and cytochrome c release that eventually led to cancer cell death.
MMP↓,
Cyt‑c↑,
selectivity↑, treatment of human lung cancer cell lines with fenbendazole (FZ)3 induces apoptotic cell death, whereas primary normal cells in culture remain widely unaffected.
eff↝, The growth-inhibitory action of FZ in H460 and A549 cells was also compared with the Food and Drug Administration-approved proteasomal inhibitor bortezomib, and the results showed that the activities of both of the compounds were comparable

2494- Fenb,    Oral Fenbendazole for Cancer Therapy in Humans and Animals
- Review, Var, NA
Glycolysis↓, fenbendazole and its promising anticancer biological activities, such as inhibiting glycolysis, down-regulating glucose uptake, inducing oxidative stress, and enhancing apoptosis in published experimental studies.
GlucoseCon↓,
ROS↑,
Apoptosis↑,
BioAv↓, Due to its poor absorption by oral administration, fenbendazole is particularly effective for targeting intestinal parasites
eff↑, Tippens began self-administering 222 mg fenbendazole orally, along with vitamin E supplements, CBD oil, and bioavailable curcumin. After three months of self-administration, a PET scan revealed no detectable cancer cells in his body.
toxicity↓, In rodents, its lethal dose (LD50) exceeded 10 g/kg, which is 1,000 times the therapeutic level
BioAv↑, vehicles for increasing the bioavailability of oral fenbendazole, it would be worthwhile to focus on dimethyl sulfoxide (DMSO), Salicylic acid, and methyl-β-cyclodextrin.
BioAv↑, Another method to improve the solubility of fenbendazole would be to complex it with methyl-β-cyclodextrin at a 1:1 ratio.
hepatoP↓, In both cases, despite the hepatotoxicity, patients’ liver function recovered rapidly upon discontinuing fenbendazole.
eff↑, combining fenbendazole with glycolysis inhibitors and hepatoprotective pharmaceutical or nutraceutical agents can lead to synergic therapeutic activity while reducing potential liver toxicity.

2847- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- in-vitro, CCA, NA
tumCV↓, Fisetin was significant in suppressing CCA cell viability and colony formation during the course of this experiment.
ChemoSen↑, fisetin significantly potentiated the cisplatin-induced CCA cells death
TumCMig↓, reduced the migration of cancer cells and demonstrated more pronounced effects on KKU-M452 cells
ROS↑, fisetin prompted cell death and apoptosis in CCA cells by stimulating the generation of ROS in KKU-100 cells at a dosage of 50 μM
TumCI↓, suppression of cell invasion and migration,prevention of angiogenesis
angioG↓,
CDK2↓, mechanisms including the suppression of cyclin-dependent kinases, the inhibition of PI3K/Akt/mTOR
PI3K↓,
Akt↓,
mTOR↓,
EGFR↓, suppression of the EGFR pathway, the stimulation of the caspase cascade
Casp↑,
mTORC1↓, suppressing the mTORC1 and 2 signaling
mTORC2↑,
cycD1/CCND1↓, decreasing the level of the cyclin D1 and cyclin E mRNA
cycE/CCNE↓,
MMP2↓, Matrix metalloproteinases (MMP) 2 and MMP 9 gene expression and enzyme activity are suppressed
MMP9↓,
ER Stress↑, Moreover, fisetin also caused endoplasmic reticulum (ER) stress-induced production of mitochondrial ROS generation and Ca2+, with the involvement of MAPK signaling
Ca+2↑,
eff↓, The ROS scavenger molecule N-acetyl cysteine decreased fisetin-activated apoptosis in multiple myeloma and oral cancer cells

2849- FIS,    Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells
- in-vitro, Melanoma, U266
TumCD↑, Fisetin elicited the cytotoxicity in U266 cells, manifested as an increased fraction of the cells with sub-G1 content or stained positively with TUNEL labeling
TumCCA↑,
Casp3↑, Fisetin enhanced caspase-3 activation, downregulation of Bcl-2 and Mcl-1L, and upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, Fisetin activated AMPK as well as its substrate acetyl-CoA carboxylase (ACC), along with a decreased phosphorylation of AKT and mTOR.
ACC↑,
p‑Akt↓,
p‑mTOR↓,
ROS↑, Fisetin also stimulated generation of ROS in U266 cells
eff↓, Conversely, compound C or N-acetyl-l-cystein blocked fisetin-induced apoptosis

2852- FIS,    A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms
- Review, CRC, NA
Risk↓, Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC)
P53↑, increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction
MDM2↓,
COX2↓, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways
Wnt↓,
NF-kB↓,
CDK2↓, regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels
CDK4↓,
p‑RB1↓,
cycE/CCNE↓,
P21↑,
NRF2↓, Pandey and Trigun revealed that fisetin induces apoptosis in CRC cells by inhibiting autophagy and suppressing Nrf2
ROS↑, Furthermore, fisetin elevated ROS levels and downregulated Nrf2 expression, indicating Nrf2 suppression in fisetin-induced apoptosis in CRC cells.
Casp8↑, fisetin treatment resulted in the upregulation of various molecular pathways, including cleaved caspase-8, Fas ligand, TRAIL, and DR5 levels, in the cancer cells
Fas↑,
TRAIL↑,
DR5↑,
MMP↓, Fisetin also caused mitochondrial membrane depolarization, leading to the release of Smac/DIABLO and cytochrome c
Cyt‑c↑,
selectivity↑, enhanced cellular uptake, and induction of apoptosis in cancer cells
P450↝, Fisetin also affected the activities of cytochrome P450 (CYP450 3A4) and glutathione-S-transferase
GSTs↝,
RadioS↑, fisetin pretreatment heightened the radiosensitivity of p53-mutant HT29 human CRC cells
Inflam↓, Fisetin suppresses inflammation in the colon and CRC
β-catenin/ZEB1↓, fisetin in treating colon cancer, revealing its capability to effectively downregulate β-catenin and COX-2
EGFR↓, fisetin decreased EGFR and NF-κB activation in HT29 cells
TumCCA↑, It induces cell cycle arrest, disrupting the transition from the G1 to the S phase, as well as causing G2/M phase arrest
ChemoSen↑, intervention with fisetin and 5-FU appeared to extend the lifespan of the experimental animals

2853- FIS,    Fisetin Inhibits Cell Proliferation and Induces Apoptosis via JAK/STAT3 Signaling Pathways in Human Thyroid TPC 1 Cancer Cells
- in-vitro, Thyroid, TPC-1
Apoptosis↑, fisetin stimulated apoptosis, which confirmed through reduced cell viability, improved ROS generation, altered MMP and cell cycle phases in TPC-1 cells.
ROS↑,
MMP↓,
TumCCA↑,
Casp3↑, fisetin up-regulated the expression of caspase (3, 8, and 9) expressions in TPC-1 cells.
Casp8↑,
Casp9↑,
JAK1↓, fisetin down-regulated the JAK 1 and STAT3 expression in TPC1 cells
STAT3↓,

2855- FIS,    Fisetin Induces Apoptosis Through p53-Mediated Up-Regulation of DR5 Expression in Human Renal Carcinoma Caki Cells
- in-vitro, RCC, Caki-1
TumCCA↑, Fisetin markedly induced sub-G1 population and cleavage of poly (ADP-ribose) polymerase (PARP), which is a marker of apoptosis, and increased caspase activation.
cl‑PARP↑,
Apoptosis↑,
Casp↑,
P53↑, fisetin induced p53 protein expression
DR5↑, fisetin-induced DR5 expression.
CHOP↑, fisetin induced up-regulation of CHOP expression and reactive oxygen species production, which had no effect on fisetin-induced apoptosis.
ROS↑,
ER Stress↑, Fisetin induced expression of ER stress-related proteins, including CHOP and activating ATF4
ATF4↑,
XBP-1↑, fisetin also increased the spliced form of the X-box binding protein (XBP)-1 mRNA
eff∅, In our study, NAC did not enhance fisetin-induced apoptosis, and the ROS scavenger, GEE, also had no effect on apoptosi

2856- FIS,    N -acetyl- L -cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells
- in-vitro, Colon, COLO205
eff↑, We now demonstrate that 10 and 20 mM NAC, non-toxic concentrations, can enhance fisetin (FIS)-mediated apoptosis in colon cancer cells COLO205.
ROS↑, N -acetyl- L -cysteine (NAC) enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis
tumCV↓, FIS at the concentrations of 60 and 120 mM inhibited the viability of COLO205 colon carcinoma cell
Casp3↑, induction of caspase 3 activation and reduction of Bcl-2 protein in accordance with a decreased MMP were detected in NAC + FIS-treated COLO205 cells.
Bcl-2↓,
MMP↓,
eff↑, Enhancement of apoptosis by NAC was also observed in HT-29, HCT-116, and HCT-15 cells under FIS treatment, and in CHR-treated COLO205 cells.

2857- FIS,    A review on the chemotherapeutic potential of fisetin: In vitro evidences
- Review, Var, NA
COX2↓, fisetin altered the expression of cyclooxygenase 2 (COX2) thereby suppressed the secretion of prostaglandin E2 ultimately resulting in the inhibition of epidermal growth factor receptor (EGFR) and NF-κB in human colon cancer cells HT29
PGE2↓,
EGFR↓,
Wnt↓, fisetin treatment inhibited the stimulation of Wnt signaling pathway via downregulating the expression of β-catenin and Tcell factor (TCF) 4
β-catenin/ZEB1↓,
TCF↑,
Apoptosis↑, fisetin triggers apoptosis in U266 cells through multiple pathways: enhancing the activation of caspase-3 and PARP cleavage, decreasing the expression of anti-apoptotic proteins (Bcl-2 and Mcl-1 L ),
Casp3↑,
cl‑PARP↑,
Bcl-2↓,
Mcl-1↓,
BAX↑, ncreasing the expression of pro-apoptotic proteins (Bax, Bim, and Bad)
BIM↑,
BAD↑,
Akt↓, decreasing the phosphorylation of AKT and mTOR and elevating the expression of acetyl CoA carboxylase (ACC
mTOR↓,
ACC↑,
Cyt‑c↑, release the cytochrome c and Smac/Diablo into the cytosol
Diablo↑,
cl‑Casp8↑, fisetin exhibited an increased level of cleaved caspase-8, Fas/Fas ligand, death receptor 5/TRAIL, and p53 levels in HCT-116 cells
Fas↑,
DR5↑,
TRAIL↑,
Securin↓, Securin gets degraded on exposure to fisetin in colon cancer cells.
CDC2↓, fisetin decreased the expression of cell division cycle proteins (CDC2 and CDC25C)
CDC25↓,
HSP70/HSPA5↓, Fisetin induced apoptosis as a result of the downregulation of HSP70 and BAG3 and the inhibition of Bcl-2, Bcl-x L and Mcl-1. T
CDK2↓, AGS 0, 25, 50, 75 μM – 24 and 48 h ↓CDK2, ↓CDK4, ↓cyclin D1, ↑casapse-3 cleavage
CDK4↓,
cycD1/CCND1↓,
MMP2↓, A549 0, 1, 5, 10 μM- 24 and 48 hr: ↓MMP-2, ↓u-PA, ↓NF- κB, ↓c-Fos, ↓c-Jun
uPA↓,
NF-kB↓,
cFos↓,
cJun↓,
MEK↓, ↓ MEK1/2 and ERK1/2 phosphorylation, ↓N-cadherin, ↓vimentin, ↓snail, ↓fibronectin, ↑E-cadherin, ↑desmoglein
p‑ERK↓,
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↓,
NF-kB↑, increased expression of NF-κB p65 leading to apoptosis was due to ROS generation on exposure to fisetin
ROS↑,
DNAdam↑, increased ROS triggered cell death through PARP cleavage, DNA damage and mitochondrial membrane depolarization.
MMP↓,
CHOP↑, Though fisetin upregulated CHOP expression and increased the production of ROS, these events fail to induce apoptosis in Caki cells.
eff↑, 50 μM fisetin + 1 mM melatonin Sk-mel-28 Enhances anti-tumour activity [54] 20 μM fisetin + 1 mM melatonin MeWo Enhances anti-tumour activity [54] 10 μM fisetin + 0.1 μM melatonin A549 Induces autophagic cell death
ChemoSen↑, 20 μM fisetin + 5 μM sorafenib A375, SK-MEL-28 Suppresses invasion and metastasis [44] 40 μM fisetin + 10 μM cisplatin A549, A549-CR Enhances apoptosis

2844- FIS,    Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells
- in-vitro, OS, U2OS
tumCV↓, Fisetin at 20-100 µM effectively reduced the viability of OS cells, and induced apoptosis by signifi-cantly inducing the expression of Caspases- 3,-8 and -9 and pro-apoptotic proteins (Bax and Bad) with subsequent down-regulation of Bcl-xL and Bcl-2
Apoptosis↑,
Casp3↑,
Casp8↑,
Casp9↑,
BAX↑,
BAD↑,
Bcl-2↓,
Bcl-xL↓,
PI3K↓, inhibited PI3K/Akt pathway and ERK1/2,
Akt↓,
ERK↓,
p‑JNK↑, it caused enhanced expressions of p-JNK, p-c-Jun and p-p38
p‑cJun↑,
p‑p38↑,
ROS↑, Fisetin-induced ROS generation and decrease in mitochondrial membrane potential
MMP↓, noticeable decline of mitochondrial transmembrane potential (ΔΨm) in a dose-dependent manner
mTORC1↓, fisetin at various concentrations (20-100 μM) caused a significant (p<0.05) decrease in the level of p-Akt and mTORC1 (an important effector protein of Akt), while up-regulated PTEN.
PTEN↑,
p‑GSK‐3β↓, Level of phosphorylated glycogensynthase kinase 3ǃ (GSK3ǃ), (a serine/threonine kinase) and cyclin D1 were potentially decreased by fisetin which is in line with raised non-phosphorylated levels of GSK3ǃ
GSK‐3β↑,
NF-kB↓, Down-regualtion of NF-κB along with significant up-regulations in IκB upon fisetin treatment correlates with the down-regulation of p-Akt levels.
IKKα↑,
Cyt‑c↑, activates the efflux of cytochrome C

2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, block multiple signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38
Akt↓,
mTOR↓,
p38↓,
*antiOx↑, antioxidant, anti-inflammatory, antiangiogenic, hypolipidemic, neuroprotective, and antitumor effect
*neuroP↑,
Casp3↑, U266 cancer cell line through activation of caspase-3, downregulation of Bcl-2 and Mcl-1L, upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, activation of 5'adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and decreased phosphorylation of AKT and mTOR were also observed
ACC↑,
DNAdam↑, DNA fragmentation, mitochondrial membrane depolarizatio
MMP↓,
eff↑, fisetin in combination with a citrus flavanone, hesperetin mediated apoptosis by mitochondrial membrane depolarization and caspase-3 act
ROS↑, NCI-H460 human non-small cell lung cancer line, fisetin generated reactive oxygen species (ROS), endoplasmic reticulum (ER) stress
cl‑PARP↑, fisetin treatment resulted in PARP cleavage
Cyt‑c↑, release of cyt. c
Diablo↑, release of cyt. c and Smac/DIABLO from mitochondria,
P53↑, increased p53 protein levels
p65↓, reduced phospho-p65 and Myc oncogene expression
Myc↓,
HSP70/HSPA5↓, fisetin causes inhibition of proliferation by the modulation of heat shock protein 70 (HSP70), HSP27
HSP27↓,
COX2↓, anti-proliferative effects of fisetin through the activation of apoptosis via inhibition of cyclooxygenase-2 (COX-2) and Wnt/EGFR/NF-κB signaling pathways
Wnt↓,
EGFR↓,
NF-kB↓,
TumCCA↑, The anti-proliferative effects of fisetin and hesperetin were shown to be occurred through S, G2/M, and G0/G1 phase arrest in K562 cell progression
CDK2↓, decrease in levels of cyclin D1, cyclin A, Cdk-4 and Cdk-2
CDK4↓,
cycD1/CCND1↓,
cycA1/CCNA1↓,
P21↑, increase in p21 CIP1/WAF1 levels in HT-29 human colon cancer cell
MMP2↓, fisetin has exhibited tumor inhibitory effects by blocking matrix metalloproteinase-2 (MMP- 2) and MMP-9 at mRNA and protein levels,
MMP9↓,
TumMeta↓, Antimetastasis
MMP1↓, fisetin also inhibited the MMP-14, MMP-1, MMP-3, MMP-7, and MMP-9
MMP3↓,
MMP7↓,
MET↓, promotion of mesenchymal to epithelial transition associated with a decrease in mesenchymal markers i.e. N-cadherin, vimentin, snail and fibronectin and an increase in epithelial markers i.e. E-cadherin
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↑,
uPA↓, fisetin suppressed the expression and activity of urokinase plasminogen activator (uPA)
ChemoSen↑, combination treatment of fisetin and sorafenib reduced the migration and invasion of BRAF-mutated melanoma cells both in in-vitro
EMT↓, inhibited epithelial to mesenchymal transition (EMT) as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin
Twist↓, inhibited expression of Snail1, Twist1, Slug, ZEB1 and MMP-2 and MMP-9
Zeb1↓,
cFos↓, significant decrease in NF-κB, c-Fos, and c-Jun levels
cJun↓,
EGF↓, Fisetin inhibited epidermal growth factor (EGF)
angioG↓, Antiangiogenesis
VEGF↓, decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF, EGFR, COX-2
eNOS↓,
*NRF2↑, significantly increased nuclear translocation of Nrf2 and antioxidant response element (ARE) luciferase activity, leading to upregulation of HO-1 expression
HO-1↑,
NRF2↓, Fisetin also triggered the suppression of Nrf2
GSTs↓, declined placental type glutathione S-transferase (GST-p) level in the liver of the fisetin- treated rats with hepatocellular carcinoma (HCC)
ATF4↓, Fisetin also rapidly increased the levels of both Nrf2 and ATF4

2824- FIS,    Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics
- Review, Var, NA
*antiOx↑, Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties.
*Inflam↓,
angioG↓,
BioAv↓, poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility
BioAv↑, The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes
TumCP↓, fisetin also inhibits tumor proliferation by repressing tumor mass multiplication, invasion, migration, and autophagy.
TumCI↓,
TumCMig↓,
*neuroP↑, figure 2
EMT↓, It affects the cell cycle and thereby cell proliferation, microtubule assembly, cell migration and invasion, epithelial to mesenchymal transition (EMT), and cell death
ROS↑, cell death caused by fisetin is possibly due to the induction of apoptosis by fisetin or other signaling molecules and reactive oxygen species (ROS)
selectivity↑, Without influencing the growth of normal cells, fisetin has the capability to hinder the formation of colonies and inhibit the multiplication of cancer cells.
EGFR↓, fisetin restricts the multiplication of EGFR 2-overexpressing SK-BR-3 breast tumor masses
NF-kB↓, fisetin inhibits cancer metastasis by reducing the expressions of nuclear factor-kB (NF-kB)-modulated metastatic proteins in a variety of tumor cell types, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP)
VEGF↓,
MMP9↓,
MMP↓, rupturing the plasma membrane, depolarizing mitochondria, cleaving PARP, and activating caspase-7, -8, and -9.
cl‑PARP↑,
Casp7↑,
Casp8↑,
Casp9↑,
*ROS↓, Fisetin is a bioactive flavonol molecule that can easily penetrate the cell membrane due to its hydrophobic nature [51,52], reducing the generation of inflammatory cytokines and reactive oxygen species (ROS) in microglial cells, (normal cells)
uPA↓, Perhaps fisetin lowers angiogenesis, consequently suppressing tumor multiplication by urokinase plasminogen activator (uPA) inhibition
MMP1↓, powerful matrix metalloproteinase (MMP)-1 inhibitor
Wnt↓, Fisetin works on several cellular pathways, such as Wnt, Akt-PI3K, and ERK, as an inhibitor
Akt↓,
PI3K↓,
ERK↓,
Half-Life↝, Fisetin exhibits a very short terminal half-life of approximately 3 hrs in its free form. This half-life is found to be less than that of its metabolites

2825- FIS,    Exploring the molecular targets of dietary flavonoid fisetin in cancer
- Review, Var, NA
*Inflam↓, present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant
*antiOx↓, fisetin possesses stronger oxidant inhibitory activity than well-known potent antioxidants like morin and myricetin.
*ERK↑, inducing extracellular signal-regulated kinase1/2 (ERK)/c-myc phosphorylation, nuclear NF-E2-related factor-2 (Nrf2), glutamate cystine ligase and glutathione (GSH) levels
*p‑cMyc↑,
*NRF2↑,
*GSH↑,
*HO-1↑, activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival
mTOR↓, in our studies on fisetin in non-small lung cancer cells, we found that fisetin acts as a dual inhibitor PI3K/Akt and mTOR pathways
PI3K↓,
Akt↓,
TumCCA↑, fisetin treatment to LNCaP cells resulted in G1-phase arrest accompanied with decrease in cyclins D1, D2 and E and their activating partner CDKs 2, 4 and 6 with induction ofWAF1/p21 and KIP1/p27
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑,
p27↑,
JNK↑, fisetin could inhibit the metastatic ability of PC-3 cells by suppressing of PI3 K/Akt and JNK signaling pathways with subsequent repression of matrix metalloproteinase-2 (MMP-2) and MMP-9
MMP2↓,
MMP9↓,
uPA↓, fisetin suppressed protein and mRNA levels of MMP-2 and urokinase-type plasminogen activator (uPA) in an ERK-dependent fashion.
NF-kB↓, decrease in the nuclear levels of NF-B, c-Fos, and c-Jun was noted in fisetin treated cells
cFos↓,
cJun↓,
E-cadherin↑, upregulation of E-cadherin and down-regulation of vimentin and N-cadherin.
Vim↓,
N-cadherin↓,
EMT↓, EMT inhibiting potential of fisetin has been reported in melanoma cells
MMP↓, The shift in mitochondrial membrane potential was accompanied by release of cytochrome c and Smac/DIABLO resulting in activation of the caspase cascade and cleavage of PARP
Cyt‑c↑,
Diablo↑,
Casp↑,
cl‑PARP↑,
P53↑, fisetin with induction of p53 protein
COX2↓, Fisetin down-regulated COX-2 and reduced the secretion of prostaglandin E2 without affecting COX-1 protein expression.
PGE2↓,
HSP70/HSPA5↓, It was shown that the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 were inhibited in HCT-116 cells exposed to heat shock at 43 C for 1 h in the presence of fisetin
HSP27↓,
DNAdam↑, DNA fragmentation, an increase in the number of sub-G1 phase cells, mitochondrial membrane depolarization and activation of caspase-9 and caspase-3.
Casp3↑,
Casp9↑,
ROS↑, This was associated with production of intracellular ROS
AMPK↑, Fisetin induced AMPK signaling
NO↑, fisetin induced cytotoxicity and showed that fisetin induced apoptosis of leukemia cells through generation of NO and elevated Ca2+ activating the caspase
Ca+2↑,
mTORC1↓, Fisetin was shown to inhibit the mTORC1 pathway and its downstream components including p70S6 K, eIF4B and eEF2 K.
p70S6↓,
ROS↓, Others have also noted a similar decrease in ROS with fisetin treatment.
ER Stress↑, Induction of ER stress upon fisetin treatment, evident as early as 6 h, and associated with up-regulation of IRE1, XBP1s, ATF4 and GRP78, was followed by autophagy which was not sustained
IRE1↑,
ATF4↑,
GRP78/BiP↑,
eff↑, Combination of fisetin and the BRAF inhibitor sorafenib was found to be extremely effective in inhibiting the growth of BRAF-mutated human melanoma cells
eff↑, synergistic effect of fisetin and sorafenib was observed in human cervical cancer HeLa cells,
eff↑, Similarly, fisetin in combination with hesperetin induced apoptosis
RadioS↑, pretreatment with fisetin enhanced the radio-sensitivity of p53 mutant HT-29 cancer cells,
ChemoSen↑, potential of fisetin in enhancing cisplatin-induced cytotoxicity in various cancer models
Half-Life↝, intraperitoneal (ip) dose of 223 mg/kg body weight the maximum plasma concentration (2.53 ug/ml) of fisetin was reached at 15 min which started to decline with a first rapid alpha half-life of 0.09 h and a longer half-life of 3.12 h.

2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1/CCND1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2828- FIS,    Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review
- Review, Var, NA
*neuroP↑, As a hydrophobic agent, FIS readily penetrates cell membranes and accumulates in cells to exert neuroprotective, neurotrophic and antioxidant effects
*antiOx↑,
*Inflam↓, FIS treatment may include alleviating inflammation, cell apoptosis and oxidative stress
RenoP↑, alleviates cell apoptosis and inflammation in acute kidney injury
COX2↓, FIS induces apoptosis in various tumor cells by, for example, inhibiting cyclooxygenase-2, inhibiting the Wnt/EGFR/NF-κB pathway, activating the caspase-3 cascade
Wnt↓,
EGFR↓,
NF-kB↓,
Casp3↑,
Ca+2↑, activating the caspase-3 and Ca2+ dependent endonuclease, and activating the caspase-8/caspase-3 dependent pathway via ERK1/2.
Casp8↑,
TumCCA↑, FIS controls the cell cycle and inhibits cyclin-dependent kinases (CDKs) in human cancer cell lines,
CDK1↓,
PI3K↓, by inhibition of PI3K/Akt/mTOR signaling [20], mitogen-activated protein kinases (MAPK) [21], and nuclear transcription factor (NF-κB)
Akt↓,
mTOR↓,
MAPK↓,
*P53↓, FIS inhibits aging by reducing p53, p21 and p16 expression in mouse and human tissues
*P21↓,
*p16↓,
mTORC1↓, FIS induces autophagic cell death by inhibiting both the mTORC1 and mTORC2 pathways
mTORC2↓,
P53↑, FIS significantly increases the expression of p53 and p21 proteins and lowers the levels of cyclin D1 [27,28], cyclin A, CDK4 and CDK2, thus contributing to cell-cycle arrest.
P21↑,
cycD1/CCND1↓,
cycA1/CCNA1↓,
CDK2↓,
CDK4↓,
BAX↑, FIS also increases Bax [27,28] and Bak [27] protein expression, but reduces the levels of Bcl-2 [27,28], Bcl-xL [27] and PCNA [28], and then starts the mitochondrial apoptotic pathway.
Bcl-2↓,
PCNA↓,
HER2/EBBR2↓, FIS reduces HER2 tyrosine phosphorylation in a dose-dependent manner and aids in proteasomal degradation of HER2 rather than lysosomal degradation
Cyt‑c↑, FIS cells causes destabilization of the mitochondrial membrane and an increase in cytochrome c levels, which is consistent with the loss of mitochondrial membrane integrity.
MMP↓,
cl‑Casp9↑,
MMP2↓, FIS reduces the enzymatic activity of both MMP-2 and MMP-9.
MMP9↓,
cl‑PARP↑, cell membrane, mitochondrial depolarization, activation of caspase-7, -8 and -9, and cleavage of PARP
uPA↓, interestingly, the promoter activity of the uPA gene is suppressed by FIS
DR4↑, induces upregulation of DR4 and DR5 death receptor expression in a dose-dependent manner
DR5↑,
ROS↓, FIS induces an increase in intracellular Ca2+ but reduces the production of ROS in WEHI-3 cells (myelomonocytic leukemia)
AIF↑, It also increases the levels of caspase-3 and AIF mRNA, but also increases necrosis markers including RIP3 and PARP1
CDC25↓, FIS reduces the expression of cdc25a, but increases the expression of p-p53, Chk1, p21 and p27, which may lead to a G0/G1 arrest.
Dose↑, FIS in concentrations from 0 to 10 μM does not affect cell viability; however, its use at concentrations of 20–40 μM significantly reduces the viability of lung cancer cells
CHOP↑, CaKi : FIS induces upregulation of CHOP expression and ROS production
ROS↑, NCI-H460 :FIS increases the ER stress signaling FIS increases the level of mitochondrial ROS FIS induces mitochondrial Ca2+ overloading and ER stress FIS induced ER stress-mediated cell death via activation of the MAPK pathway
cMyc↓, FIS influences proliferation related genes such as cyclin D1, c-myc and cyclooxygenase (COX)-2 by downregulating them.
cardioP↑, cardioprotective activity

2829- FIS,    Fisetin: An anticancer perspective
- Review, Var, NA
TumCP↓, Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion), prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage
TumCI↓,
TumCCA↑,
TumCG↓,
Apoptosis↑,
cl‑PARP↑,
PKCδ↓, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF‐κB activation, and down‐regulates the level of the oncoprotein securin
ROS↓,
ERK↓,
NF-kB↓,
survivin↓,
ROS↑, In human multiple myeloma U266 cells, fisetin stimulated the production of free radical species that led to apoptosis
PI3K↓, Multiple studies also authenticated the anticancer role of fisetin through various signaling pathways such as blocking of mammalian target of rapamycin (PI3K/Akt/mTOR)
Akt↓,
mTOR↓,
MAPK↓, phosphatidylinositol‐3‐kinase/protein kinase B, mitogen‐activated protein kinases (MAPK)‐dependent nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and p38, respectively,
p38↓,
HER2/EBBR2↓, (HER2)/neu‐overexpressing breast cancer cell lines. Fisetin caused induction through inactivating the receptor, inducing the degradation of the proteasomes, reducing its half‐life
EMT↓, In addition, mutation of epithelial‐to‐mesenchymal transition (EMT)
PTEN↑, up‐regulation of expression of PTEN mRNA and protein were reported after fisetin treatment
HO-1↑, In breast cancer cells (4T1 and JC cells), fisetin increased HO‐1 mRNA and protein expressions, elevated Nrf2 expression
NRF2↑,
MMP2↓, fisetin reduced MMP‐2 and MMP‐9 enzyme activity and gene expression for both mRNA levels and protein
MMP9↓,
MMP↓, fisetin treatment further led to permeabilization of mitochondrial membrane, activation of caspase‐8 and caspase‐9, as well as the cleavage of poly(ADP‐ribose) polymerase 1
Casp8↑,
Casp9↑,
TRAILR↑, enhanced the levels of TRAIL‐R1
Cyt‑c↑, mitochondrial releasing of cytochrome c into cytosol, up‐regulation and down‐regulation of X‐linked inhibitor of apoptosis protein
XIAP↓,
P53↑, fisetin also enhanced the protein p53 levels
CDK2↓, lowered cell number, the activities of CDK‐2,4)
CDK4↓,
CDC25↓, it also decreased cell division cycle protein levels (CDC)2 and CDC25C, and CDC2 activity (Lu et al., 2005)
CDC2↓,
VEGF↓, down‐regulating the expressions of p‐ERK1/2, vascular endothelial growth factor receptor 1(VEGFR1), p38, and pJNK, respectively
DNAdam↑, Fisetin (80 microM) showed dose‐dependently caused DNA fragmentation, induced cellular swelling and apoptotic death, and showed characteristics of apoptosis.
TET1↓, lowered the TET1 expression levels
CHOP↑, caused up‐regulation of (C/EBP) homologous protein (CHOP) expression and reactive oxygen species production,
CD44↓, down‐regulation of CD44 and CD133 markers
CD133↓,
uPA↓, down‐regulation of levels of matrix metalloproteinase‐2 (MMP‐2), urokinase‐type plasminogen activator (uPA),
CSCs↓, Being a potent anticancer agent, fisetin administration in in vitro and in vivo studies in kidney renal stem cells (HuRCSCs) effectively inhibited cancer cell stages such as proliferation,

2830- FIS,    Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent
- Review, Var, NA
TumCG↓, suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration.
angioG↓,
*ROS↓,
TumCMig↓,
VEGF↓, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1.
MAPK↑, including the activation of MAPK. activation of MAPK is crucial for mediating cancer cell proliferation, apoptosis, and invasion
NF-kB↓, ability of fisetin to suppress NF-κB activity has been demonstrated in various diseases
PI3K↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT
Akt↓,
mTOR↓, Fisetin has been shown to be effective against PI3K expression, AKT phosphorylation, and mTOR activation in various cancer cells,
NRF2↑, effects of fisetin on the activation of Nrf2 and upregulation of HO-1 have been demonstrated in various diseases
HO-1↑,
ROS↓, Liver cancer Resist proliferation, migration and invasion, induce apoptosis, attenuate ROS and inflammation
Inflam↓,
ER Stress↑, Oral cancer Induce apoptosis and autophagy, promote ER stress and ROS, suppress proliferation
ROS↑, Multiple studies have demonstrated that fisetin has the ability to induce apoptosis in cancer cells, and various mechanisms are involved, including the activation of MAPK, NF-κB, p53, and the generation of reactive oxygen species (ROS)
TumCP↓,
ChemoSen↑, Breast cancer Promote apoptosis and invasion and metastasis, enhance chemotherapeutic effects
PTEN↑,
P53↑, activation of MAPK, NF-κB, p53,
Casp3↑,
Casp8↑,
Casp9↑,
COX2↓, fisetin inhibits COX2 expression
Wnt↓, regulating a number of important angiogenesis-related factors in cancer cells, such as VEGF, MMP2/9, eNOS, wingless and Wnt-signaling.
EGFR↓,
Mcl-1↓,
survivin↓, fisetin interferes with NF-κB signaling, resulting in the reduction of survivin, TRAF1, Bcl-xl, Bcl-2, and IAP1/2 levels, ultimately inhibiting apoptosis
IAP1↓,
IAP2↓,
PGE2↓, fisetin inhibits COX2 expression, leading to the down-regulation of PGE2 secretion and inactivation of β-catenin, thereby inducing apoptosis
β-catenin/ZEB1↓,
DR5↑, fisetin markedly induces apoptosis in renal carcinoma through increased expression of DR5, which is regulated by p53.
MMP2↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT and JNK pathways, resulting in the suppression of MMP-2 and MMP-9 expression
MMP9↓,
FAK↓, fisetin can inhibit cell migration and reduce focal adhesion kinase (FAK) phosphorylation levels
uPA↓, fisetin significantly suppresses the invasion of U-2 cells by decreasing the expression of NF-κB, urokinase-type plasminogen activator (uPA), FAK, and MMP-2/9
EMT↓, Fisetin has been shown to have the ability to reverse EMT, thereby inhibiting the invasion and migration of cancer cells
ERK↓, fisetin has the ability to suppress ERK1/2 activation and activate JNK/p38 pathways
JNK↑,
p38↑,
PKCδ↓, fisetin reduces the expression of MMP-9 by inhibiting PKCα/ROS/ERK1/2 and p38 MAPK activation
BioAv↓, low water solubility of fisetin poses a significant challenge for its administration, which can limit its biological effects
BioAv↑, Compared to free fisetin, fisetin nanoemulsion has demonstrated a 3.9-fold increase in the generation of reactive oxygen species (ROS) and induction of apoptosis, highlighting its enhanced efficacy
BioAv↑, Liposomal encapsulation has shown potential in enhancing the anticancer therapeutic effects of fisetin

2833- FIS,  AgNPs,    Glucose-capped fisetin silver nanoparticles induced cytotoxicity and ferroptosis in breast cancer cells: A molecular perspective
- in-vitro, BC, MDA-MB-231
MMP↓, MDA-MB-231 cells treated with glucose-capped fisetin silver nanoparticles showed signs of apoptosis, decreased mitochondrial membrane potential, and elevated Reactive oxygen species (ROS) production.
ROS↑,
NRF2↑, upregulation of SLC7A11, SLC40A1, NRF2F, NOX2, and NOX5 genes that are associated with various crucial cellular events
NOX↑,
selectivity↑, Glucose nanoparticles selectively deliver cytotoxic agents to cancer cells by targeting the glucose transporters overexpressed in cancer cells, resulting in minimal toxicity to healthy tissues

2838- FIS,    Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)
cl‑Casp3↑, enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells
cl‑PARP↑,
MMP↓, This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c
Cyt‑c↑,
ROS↑, fisetin-treated cells showed increased ROS level
NRF2↓, and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells.

2839- FIS,    Dietary flavonoid fisetin for cancer prevention and treatment
- Review, Var, NA
DNAdam↑, Fisetin induced DNA fragmentation, ROS generation, and apoptosis in NCI-H460 cells via a reduction in Bcl-2 and increase in Bax expression
ROS↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
cl‑Casp9↑, Fisetin treatment increased cleavage of caspase-9 and caspase-3 thereby increasing caspase-3 activation
cl‑Casp3↑,
Cyt‑c↑, leading to cytochrome-c release
lipid-P↓, Fisetin (25 mg/kg body weight) decreased histological lesions and levels of lipid peroxidation and modulated the enzymatic and nonenzymatic anti-oxidants in B(a)P-treated Swiss Albino mice
TumCG↓, We observed that fisetin treatment (5–20 μM) inhibits cell growth and colony formation in A549 NSC lung cancer cells.
TumCA↓, Another study showed that fisetin inhibits adhesion, migration, and invasion in A549 lung cancer cells by downregulating uPA, ERK1/2, and MMP-2
TumCMig↓,
TumCI↓,
uPA↓,
ERK↓,
MMP9↓,
NF-kB↓, Treatment with fisetin also decreased the nuclear levels of NF-kB, c-Fos, c-Jun, and AP-1 and inhibited NF-kB binding.
cFos↓,
cJun↓,
AP-1↓,
TumCCA↑, Our laboratory has previously shown that treatment of LNCaP cells with fisetin caused inhibition of PCa by G1-phase cell cycle arrest
AR↓, inhibited androgen signaling and tumor growth in athymic nude mice
mTORC1↓, induced autophagic cell death in PCa cells through suppression of mTORC1 and mTORC2
mTORC2↓,
TSC2↑, activated the mTOR repressor TSC2, commonly associated with inhibition of Akt and activation of AMPK
EGF↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
TGF-β↓,
EMT↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
P-gp↓, decrease the P-gp protein in multidrug resistant NCI/ADR-RES cells.
PI3K↓, Fisetin also inhibited the PI3K/AKT/NFkB signaling
Akt↓,
mTOR↓, Fisetin inhibited melanoma progression in a 3D melanoma skin model with downregulation of mTOR, Akt, and upregulation of TSC
eff↑, combinational treatment study of melatonin and fisetin demonstrated enhanced antitumor activity of fisetin
ROS↓, Fisetin inhibited ROS and augmented NO generation in A375 melanoma cells
ER Stress↑, induction of ER stress evidenced by increased IRE1α, XBP1s, ATF4, and GRP78 levels in A375 and 451Lu cells.
IRE1↑,
ATF4↑,
GRP78/BiP↑,
ChemoSen↑, combination of fisetin with sorafenib effectively inhibited EMT and augmented the anti-metastatic potential of sorafenib by reducing MMP-2 and MMP-9 proteins in melanoma cell xenografts
CDK2↓, Fisetin (0–60 μM) was shown to inhibit activity of CDKs dose-dependently leading to cell cycle arrest in HT-29 human colon cancer cells
CDK4↓, Fisetin treatment decreased activities of CDK2 and CDK4 via decreased levels of cyclin-E, cyclin-D1 and increase in p21 (CIP1/WAF1) levels.
cycE/CCNE↓,
cycD1/CCND1↓,
P21↑,
COX2↓, fisetin (30–120 μM) induces apoptosis in colon cancer cells by inhibiting COX-2 and Wnt/EGFR/NF-kB -signaling pathways
Wnt↓,
EGFR↓,
β-catenin/ZEB1↓, Fisetin treatment inhibited Wnt/EGFR/NF-kB signaling via downregulation of β-catenin, TCF-4, cyclin D1, and MMP-7
TCF-4↓,
MMP7↓,
RadioS↑, fisetin treatment was found to radiosensitize human colorectal cancer cells which are resistant to radiotherapy
eff↑, Combined treatment of fisetin with NAC increased cleaved caspase-3, PARP, reduced mitochondrial membrane potential with induction of caspase-9 in COLO25 cells

2840- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- NA, CCA, NA
ROS↑, The mechanism of cell death and apoptosis was measured by reactive oxygen species (ROS) generation
TumCMig↓, Fisetin may inhibit cholangiocarcinoma (CCA) cell migration and proliferation;
TumCP↓,

2842- FIS,    Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells
- in-vitro, GC, AGS
TumCCA↑, Fisetin (25-100 μM) caused significant decrease in the levels of G1 phase cyclins and CDKs, and increased the levels of p53 and its S15 phosphorylation in gastric cancer cells.
CDK2↓,
P53↑,
selectivity↑, observed that growth suppression and death of non-neoplastic human intestinal FHs74int cells were minimally affected by fisetin
MMP↓, Fisetin strongly increased apoptotic cells and showed mitochondrial membrane depolarization in gastric cancer cells
DNAdam↑, DNA damage was observed as early as 3 h after fisetin treatment which was accompanied with gamma-H2A.X(S139) phosphorylation and cleavage of PARP
cl‑PARP↑,
mt-ROS↑, showed an increase in mitochondrial ROS generation in time- and dose-dependent fashion
eff↓, Pre-treatment with N-acetyl cysteine (NAC) inhibited ROS generation and also caused protection from fisetin-induced DNA damage
survivin↓, We observed a decrease in the levels of survivin by fisetin in gastric cancer cells which further strengthens our results that fisetin decreases antiapoptotic proteins to promote apoptosis.

2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1/CCND1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE/CCNE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,

2832- FIS,    Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies
- Review, Var, NA
MMP↓, fraction of cells with reduced mitochondrial membrane potential also increased, indicating that fisetin-induced apoptosis also destroys mitochondria.
mtDam↑,
Cyt‑c↑, Cytochrome c and Smac/DIABLO levels are also released when the mitochondrial membrane potential changes, and this results in the activation of the caspase cascade and the cleavage of poly [ADP-ribose] polymerase (PARP)
Diablo↑,
Casp↑,
cl‑PARP↑,
Bak↑, Fisetin induced apoptosis in HCT-116 human colon cancer cells by upregulating proapoptotic proteins Bak and BIM and downregulating antiapoptotic proteins B cell lymphoma (BCL)-XL and -2.
BIM↑,
Bcl-xL↓,
Bcl-2↓,
P53↑, fisetin through the activation of p53
ROS↑, over generation of ROS, which is also directly initiated by fisetin, the stimulation of AMPK
AMPK↑,
Casp9↑, activating caspase-9 collectively, then activating caspase-3, leading to apopotosis
Casp3↑,
BID↑, Bid, AIF and the increase of the ratio of Bax to Bcl-2, causing the activation of caspase 3–9
AIF↑,
Akt↓, The inhibition of the Akt/mTOR/MAPK/
mTOR↓,
MAPK↓,
Wnt↓, Fisetin has been shown to degrade the Wnt/β/β-catenin signal
β-catenin/ZEB1↓,
TumCCA↑, fisetin triggered G1 phase arrest in LNCaP cells by activating WAF1/p21 and kip1/p27, followed by a reduction in cyclin D1, D2, and E as well as CDKs 2, 4, and 6
P21↑,
p27↑,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
TumMeta↓, reduces PC-3 cells' capacity for metastasis
uPA↓, fisetin decreased MMP-2 protein, messenger RNA (mRNA), and uPA levels through an ERK-dependent route
E-cadherin↑, Fisetin can upregulate the epithelial marker E-cadherin, downregulate the mesenchymal marker vimentin, and drastically lower the EMT regulator twist protein level at noncytotoxic dosages, studies have revealed.
Vim↓,
EMT↓,
Twist↓,
DNAdam↑, Fisetin induces apoptosis in the human nonsmall lung cancer cell line NCI-H460, which causes DNA breakage, the growth of sub-G1 cells, depolarization of the mitochondrial membrane, and activation of caspases 9, 3, which are involved in prod of iROS
ROS↓, fisetin therapy has been linked to a reduction in ROS, according to other research.
COX2↓, Fisetin lowered the expression of COX-1 protein, downregulated COX-2, and decreased PGE2 production
PGE2↓,
HSF1↓, Fisetin is a strong HSF1 inhibitor that blocks HSF1 from binding to the hsp70 gene promoter.
cFos↓, NF-κB, c-Fos, c-Jun, and AP-1 nuclear levels were also lowered by fisetin treatment
cJun↓,
AP-1↓,
Mcl-1↓, inhibition of Bcl-2 and Mcl-1 all contribute to an increase in apoptosis
NF-kB↓, Fisetin's ability to prevent NF-κB activation in LNCaP cells
IRE1↑, fisetin (20–80 µM) was accompanied by brief autophagy and the production of ER stress, which was shown by elevated levels of IRE1 α, XBP1s, ATF4, and GRP78 in A375 and 451Lu cells
ER Stress↑,
ATF4↑,
GRP78/BiP↑,
MMP2↓, lowering MMP-2 and MMP-9 proteins in melanoma cell xenografts
MMP9↓,
TCF-4↓, fisetin therapy reduced levels of β-catenin, TCF-4, cyclin D1, and MMP-7,
MMP7↓,
RadioS↑, fisetin treatment could radiosensitize human colorectal cancer cells that are resistant to radiotherapy.
TOP1↓, fisetin blocks DNA topoisomerases I and II in leukemia cells.
TOP2↓,

4024- FulvicA,    ANTI-CARCINOGENIC ACTIVITY OF SHILAJIT REGARDING TO APOPTOSIS ASSAY IN CANCER CELLS: A SYSTEMATIC REVIEW OF IN-VITRO STUDIES
- Review, Var, NA
*Inflam↓, Shilajit, a natural mineral substance with a long history of use in traditional Ayurvedic medicine, has garnered attention for its potential therapeutic properties, including anti-oxidant, immunomodulatory and anti-inflammatory effects.
*antiOx↑,
TumCG↓, reviewed studies reveal that Shilajitexhibitssignificant dose and time dependent cytotoxic effects in various human cancer cell lines, including breast, lung, liver, ovarian, cervical, and colorectal cancers.
tumCV↓, increased cell death and reduced cell viability correlating with higher concentrations of Shilajit.
ROS↑, reactive oxygen species production and suppression of key anti-apoptotic proteins.
ChemoSen↑, multiple studies suggest that Shilajit may act as a potential chemopreventive agent by inducing apoptosis and inhibiting the proliferation of cancer cells.
toxicity↝, However, the high dosages recommended in Ayurvedic texts, particularly in the context of cancer treatment, warrant caution due to potential cytotoxicity at excessive levels along with minimal toxicity to normal cells at controlled dosages.

4028- FulvicA,    Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells
- in-vitro, Liver, HUH7
Apoptosis↑, MP enhanced anti-cancer effects by inducing apoptosis and inhibiting proliferation.
TumCP↓,
ROS↑, MP induced both ROS and NO, upon neutralizing them, there was a partial recovery of apoptosis and proliferation.
NO↑,
Dose↝, MP is a humic matter, shown to contain fulvic acid and humic acid, which are responsible for its biochemical activities.
MMP↓, mitochondrial membrane potential is reduced, cytochrome c is released, the transition pores are opened and calcium is released by the increased NO level which eventually leads to apoptosis
Cyt‑c↑,
SOD↓, SOD activity in Huh-7 cells was found to be decreasing with increasing concentrations of MP
Catalase↓, catalase activity was significantly decreased in all the concentrations of MP that was tested.
GSH↑, Glutathione production was significantly increased with the increasing concentrations of MP. There was a more than 7-fold increase of glutathione production with 100, 500 and 1000 μg/ml of MP
lipid-P↑, lipid peroxidation of the cancer cells was found to be increased in concentration dependent manner.
miR-21↓, MP induces ROS and nitric oxide, enhances the expression of miRNA-22 and decreases the expression of miRNA-21, a known onco-miR.
miR-22↑,

1624- GA,    Anticancer Effect of Pomegranate Peel Polyphenols against Cervical Cancer
- in-vitro, Cerv, NA
ROS↑, GA was found to increase ROS levels
Dose∅, (50–400 µM, from a time phase of 30 min to 24 h)
MMP↓, loss of mitochondrial membrane potential
GSH↑, antioxidant enzyme glutathione peroxidase (GSH) decreased when treatment was administered above 100 µM

5205- Gallo,    Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells
- in-vitro, Endo, ISH
LDH↓, novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer.
TumCG↓, Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer
LDHA↓, GF significantly reduced LDHA activity
Apoptosis↑, GF was responsible for the activation of the mitochondrial apoptosis pathway, accompanied by an increase in cleaved caspase3 and a decrease in MCL-1 and BCL-2 protein
cl‑Casp3↑,
Mcl-1↓,
Bcl-2↓,
TumCCA↑, GF induces cell cycle changes by altering different checkpoints in different endometrial cancer cells
ROS↑, GF was also shown to increase reactive oxygen species (ROS) and mitochondrial DNA damage after 24 hours
mt-DNAdam↑,
GlucoseCon↓, Inhibition of LDHA activity by GF resulted in a decreased rate of glucose uptake and ATP production
ATP↓,
PDH↑, with subsequent increased pyruvate dehydrogenase (PDH) protein expression and production of pyruvate
Pyruv↑,
Glycolysis↓, direct effect of GF on the glucose metabolism by impairing cytosolic glycolysis in the endometrial cancer cells
TCA↑, GF increased glutaminase protein expression, and enhanced Krebs cycle activity, by increasing the production of malate,
cMyc↓, GF decreased c-Myc expression in a dose-dependent manner after 24 hours of treatment.
E-cadherin↑, E–cadherin increased while Slug proteins decreased after treatment with GF (
Slug↓,

935- Gallo,    Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
LDH↓, our experimental data show that the inhibition of LDH caused by GF can exert comparable growth inhibitory effects on breast cancer cells
ROS↑, induction of an oxidative stress condition
TumCP↓, Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production.
Glycolysis↓,
ATP↓,
ER-α36↓, In MCF-7 cells we observed a down regulation of the ERα-mediated signaling needed for cell survival
Apoptosis?, mechanism of cell death was found to be apoptosis induction

5152- GamB,    Gambogic Acid as a Candidate for Cancer Therapy: A Review
- Review, Var, NA
AntiCan↑, GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis.
Apoptosis↑,
TumAuto↑,
TumCCA↑,
TumCI↓,
TumMeta↓,
angioG↓,
eff↑, In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form micelles, nanoparticles, nanofibers
NF-kB↓, GA could inhibit the activation of NF-κB
P53↑, GA increases p53 expression via down-regulating MDM2 in wild type p53 expressing human cancer cells (non-small cell lung H1299)
P21↑, GA could enhance p21Waf1/CIP1 expression to induce cell apoptosis in human breast cancer cells (MCF-7) via suppressing MDM2
MDM2↓,
HSP90↓, GA was considered as a natural product inhibitor of Hsp90
Bcl-2↓, bcl-2 reduction is associated with the release of cytochrome c, leading to an apoptosis cascade reaction
Cyt‑c↑,
Casp↑,
MMP↓, rapid mitochondrial membrane depolarization and fragmentation
Casp3↑, activation of caspase-3, 9 and cleaved PARP and increased ratio of bax/bcl-2.
Casp9↑,
cl‑PARP↑,
Bax:Bcl2↑,
ROS↑, GA-induced reactive oxygen species (ROS) may be the cause of the collapse of mitochondrial transmembrane potential, which could also down-regulate SIRT1 in multiple myeloma
SIRT1↓,
TrxR1↓, GA may also interact with the thioredoxin reductase 1 (TrxR1) to elicit oxidative stress leading to ROS accumulation in hepatocellular carcinoma
Fas↓, GA with increased death receptor (Fas, FasL, Fas-associated protein with death domain (FADD) and Apaf-1) and deoxyribonucleic acid (DNA) fragmentation.
FasL↑,
FADD↑,
APAF1↑,
DNAdam↑,
NF-kB↓, GA could inhibit NF-κB pathway through suppressing IκBα and p65 phosphorylation
STAT3↓, GA also suppressed the signal transducer and activator of transcription (STAT3) phosphorylation to induce cell apoptosis
MAPK↓, GA induced cell apoptosis via suppression of mitogen-activated protein kinases (MAPK) pathway and c-fos
cFos↓,
EGFR↓, GA could also enhance epidermal growth factor receptor (EGFR) degradation and inhibit AKT/mTOR complex 1 (mTORC1) via up-regulating AMP-activated protein kinase (AMPK)-
Akt↓,
mTOR↓,
AMPK↑,
TumCCA↑, GA could obviously induce G2/M or G0/G1 arrest in various cancer cell lines, such as MCF-7 cells, K562 cells, U2OS cells, and so on
ChemoSen↑, GA distinctly sensitized doxorubicin (DOX)-resistant breast cancer cells through inhibiting P-glycoprotein and suppressing the survivin expression revealed by ROS-mediated activation of the p38 MAPK
P-gp↓,
survivin↓,

5148- GamB,    Gambogic acid: A shining natural compound to nanomedicine for cancer therapeutics
- Review, Var, NA
AntiCan↑, In this review, we document distinct biological characteristics of GA as a novel anti-cancer agent.
angioG↓, anti-angiogenesis, and chemo-/radiation sensitizer activities
ChemoSen↑, Moreover, GA has shown chemotherapy/radiation sensitization properties in different types of cancers
RadioS↑,
VEGF↓, Figure 2
MMP2↓,
MMP9↓,
Telomerase↓,
TrxR↓,
ERK↓,
HSP90↓,
ROS↑,
SIRT1↑,
survivin↓,
cFLIP↓,
Casp3↑,
Casp8↑,
Casp9↑,
BAD↓,
BID↓,
Bcl-2↓,
BAX↑,
STAT3↓,
hTERT/TERT↓,
NF-kB↓,
Myc↓,
Hif1a↓,
FOXD3↑,
BioAv↓, Unfortunately, the aqueous solubility of GA (0.013 mg/mL) is very low, thus limiting its clinical application.
BioAv↑, For example, GA can be coupled with alkanolamines to improve aqueous solubility and achieve equivalent anti-proliferation effects
P53↑, This inhibition was co-related with increase of p53 levels and reduced bcl-2 levels
eff↓, Such effect was received for GA due to production of ROS which can be removed by N-acetyl-L-cysteine (NAC, a ROS inhibitor)
OCR↓, GA exhibited a dose-dependent generation of intracellular ROS levels and lowered the oxygen consumption rate and the mitochondrial membrane potential.
MMP↓,
PI3K↓, GA happens to promote antimetastasis properties in melanoma cells by active inhibition of PI3K/Akt and ERK signaling pathways
Akt↓,
BBB↑, This study demonstrated successful uptake of GA through blood-brain barrier (BBB)
TumCG↓, GA-based nanomedicine is efficient in targeting tumors, capable to inhibit tumor growth, metastasis, angiogenesis, and reverse drug resistance
TumMeta↓,
BioAv↑, deliver GA using nanoparticles for enhanced solubility, bioavailability, adsorption and tumor imaging and targeting

1954- GamB,    Gambogic acid induces apoptosis in hepatocellular carcinoma SMMC-7721 cells by targeting cytosolic thioredoxin reductase
- in-vitro, HCC, SMMC-7721 cell
AntiTum↑, Gambogic acid (GA), a natural product that has been used in traditional Chinese medicine for centuries, demonstrates potent anticancer activity in numerous types of human cancer cells and has entered phase II clinical trials
TrxR↓, GA may interact with TrxR1 to elicit oxidative stress
TrxR1↓,
ROS↑,
Apoptosis↑, eventually induce apoptosis in human hepatocellular carcinoma SMMC-7721 cells.
Dose∅, GA effectively inhibited TrxR1 with an IC 50 around 1.2 uM,
Dose?, Under our experimental conditions, GA with concentration less than 5 uM gives only marginal inhibition of Trx

1955- GamB,    Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ROS↑, GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death.
Apoptosis↑,
Ferroptosis↑,
Trx↓, GA inhibited thioredoxin
eff↑, Auranofin (AUR), a thioredoxin reductase (TrxR) inhibitor was the one compound that demonstrated additive growth inhibition together with GA when both were combined at sub-thresh hold concentrations
TrxR↓, GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
Dose∅, GA demonstrated sub-micromolar activity (IC50 = 185nM) which was 50 times more potent than the next most active compounds, curcumin and tanshinone (CT)
MMP↓, GA treatment showed increasing loss of membrane polarity at 4 and 6 hours in PCAP-1 cells
eff↑, GA enhanced the cell killing observed for either docetaxel (DOX) or enzalutamide (ENZA)
Casp↑, These results suggest that GA initiates CASP-dependent death of PCAP-1 cells and that both iron-dependent oxidative injury and direct CASP activation contribute
NADPH↓, These results suggest that GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
TrxR↓,
ChemoSen↑, potential use of GA in combination with standard chemotherapeutic (docetaxel) and anti-androgen endocrine (enzalutamide) therapies for advanced PrCa.
AR↓, inhibit PrCa growth, in part by inhibiting AR signaling

1956- GamB,    Gambogic Acid Inhibits Malignant Melanoma Cell Proliferation Through Mitochondrial p66shc/ROS-p53/Bax-Mediated Apoptosis
- in-vitro, Melanoma, A375
tumCV↓, Incubation of A375 cells with 1-10 μg/ml GA decreased cell viability and increased apoptosis.
Apoptosis↑,
ROS↑, GA concentration-dependently increased p66shc expression and intracellular ROS levels.
p66Shc↑,

1957- GamB,    Nanoscale Features of Gambogic Acid Induced ROS-Dependent Apoptosis in Esophageal Cancer Cells Imaged by Atomic Force Microscopy
- in-vitro, ESCC, EC9706
AntiCan↑, Gambogic acid (GA), a kind of polyprenylated xanthone derived from Garcinia hanburyi tree, has showed spectrum anticancer effects both in vitro and in vivo with low toxicity.
toxicity↓,
TumCP↓, GA could inhibit cell proliferation, induce apoptosis, induce cell cycle arrest,
Apoptosis↑,
TumCCA↑, GA could induce EC9706 cell cycle arrest at G2/M phase in ROS-dependent way
MMP↓, induce mitochondria membrane potential disruption in a ROS-dependent way.
ROS↑,
eff↓, removal of GA-induced excessive ROS by N-acetyl-L-cysteine (NAC) could reverse GA-inhibited EC9706 cell proliferation
RadioS↑, GA is also found to enhance the radiosensitivity of human esophageal cancer cells

1958- GamB,    Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells
- in-vitro, Pca, NA - in-vivo, NA, NA
AntiCan↑, Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers.
TumCP↓, GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells.
TumAuto↑,
eff↑, In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA.
JNK↑, activation of JNK pathway
ROS↑, GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress.
ER Stress↑,
eff↓, ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA.
TumCG↓, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo.

1960- GamB,  Vem,    Calcium channel blocker verapamil accelerates gambogic acid-induced cytotoxicity via enhancing proteasome inhibition and ROS generation
- in-vitro, Liver, HepG2 - in-vitro, AML, K562
Proteasome↓, GA is a potent proteasome inhibitor, with anticancer efficiency comparable to bortezomib but much less toxicity
eff↑, either GA (0.3, 0.4, 0.5 uM) or Ver (20, 30, 40 uM) only slightly decreased cell viability in HepG2 cells after 72 h, while the combination of GA and Ver dramatically decreased the HepG2 cell viability
Casp↑, (ii) a combinational treatment with Ver and GA induces caspase activation, endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production;
ER Stress↑,
ROS↑,
eff↑, GA at 0.5 lM or Ver at 30 lM alone did not alter CHOP protein expression levels after 48 h treatment the combination of GA and Ver markedly increased CHOP

1961- GamB,    Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS
- in-vitro, Melanoma, RPMI-8226
TumCG↓, GA was found to have a significant, dose-dependent effect on growth inhibition and apoptosis induction in RPMI-8226 cells.
Apoptosis↑,
ROS↑, This activity is associated with the accumulation of ROS
Casp3↑, which contributes to the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP)
cl‑PARP↑,
SIRT1↓, demonstrated that GA has the potential to downregulate the expression of SIRT1 via ROS accumulation.
eff↓, NAC reduced the apoptosis rate in RPMI-8226 cells treated with GA

1962- GamB,  HCQ,    Gambogic acid induces autophagy and combines synergistically with chloroquine to suppress pancreatic cancer by increasing the accumulation of reactive oxygen species
- in-vitro, PC, NA
LC3II↑, Gambogic acid induced the expression of LC3-II and Beclin-1 proteins in pancreatic cancer cells, whereas the expression of P62 showed a decline.
Beclin-1↑,
p62↓,
MMP↓, gambogic acid reduced the mitochondrial membrane potential and promoted ROS production, which contributed to the activation of autophagy
ROS↑,
TumAuto↑,
eff↑, inhibition of autophagy by chloroquine further reduced the mitochondrial membrane potential and increased the accumulation of ROS

1963- GamB,    Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model
- in-vitro, Lung, NA
ROS↑, anti-cancer activity of GA depended on reactive oxygen species (ROS)
6PGD↓, anticancer mechanism of GA, which involves the inhibition of 6PGD
PPP↓,

1965- GamB,  doxoR,    Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis
- in-vitro, Ovarian, SKOV3
eff↑, In this study, we showed that gambogic acid, a natural compound, could potentiate the anticancer activity of doxorubicin in ovarian cancer through ROS-mediated apoptosis.
AntiCan↑,
ROS↑,
ChemoSen↑, strategy to enhance chemosensitivity of ovarian cancer to doxorubicin.

1966- GamB,  Cisplatin,    Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling
- in-vitro, Lung, A549 - in-vitro, Lung, NCIH1299
TumCCA↑, Increased sub-G1 phase cells and enhanced PARP cleavage
PARP↑,
eff↑, sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) i
ROS↑, increased apoptosis was correlated with enhanced reactive oxygen species generation.
ChemoSen↑, combination of CDDP and GA exerted increased antitumour effects on A549 xenograft models through inhibiting NF-κB, HO-1, and subsequently inducing apoptosis.

1967- GamB,    Gambogic acid induces apoptotic cell death in T98G glioma cells
- in-vitro, GBM, T98G
BAX↑, GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expression was downregulated.
AIF↑,
Cyt‑c↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↓,
Bcl-2↓,
ROS↑, GA induced reactive oxygen species (ROS) generation in T98G cells.

1968- GamB,    Gambogic Acid Shows Anti-Proliferative Effects on Non-Small Cell Lung Cancer (NSCLC) Cells by Activating Reactive Oxygen Species (ROS)-Induced Endoplasmic Reticulum (ER) Stress-Mediated Apoptosis
- in-vitro, Lung, A549
tumCV↓, GA treatment significantly reduced cell viabilities of NSCLC cells in a concentration-dependent manner.
ROS↑, GA treatment increased intracellular ROS level,
GRP78/BiP↑, expression levels of GRP (glucose-regulated protein) 78
CHOP↑, CHOP (C/EBP-homologous protein),
ATF6↑, ATF (activating transcription factor) 6 and caspase 12,
Casp12↑,
p‑PERK↑, phosphorylation levels of PERK
ER Stress↑, Induced Endoplasmic Reticulum (ER) Stress-Mediated Apoptosis

1969- GamB,    Gambogic acid promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells
- in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
AntiTum↑, (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo
TumCI↓, Low concentrations of GA (0.3-1.2 µmol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability
Apoptosis↑, GA (3 and 6 µmol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS).
ROS↑,
Cyt‑c↑, release of cytochrome c (Cyt c) from mitochondria
Akt↓, GA also inhibited cell survival via blocking Akt/mTOR signaling
mTOR↓,
TumCG↓, In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells.
TumMeta↓,

1970- GamB,    Gambogic acid-induced autophagy in nonsmall cell lung cancer NCI-H441 cells through a reactive oxygen species pathway
- NA, Lung, NCI-H441
TumCG↓, NCI‑H441 is a human lung adenocarcinoma cell line that is widely used as a model system for studying pulmonary epithelial functions, particularly those of alveolar type II cells.
TumAuto↑, GA induced NCI-H441 cells autophagy
Beclin-1↑, upregulation of Beclin 1
LC3‑Ⅱ/LC3‑Ⅰ↑, conversion of LC3 I to LC3 II (autophagosome marker)
ROS↑, generated ROS
eff↓, ROS scavenger N-acetylcysteine reversed GA-induced autophagy and restored the cell survival, which indicated GA-induced autophagy in NCI-H441 cells through an ROS-dependent pathway.

1972- GamB,  doxoR,    Gambogic acid sensitizes resistant breast cancer cells to doxorubicin through inhibiting P-glycoprotein and suppressing survivin expression
- in-vitro, BC, NA
eff↑, we found that GA can markedly sensitize doxorubicin (DOX)-resistant breast cancer cells to DOX-mediated cell death
P-gp↓, GA increased the intracellular accumulation of DOX by inhibiting both P-gp expression and activity
ROS↑, combination effect was associated with the generation of intracellular reactive oxygen species (ROS)
survivin↓, and the suppression of anti-apoptotic protein survivin
p38↑, ROS-mediated activation of p38 MAPK was revealed in GA-mediated suppression of survivin expression

1973- GamB,    Gambogic acid deactivates cytosolic and mitochondrial thioredoxins by covalent binding to the functional domain
- in-vitro, Liver, SMMC-7721 cell
Apoptosis↑, selectively induces apoptosis in cancer cells, at least partially, by targeting the stress response to reactive oxygen species (ROS).
ROS↑,
Trx↓, deactivates TRX-1/2 proteins by covalent binding to the active cysteine residues in the functional domain via Michael addition reactions.
Trx1↓,
Trx2↓,
Mich↑, can react with small nucleophilic molecules, such as GSH and a cysteine-containing peptide, via a Michael addition reaction.

2060- GamB,    Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells
- in-vitro, Pca, NA
TumCP↓, GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells
TumAuto↑,
eff↑, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA.
ROS↑, GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress
ER Stress↑,
JNK↑, activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA

805- GAR,  Cisplatin,  PacT,    Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells
- Review, NA, NA
ERK↓, ERK1/2
PI3K/Akt↓,
Wnt/(β-catenin)↓,
STAT3↓,
NF-kB↓,
ChemoSen↑, cisplatin or paclitaxel, in the presence of garcinol can lead to a significant increase in the treatment outcome
COX2↓,
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
VEGF↓,
TGF-β↓,
HATs↓,
E-cadherin↑,
Vim↓,
Zeb1↓,
ZEB2↓,
Let-7↑,
MMP9↓,
TumCCA↑, cycle arrest at G0/G1 phase
ROS↑,
MMP↓,
IL6↓,
NOTCH1↓,

820- GAR,    Garcinol in gastrointestinal cancer prevention: recent advances and future prospects
- Review, NA, NA
Fas↑, Fas ligand
TRAIL↑,
PARP↑,
BAX↑,
Bcl-2↓,
ROS↑, induces oxidative stress through increased ROS production
STAT3↓,
Apoptosis↑,
MMP2↓,
MMP9↓,

821- GAR,    Garcinol inhibits cell growth in hepatocellular carcinoma Hep3B cells through induction of ROS-dependent apoptosis
- in-vitro, Liver, Hep3B
ROS↑, Garcinol treatment led to the accumulation of reactive oxygen species (ROS)
CHOP↑, increased GADD153 expression
MMP↓,
Bax:Bcl2↑,
Casp8↑,
Casp3↑, 13x
Casp9↑, 7.8x
cl‑PARP↑,
DFF45↑,

822- GAR,    Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma
- vitro+vivo, HNSCC, NA
ROS↑, generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol.
STAT3↓,
cSrc↓,
JAK1↓,
JAK2↓,
NF-kB↓,
TGF-β↓,
TumCG↓,

823- GAR,    Garcinol Potentiates TRAIL-Induced Apoptosis through Modulation of Death Receptors and Antiapoptotic Proteins
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10 - in-vitro, CRC, HCT116
Casp3↑,
Casp9↑,
Casp8↑,
DR5↑,
survivin↓,
Bcl-2↓,
XIAP↓,
cFLIP↓,
BAX↑,
Cyt‑c↑,
ROS↑, ROS in MCF-7 breast cancer cells, the production of ROS was not observed in non-tumorigenic MCF-10A
GSH↓, Glutathione (GSH) also abolished the garcinol-induced induction of both DR5 and DR4 expression in a dose-dependent manner
*eff↓, Garcinol neither induced the receptors on normal cells, nor sensitized them to TRAIL

4513- GLA,    Antineoplastic Effects of Gamma Linolenic Acid on Hepatocellular Carcinoma Cell Lines
- in-vitro, Liver, HUH7
TumCP↓, GLA treatment significantly reduced cell proliferation, generated ROS, and induced apoptosis.
ROS↑, The ROS levels were increased 3.4-fold by 3 h exposure to GLA compared to the control
Apoptosis↑,
HO-1↑, antioxidant proteins to be upregulated: heme oxygenase-1 (HO-1), aldo-keto reductase 1 family C1 (AKR1C1), C4 (AKR1C4), and thioredoxin (Trx).
Trx↑,
lipid-P↑, GLA treatment has induced cell growth inhibition, ROS generation including lipid peroxidation, and HO-1 production for antioxidant protection against oxidative stress caused by GLA in Huh7 cells.
eff↓, Our study showed that the cytotoxic effect of GLA was almost blocked when the Huh7 cells were supplemented with Vitamin E in addition to GLA.
MMP↓, decreased mitochondrial membrane potential was observed in our study.
DNAdam↑, we observed DNA fragmentation in Huh7 cells under GLA expose.
selectivity↑, We had observed that no cytotoxicity of primary cultured hepatocytes from rat liver was observed in a concentration of GLA of 250 µM

4510- GLA,    Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies
- Review, NA, NA
Apoptosis↑, (GLA) induced apoptosis of tumor cells without harming normal cells.
selectivity↑,
eff↓, anti-oxidants such as vitamin E blocked the tumoricidal action of GLA.
ROS↑, GLA-treated tumor but not normal cells produced a 2-3-fold increase in free radicals and lipid peroxides.
lipid-P↑,
P53↑, enhanced the activity of p53
radioP↑, protected normal cells and tissues from the toxic actions of radiation and anti-cancer drugs, enhanced the cytotoxic action of anti-cancer drugs and reversed tumor cell drug resistance.
chemoP↑,

4506- GLA,    A basal level of γ-linolenic acid depletes Ca2+ stores and induces endoplasmic reticulum and oxidative stresses to cause death of breast cancer BT-474 cells
- in-vitro, BC, BT474
Apoptosis↓, GLA at 30 μM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death.
Ca+2↑, GLA caused an elevation in mitochondrial Ca2+ level and a decrease in mitochondrial membrane potential.
MMP↓,
p‑eIF2α↑, suggesting GLA-treated cells had increased expressions of p-eIF2α and CHOP, which suggest endoplasmic reticulum (ER) stress.
CHOP↑,
ER Stress↑,
ROS↑, GLA elicited increased production of reactive oxygen species

3526- GoldNP,  Rad,    Advances in nanoparticle-based radiotherapy for cancer treatment
- Review, Var, NA
RadioS↑, Specifically, numerous NPs, particularly gold NPs (AuNPs) and hafnium oxide (HfO2) NPs (such as NBTXR3), have been shown to substantially augment the local radiation dose
EPR↑, Functionalized NPs have the capability to preferentially accumulate in tumor tissues via the enhanced permeability and retention (EPR) effect, thereby minimizing adverse effects on healthy tissues and enhancing the specificity of therapeutic interve
ROS↑, encompass enhanced ROS generation, inhibition of hypoxia, targeted radiation, improvement of the tumor immune microenvironment, and induction of G2/M cell cycle arrest (Table 1)
TumCCA↑,

1901- GoldNP,  Rad,    The role of thioredoxin reductase in gold nanoparticle radiosensitization effects
- in-vitro, Lung, A549
MMP↓, GNP incubation led to a time-dependent mitochondria membrane depolarization, oxidative stress and to x-ray and proton radiosensitization.
ROS↑,
RadioS↑,
TrxR↓, We reported a marked inhibition of thioredoxin reductase (TrxR) in cells incubated with GNPs

1904- GoldNP,  AgNPs,    Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis
- in-vitro, Lung, H157 - in-vitro, BC, MCF-7 - in-vitro, Colon, HCT15 - in-vitro, Melanoma, A375
TrxR↓, selectively inhibit the redox‐regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin
selectivity↑, Innovative Au(I) and Ag(I) NHC‐based selenourea complexes exhibit a prominent anticancer effect by selectively targeting TrxR in human cancer cells
eff↑, [AuCl{Se(SIMes)}] being the most effective derivative, and able to almost completely abolish TrxR1 activity even at 0.5 nM
eff↝, These results, highlighting the superior activity of gold with respect to silver complexes
ROS↑, treatment of H157 cells with either Au(I) or Ag(I) complexes determined a substantial time‐dependent increase in cellular basal ROS production
MMP↓, collapse of mitochondrial membrane potential (MMP) as well as loss of mitochondrial shape and integrity (swelling), possibly leading to the induction of cell apoptosis.
Apoptosis↑,
eff↑, both Ag(I) and Au(I) selenourea complexes were found to selectively and strongly inhibit mammalian TrxR, being even much more effective than the reference metallodrug auranofin

1407- GoldNP,  Z,    The antioxidant effects of silver, gold, and zinc oxide nanoparticles on male mice in in vivo condition
- in-vivo, NA, NA
ROS↑, decreased antioxidant enzyme activities
GPx↓, significant decreases were seen in the GPX and CAT activities in mice treated with ZnONPs (P < 0.05) and in mice treated with AuNPs (P < 0.05).
Catalase↓,

845- Gra,    A Review on Annona muricata and Its Anticancer Activity
- Review, NA, NA
GlucoseCon↓, decreased glucose absorption
ATP↓,
HIF-1↓,
GLUT1↓,
GLUT4↓,
HK2↓,
LDHA↓,
ERK↓,
Akt↓,
Apoptosis↑,
NF-kB↓,
ROS↑, increases ROS production
Bax:Bcl2↑,
MMP↓,
Casp3↑,
Casp9↑,
p‑JNK↓,

844- Gra,    Annona muricata Leaf Extract Triggered Intrinsic Apoptotic Pathway to Attenuate Cancerous Features of Triple Negative Breast Cancer MDA-MB-231 Cells
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7
tumCV↓,
TumCI↓, only MDA-MB-231 line
ROS↑, GLE increased intracellular ROS accompanied by mitochondrial apoptotic pathways in MDA-MB-231 cells only

835- Gra,    Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB
- in-vitro, Lung, A549
ROS↑,
MMP↓,
BAX↑,
Bcl-2↓,
Cyt‑c↑, cytochrome c release to the cytosol
Casp9↑,
Casp3↑,
Apoptosis↑,
TumCCA↑, cell cycle arrest at G0/G1 phase

834- Gra,    Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review
- Review, NA, NA
EGFR↓,
PI3K/Akt↓,
NF-kB↓,
JAK↓,
STAT↓,
Hif1a↓, inhibition of HIF-1α, GLUT1, and GLUT4 [
GLUT1↓,
GLUT4↓,
ROS↑, generation of reactive oxygen species (ROS) via upregulatoin of enzyme systems like catalase (CAT), superoxide dismutase (SOD), and heme-oxygenase (HO-1) expression
Catalase↑,
SOD↑,
HO-1↑,

858- Gra,    Annona muricata leaves induce G₁ cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells
- in-vitro, CRC, HT-29 - in-vitro, CRC, HCT116
TumCCA↑, cell cycle arrest at G1 phase
Apoptosis↑, phosphatidylserine externalization confirming the induction of apoptosis
ROS↑,
MMP↓,
Cyt‑c↑, cytochrome c leakage
Casp↑,
BAX↑,
Bcl-2↓,
TumCMig↓,
TumCI↓,

856- Gra,    https://pubmed.ncbi.nlm.nih.gov/33048613/
- in-vitro, BC, MCF-7
TumCCA↑, inducing cell cycle arrest at G1 phase
ROS↑,
Casp↑, suggesting caspase-dependent apoptosis

848- Gra,  AgNPs,    Synthesis, Characterization and Evaluation of Antioxidant and Cytotoxic Potential of Annona muricata Root Extract-derived Biogenic Silver Nanoparticles
- in-vitro, CRC, HCT116
ROS↑,
PUMA↝,
Casp3↑,
Casp8↑,
Casp9↑,
Apoptosis↑,

1232- Gra,    Graviola: A Systematic Review on Its Anticancer Properties
- Review, NA, NA
EGFR↓,
cycD1/CCND1↓,
Bcl-2↓,
TumCCA↑, G1 cell cycle arrest, 2nd ref :G0/G1 phase cell arrest
Apoptosis↑,
ROS↑,
MMP↓,
BAX↑,
Cyt‑c↑, cytochrome c release
Hif1a↓,
NF-kB↓,
GLUT1↓,
GLUT4↓,
HK2↓,
LDHA↓,
ATP↓,

2511- H2,    Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation
- in-vivo, GBM, U87MG
TumCG↓, hydrogen inhalation could effectively suppress GBM tumor growth and prolong the survival of mice with GBM
OS↑,
CD133↓, hydrogen treatment markedly downregulated the expression of markers involved in stemness (CD133, Nestin), proliferation (ki67), and angiogenesis (CD34) and also upregulated GFAP expression, a marker of differentiation.
Ki-67↓,
angioG↓,
Diff↑, pregulated GFAP expression, a marker of differentiation
TumCMig↓, Moreover, hydrogen treatment also suppressed the migration, invasion
TumCI↓,
Dose↝, AMS-H-3 hydrogen-oxygen nebulizer machine (Asclepius Meditec Inc., Shanghai, China), which produces 67% H2 and 33% O. inhaled the mixed air for 1 h two times per day
BBB↑, hydrogen gas can easily cross the BBB.
mt-ROS↑, Intriguingly, molecular hydrogen has also been reported to act as a mitohormetic effector by mildly inducing mitochondrial superoxide production [28]. Perhaps hydrogen-induced ROS promoted the differentiation and downregulation of stemness in GSCs.

2522- H2,    A Systematic Review of Molecular Hydrogen Therapy in Cancer Management
- Review, Var, NA
chemoP↑, H2 plays a promising therapeutic role as an independent therapy as well as an adjuvant in combination therapy, resulting in an overall improvement in survivability, quality of life, blood parameters, and tumour reduction.
OS↑,
QoL↑,
TumVol↑,
ROS↑, Hydrogen, the lightest element on the earth, is an effective antioxidant that has been shown to selectively reduce harmful reactive oxygen species (ROS) in tissues
AntiTum↑, Although H2 has demonstrated significant anti-tumoural effects, the underlying mechanisms have not yet been elucidated.
other↝, Many studies have shown that H2 therapy can reduce oxidative stress. This, however, contradicts radiation therapy and chemotherapy, in which ROS are required to induce apoptosis and combat cancer.

2519- H2,    Hydrogen: an advanced and safest gas option for cancer treatment
- Review, Var, NA
antiOx↑, H2 has remarkable antioxidant and neuroprotective effects and other advantages
neuroP↓,
BBB↑, swift penetration ability to cross the blood–brain barrier
toxicity∅, H2 inhalation therapy has also been proposed in several countries as the safest mode of H2 administration
TumCP↓, A HeLa xenograft mouse model showed that H2 inhalation may increase the apoptosis rate, proliferation, and oxidative stress in HeLa cells
Apoptosis↓,
ROS↑,
Hif1a↓, H2 may affect tumor growth by regulating the expression of overexpressed subunits of transcription factors, such as hypoxia-inducible factor 1α and the nuclear factor-κB p65 subunit
NF-kB↓,
P53?, Hydrogen also increases the expression level of p53 tumor suppressor proteins.
OS↑, This study revealed that hydrogen gas inhalation 3 h/d can improve the prognosis and overall survival of stage IV colorectal carcinoma patients by decreasing the number of programmed cell death 1/CD8+ T cells
chemoP↑, H 2 anticancer therapy can minimize the debilitating side effects of conventional anticancer therapies by improving survival, quality of life, and blood parameters.

2516- H2,    Hydrogen Gas in Cancer Treatment
- Review, Var, NA
*Half-Life↓, Except the thigh muscle required a longer time to saturate, the other organs need 5–10 min to reach Cmax (maximum hydrogen concentration).
*ROS↓, regulate several key players in cancer, including ROS, and certain antioxidant enzymes
*selectivity↑, hydrogen gas could selectively scavenge the most cytotoxic ROS, •OH, as tested in an acute rat model of cerebral ischemia and reperfusion
*SOD↑, the expression of superoxide dismutase (SOD) (48), heme oxyganase-1 (HO-1) (49), as well as nuclear factor erythroid 2-related factor 2 (Nrf2) (50), increased significantly, strengthening its potential in eliminating ROS.
*HO-1↑,
*NRF2↑,
*chemoP↑, reduce the adverse effects in cancer treatment while at the same time doesn't abrogate the cytotoxicity of other therapy, such as radiotherapy and chemotherapy
*radioP↑,
ROS↑, Interestingly, due the over-produced ROS in cancer cells (38), the administration of hydrogen gas may lower the ROS level at the beginning, but it provokes much more ROS production as a result of compensation effect, leading to the killing of cancer
*Inflam↓, By regulating inflammation, hydrogen gas can prevent tumor formation, progression, as well as reduce the side effects caused by chemotherapy/radiotherapy
eff↑, More importantly, hydrogen-rich water didn't impair the overall anti-tumor effects of gefitinib both in vitro and in vivo, while in contrast, it antagonized the weight loss induced by gefitinib and naphthalene, and enhanced the overall survival rate
*TNF-α↓, hydrogen-rich saline treatment exerted its protective effects via inhibiting the inflammatory TNF-α/IL-6 pathway, increasing the cleaved C8 expression and Bcl-2/Bax ratio, and attenuating cell apoptosis in both heart and liver tissue
*IL6↓,
*cl‑Casp8↑,
*Bax:Bcl2↓,
*Apoptosis↓,
*cardioP↑,
*hepatoP↑,
*RenoP↑, Hydrogen-rich water also showed renal protective effect against cisplatin-induced nephrotoxicity in rats.
*chemoP↑, nother study showed that both inhaling hydrogen gas (1% hydrogen in air) and drinking hydrogen-rich water (0.8 mM hydrogen in water) could reverse the mortality, and body-weight loss caused by cisplatin via its anti-oxidant property
eff↝, More importantly, hydrogen didn't impair the anti-tumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice
chemoP↑, hydrogen-rich water combinational treatment group exhibited no differences in liver function during the treatment, probably due to its antioxidant activity, indicating it a promising protective agent to alleviate the mFOLFOX6-related liver injury
radioP↑, consumption of hydrogen-rich water reduced the radiation-induced oxidative stress while at the same time didn't compromise anti-tumor effect of radiotherapy
eff↑, Hydrogen Gas Acts Synergistically With Thermal Therapy
TumCG↓, in vivo study showed that under hydrogen gas treatment, tumor growth was significantly inhibited, as well as the expression of Ki-67, VEGF and SMC3
Ki-67↓,
VEGF↓,
selectivity↑, H2-silica could concentration-dependently inhibit the cell viability of human esophageal squamous cell carcinoma (KYSE-70) cells, while it need higher dose to suppress normal human esophageal epithelial cells (HEEpiCs), indicating its selective profi

2509- H2,    Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway
- in-vitro, Endo, AN3CA - in-vivo, Endo, NA
selectivity↑, Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis.
mt-ROS↑, We therefore concluded that molecular hydrogen activated ROS and mtROS generation in endometrial cancer cells.
ROS↑,
TumW↓,
GSDMD↑, ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis
Pyro↑,
Dose↝, Hydrogenated water was produced by H2 dissolved in water saturantly under 0.4 MPa pressure for 6 h with a concentration of 1.0 ppm produced by hydrogen water apparatus
eff↓, In contrast, NAC decreased ROS levels in hydrogen-treated endometrial cancer cells
TumVol↓, We demonstrated that drinking hydrogen-rich water reduced the volume of endometrial tumors in a xenograft mouse model.

2508- H2,    Molecular hydrogen is a promising therapeutic agent for pulmonary disease
- Review, Var, NA - Review, Sepsis, NA
*ROS↓, inhalation of 2% molecular hydrogen results in the selective scavenging of hydroxyl free radical (·OH) and peroxynitrite anion (ONOO-), significantly improving oxidative stress injury caused by cerebral ischemia/reperfusion (I/R)
eff↝, Molecular hydrogen can exert biological effects on almost all organs, including the brain, heart, lung, liver, and pancreas.
*Inflam↓, including roles in the regulation of oxidative stress and anti-inflammatory and anti-apoptotic effects
*NRF2↑, By stimulating nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the basal and induces expression of many antioxidant enzymes
*HO-1↑, hydrogen can increase the expression of heme oxygenase-1 (HO-1)
*SOD↑, increases the activity of the antioxidant enzymes SOD, CAT, and myeloperoxidase (MPO)
*Catalase↑,
*MPO↑,
*ASK1↓, Molecular hydrogen can block the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway
*NADPH↓, thereby inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and decreasing free radical production
*Sepsis↓, Emerging evidence suggests that hydrogen can prevent sepsis, providing a novel treatment strategy for sepsis-induced ALI.
*HMGB1↓, Hydrogen attenuates tissue injury and dysfunction by inhibiting HMGB-1.
ROS↑, it has been shown that hydrogen pretreatment enhances ROS and the expression of pyroptosis-related proteins, stimulates NLRP3 inflammasome/gasdermin D (GSDMD) activation, and inhibits endometrial cancer
NLRP3↑,
GSDMD↑,
chemoP↑, Hydrogen can alleviate the side effects of conventional anti-cancer therapies, such as chemotherapy and radiotherapy, and improve quality of life
eff↑, It significantly improves the physical status of patients, reduces fatigue, insomnia, anorexia, and pain, and decreases elevated tumor markers.

2528- H2,    Local generation of hydrogen for enhanced photothermal therapy
- in-vitro, Var, NA
eff↑, release of bio-reductive hydrogen as well as generation of heat. This hydrogenothermal approach has presented a cancer-selective strategy for synergistic cancer treatment
ROS↓, PdH0.2 nanocrystals immediately caused remarkable decrease of the intracellular ROS level in both cancer and normal cell models in a concentration-dependent way
selectivity↑, Cancer cells were more sensitive to PdH0.2 nanocrystals than normal cells, possibly owing to the higher initial ROS level in cancer cells.
ROS↑, Owing to the relatively higher ROS level in cancer cells, the initial ROS loss in cancer cells was higher and the subsequent ROS rebound was also intenser/higher than that in normal cells.
other↝, The highly overexpressed ROS in cancer cells was hardly eliminated to the normal level, leading to the oxidative stress remarkably . see figure 3
ROS↑, The damage to the mitochondria of cancer cells was possibly attributed to the increase of intracellular ROS level (Fig. 3c).

1628- HCA,  ALA,    Addition of Hydroxy Citrate improves effect of ALA
- Review, Var, NA
ACLY↓, Hydroxycitrate is a known inhibitor of ATP citrate lyase ( also called ATP-citric synthase
other↓, Lipoic Acid Increases PDC (pyruvate dehydrogenase complex)
ROS↑, oxidative onslaught, making the cancer cell susceptible to oxidative therapies such as alpha lipoic acid.
eff↑, the addition of hydroxycitrate increases the effect of ALA.
PDKs↓, An inhibitory effect of lipoic acid on PDKs would result in… increased PDC pyruvate dehydrogenase complex (PDC) activity.

602- HCAs,    Prooxidant activity of hydroxycinnamic acids on DNA damage in the presence of Cu(II) ions: mechanism and structure-activity relationship
- Analysis, NA, NA
ROS↑,
DNAdam↑,

1638- HCAs,    Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications
- Review, Nor, NA
*BioAv↓, Hydroxycinnamic acids are sensitive compounds to the environment in the gastrointestinal track. They may interact with the components in the digestion system or can be affected by pH differences
Inflam↓, Hydroxycinnamic acids (p-coumaric, CAPE, chlorogenic, caffeic, and ferulic acids) exhibit anti-inflammatory activity both in vitro and in vivo
COX2↓, caffeic acid targets COX-2 and its product prostaglan-din E2
TumCCA↑, These phenolics can cause cell cycle arrest at various phases, including G1, S, S-G2, and G2.
ChemoSen↑, sensitize cancer cells to chemotherapy and radiation therapy.
RadioS↑,
selectivity↑, HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to normal cells.
ROS↑, 100uM(CA) and 10mM(metforin) cervical Cancer, also 100uM@24hr in A549cells
DNAdam↑,
antiOx↑, Hydroxy-cinnamic acids have an antioxidant effect by suppressing reactive oxygen/nitrogen species (ROS/RNS) and superoxide dismutases (SODs) production
SOD↑,
Catalase↑,
GPx↑,
GSH↑,
NRF2↑,
NF-kB↓, In the promotion stage, these compounds possess anti-inflammatory effects, particularly by inhibit-ing nuclear factor kappa B (NF-kB)
Cyc↓,
CDK1↑, CDKs
P21↑,
p27↑,
P53↑,
VEGF↓,
MAPK↓,

1641- HCAs,    Lung cancer induced by Benzo(A)Pyrene: ChemoProtective effect of sinapic acid in swiss albino mice
- in-vitro, Lung, A549 - in-vivo, Lung, NA
AntiCan↑, administration of sinapic acid ameliorates the exposure of B[a]P mediated lung cancer in swiss albino mice
Igs↓, administration of sinapic acid ameliorates the exposure of B[a]P mediated lung cancer in swiss albino mice by a decline in IgG and IgM level
lipid-P↓,
ROS↑, elevation of ROS production and caspase activity (caspase-3 and caspase-9)
Casp3↑,
Casp9↑,
ChemoSideEff↓, effective chemo preventative agent against lung carcinogenesis.
Dose∅, The IC50 value of sinapic acid was 50 µM. Hence, 50 and 75 µM dosage was selected for the additional assessments of anti-cancer efficacy of sinapic acid in the A459 cells

1643- HCAs,    Mechanisms involved in the anticancer effects of sinapic acid
- Review, Var, NA
*BioAv↓, Studies have shown that SA is poorly soluble in water, but soluble in carbitol and freely soluble in DMSO
*toxicity↓, SA is found to be generally non-toxic
Dose∅, oral administration of SA up to 80 mg/kg body weight reduced the number of aberrant crypt foci up to 34.55%
ROS⇅, Other than its potent antioxidant function, SA also possesses pro-oxidant effect that has been identified to affect the redox state of tumor cells
ROS↑, SA at higher concentrations acts as a potent pro-oxidant agent, resulting in increased generation of free radicals. (50 and 75 μM) increased ROS accumulation
Igs↑, SA administration markedly improved the levels of IgG and IgA in
TumCCA↑, SA induced G2/M phase cell cycle arrest
TumAuto↑, autophagy inducing effect of SA has been reported by Zhao et al. (2021) in HepG2 and SMMC-7721 cells
eff↑, Beclin, Atg 5 increased and expression of p62 decreased in SA along with cisplatin treated HepG2 and SMMC-7721 cells
angioG↓, SA has been demonstrated to inhibit angiogenesis, cell invasion and metastasis in cancer cells
TumCI↓,
TumMeta↓,
EMT↓, SA (10 mM) treated cells showed decreased protein expression of EMT related proteins such as vimentin, MMP-9, MMP-2, and Snail and increased expression of E-cadherin in PANC-1 and SW1990 cell lines.
Vim↓,
MMP9↓,
MMP2↓,
Snail↓,
E-cadherin↑,
p‑Akt↓, SA treatment downregulated phosphorylated AKT and Gsk-3β in PANC-1 and SW1990 prostate cancer cell lines.
GSK‐3β↓,
TumCP↓, SA can inhibit cell proliferation in prostate cancer
ChemoSen↑, SA acts in collaboration with other chemotherapeutic agents to improve treatment sensitivity

2079- HNK,    Honokiol Microemulsion Causes Stage-Dependent Toxicity Via Dual Roles in Oxidation-Reduction and Apoptosis through FoxO Signaling Pathway
- in-vitro, Nor, PC12
*toxicity↝, Our previous studies have already demonstrated that a high dose of the honokiol microemulsion (0.6 μg/mL) induces developmental toxicity in rats and zebrafish by inducing oxidative stress.
*ROS↓, In zebrafish, low doses of honokiol microemulsion (0.15, 0.21 μg/mL) significantly decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the mRNA expression of bcl-2.
*ROS↑, In contrast, high dose (0.6 μg/mL) increased the levels of ROS and MDA, decreased activities and mRNA expression of superoxide dismutase (SOD) and catalase (CAT), and increased mRNA expression of bax, c-jnk, p53 and bim.
*Dose⇅, In rat pheochromocytoma cells (PC12 cells), low doses of the honokiol microemulsion (1, 5, 10 µM) exerted a protective effect against H2O2-induced oxidative damage while high doses (≥20 µM) induced oxidative stress, which further confirms the dual ef
*BioAv↑, highly lipophilic property of honokiol allows it to readily cross the blood-brain barrier and blood-cerebrospinal fluid barrier with high bioavailability.
*BioAv↓, However, this property also limits its clinical usage due to low oral bioavailability and difficulty in intravenous administration.
*ROS⇅, levels of ROS and MDA were significantly decreased at a concentration of 0.21 μg/mL and increased at a concentration of 0.6 μg/mL in both 24 and 96 hpf embryos
*SOD↓, The activity of SOD showed only a slight reduction at 20 µM but was significantly reduced at 40 and 80 μM
*toxicity↑, According to the human rat equivalent dosage conversion, the potential toxic dose in humans may be 320 µg/kg/d

2072- HNK,    Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells
- in-vitro, Thyroid, NA
ROS↑, honokiol induced ROS activation
eff↓, and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC).

2073- HNK,    Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo
- in-vitro, OS, U2OS - in-vivo, NA, NA
TumCD↑, honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells
TumAuto↑, death induced by honokiol were primarily autophagy and apoptosis.
Apoptosis↑,
TumCCA↑, honokiol induced G0/G1 phase arrest,
GRP78/BiP↑, elevated the levels of glucose-regulated protein (GRP)−78, an endoplasmic reticular stress (ERS)-associated protein
ROS↑, increased the production of intracellular reactive oxygen species (ROS)
eff↓, In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest.
p‑ERK↑, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2.
selectivity↑, human fibroblasts showed strong resistance to HNK, the IC50 values for which were 118.9 and 71.5 μM
Ca+2↑, HNK increased intracellular Ca2+ in both HOS and U2OS cells
MMP↓, mitochondrial membrane potential (MMP) sharply decreased following HNK treatment
Casp3↑, HNK markedly activated caspase-3, caspase-9
Casp9↑,
cl‑PARP↑, led to PARP cleavage
Bcl-2↓, expression of Bcl-2, Bcl-xl, and survivin was found to be decreased
Bcl-xL↓,
survivin↓,
LC3B-II↑, HNK increased the level of LC3B-II and Atg5 in HOS and U2OS cells.
ATG5↑,
TumVol↓, HNK at doses of 40 mg/kg resulted in significant decrease in tumor volume and weight, after 7 days of drug administration
TumW↓,
ER Stress↑, ER stress can trigger ROS production through release of calcium

2081- HNK,    Honokiol induces ferroptosis in colon cancer cells by regulating GPX4 activity
- in-vitro, Colon, RKO - in-vitro, Colon, HCT116 - in-vitro, Colon, SW48 - in-vitro, Colon, HT-29 - in-vitro, Colon, LS174T - in-vitro, Colon, HCT8 - in-vitro, Colon, SW480 - in-vivo, NA, NA
tumCV↓, HNK reduced the viability of CC cell lines by increasing ROS and Fe2+ levels
ROS↑, observations suggest that ROS production is a determining factor of HNK cytotoxicity. exact mechanism underlying the pro-oxidant activity of HNK is unclear in CC
Iron↑,
GPx4↓, HNK decreased the activity of Glutathione Peroxidase 4 (GPX4)
mtDam↑, intracellular mitochondria decreased, the membrane density increased, the mitochondrial ridge shrank or disappeared, and the bilayer membrane density increased.
Ferroptosis↑, results suggested that GPX4 may be the key molecule that regulates HNK-induced ferroptosis in CC cells
TumVol↓, tumor volumes and weights were significantly lower in the Lv-NC group than in the Lv-GPX4 group
TumW↓,

1004- HNK,  RAPA,    Honokiol downregulates PD-L1 expression and enhances antitumor effects of mTOR inhibitors in renal cancer cells
- in-vitro, RCC, NA
Apoptosis↑, HNK is more potent than RAPA, both HNK and RAPA inhibited the proliferation of renal cancer cells and promoted apoptosis
TumCCA↑, G1 phase cell cycle arrest
ROS↑, HNK and RAPA significantly increased ROS generation in these cells and it was much higher in the HNK and RAPA combinatorial treatment.
PD-L1↓, HNK, but not RAPA, significantly decreased the expression of PD-L1
IFN-γ↓, HNK can also downmodulate IFN-γ-induced PD-L1expression

2879- HNK,    Honokiol Inhibits Lung Tumorigenesis through Inhibition of Mitochondrial Function
- in-vitro, Lung, H226 - in-vivo, NA, NA
tumCV↓, honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol treated group (p= 0.01) while protecting normal bronchial histology (present in 20.5%
selectivity↑,
TumCP↓, In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1/S cell cycle checkpoint, while also leading to increased apoptosis.
TumCCA↑,
Apoptosis↑,
mt-ROS↑, interfering with mitochondrial respiration is a novel mechanism by which honokiol increased generation of reactive oxygen species (ROS) in the mitochondria, : mitochondrial ROS generation
Casp3↑, cells treated with honokiol showed a significant increase in caspase 3/7 activity, which occurred in dose- and time-dependent manners
Casp7↑,
OCR↓, Honokiol caused a fast and concentration-dependent decrease in basal oxygen consumption rate (OCR) in both cell lines
Cyt‑c↑, cytochrome c release was increased in honokil treated mouse lung SCC tissue
ATP↓, found a dramatic decrease in cellular ATP content
mitResp↓, Honokiol inhibits mitochondrial respiration and decreases ATP levels in H226 and H520 cells, which may elevate AMP and the intracellular AMP/ATP ratio, leading to activation of the AMPK
AMP↑,
AMPK↑,

2883- HNK,    Honokiol targets mitochondria to halt cancer progression and metastasis
- Review, Var, NA
ChemoSen↑, Combination of HNK with many traditional chemotherapeutic drugs as well as radiation sensitizes cancer cells to apoptotic death
BBB↓, HNK is also capable of crossing the BBB
Ca+2↑, HNK promotes human glioblastoma cancer cell apoptosis via regulation of Ca(2+) channels
Cyt‑c↑, release of mitochondrial cytochrome c and activation of caspase-3
Casp3↑,
chemoPv↑, potent chemopreventive agent against lung SCC development in a carcinogen-induced lung SCC murine model
OCR↓, HNK treatment results in a decreased oxygen consumption rate (OCR) in whole intact cells, rapidly, and persistently inhibiting mitochondrial respiration, which leads to the induction of apoptosis
mitResp↓,
Apoptosis↑,
RadioS↑, Honokiol as a chemo- and radiosensitizer
NF-kB↓, HNK as an anticancer drug is its potential to inhibit multiple important survival pathways, such as NF-B and Akt
Akt↓,
TNF-α↓, by inhibiting TNF-induced nerve growth factor IB expression in breast cancer cells
PGE2↓, reduced prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) secretion levels
VEGF↓,
NO↝, HNK inhibits cancer cell migration by targeting nitric oxide and cyclooxygenase-2 or Ras GTPase-activating-like protein (IQGAP1) [
COX2↓,
RAS↓,
EMT↓, HNK can reverse the epithelial-mesenchymal-transition (EMT) process, which is a key step during embryogenesis, cancer invasion, and metastasis,
Snail↓, HNK reduced the expression levels of Snail, N-cadherin and -catenin, which are mesenchymal markers, but increased E-cadherin,
N-cadherin↓,
β-catenin/ZEB1↓,
E-cadherin↑,
ER Stress↑, induction of ER stress
p‑STAT3↓, HNK inhibited STAT3 phosphorylation
EGFR↓, inhibiting EGFR phosphorylation and its downstream signaling pathways such as the mTOR signaling pathway
mTOR↓,
mt-ROS↑, We demonstrated that HNK treatment suppresses mitochondrial respiration and increases generation of ROS in the mitochondria, leading to the induction of apoptosis in lung cancer cells
PI3K↓, inhibition of PI3K/Akt/ mTOR, EMT, and Wnt signaling pathways.
Wnt↓,

2865- HNK,    Liposomal Honokiol induces ROS-mediated apoptosis via regulation of ERK/p38-MAPK signaling and autophagic inhibition in human medulloblastoma
- in-vitro, MB, DAOY - vitro+vivo, NA, NA
BioAv↓, poor water solubility of HNK results in its low bioavailability, thus limiting its wide use in clinical cancer treatments
BioAv↓, Liposomes can overcome this limitation, and liposomal HNK (Lip-HNK) has promising clinical applications in this aspect
TumCP↓, increased Lip-HNK concentration could inhibit the proliferation of DAOY and D283 cells, without exerting effects on the growth of non-tumor cells
selectivity↑,
P53↑, P53 and P21 proteins (inhibiting cell cycle progression) was increased
P21↑,
CDK4↓, Lip-HNK also downregulated the expression of CDK4 and cyclin D1
cycD1/CCND1↓,
mtDam↑, Lip-HNK caused apoptosis and death, which, in turn, led to the failure of mitochondrial membrane function
ROS↑, Lip-HNK induced ROS production, which, as hypothesized, was blocked by the ROS scavenger NAC
eff↓, Lip-HNK induced ROS production, which, as hypothesized, was blocked by the ROS scavenger NAC
Casp3↑, caspase-3 sectioned and the Bax protein level increased by Lip-HNK
BAX↑,
LC3II↑, LC3BII protein in the Lip-HNK-treated group was noticeably elevated
Beclin-1↑, Beclin-1 (BECN), Atg7 proteins, and LC3BII were dramatically upregulated in the Lip-HNK-treated cells
ATG7↑,
p62↑, Lip-HNK treatment remarkably increased p62 expression, which was dose-dependent
eff↑, Lip-HNK treatment (20 mg/kg) drastically inhibited tumor growth. The combined treatment of Lip-HNK, Chloroquine , and Carboplatin showed more superior antitumor effects
ChemoSen↑, Lip-HNK alone or combined with chemotherapy (Carboplatin or Etoposide) causes significant regression of orthotopic xenografts
*toxicity↓, We also found that Lip-HNK did not damage the liver and kidney

2864- HNK,    Honokiol: A Review of Its Anticancer Potential and Mechanisms
- Review, Var, NA
TumCCA↑, induction of G0/G1 and G2/M cell cycle arrest
CDK2↓, (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins),
EMT↓, epithelial–mesenchymal transition inhibition via the downregulation of mesenchymal markers
MMPs↓, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases
AMPK↑, (activation of 5′ AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling)
TumCI↓, inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)
TumCMig↓,
TumMeta↓,
VEGFR2↓,
*antiOx↑, diverse biological activities, including anti-arrhythmic, anti-inflammatory, anti-oxidative, anti-depressant, anti-thrombocytic, and anxiolytic activities
*Inflam↓,
*BBB↑, Due to its ability to cross the blood–brain barrier
*neuroP↑, beneficial towards neuronal protection through various mechanism, such as the preservation of Na+/K+ ATPase, phosphorylation of pro-survival factors, preservation of mitochondria, prevention of glucose, reactive oxgen species (ROS), and inflammatory
*ROS↓,
Dose↝, Generally, the concentrations used for the in vitro studies are between 0–150 μM
selectivity↑, Interestingly, honokiol has been shown to exhibit minimal cytotoxicity against on normal cell lines, including human fibroblast FB-1, FB-2, Hs68, and NIH-3T3 cells
Casp3↑, ↑ Caspase-3 & caspase-9
Casp9↑,
NOTCH1↓, Inhibition of Notch signalling: ↓ Notch1 & Jagged-1;
cycD1/CCND1↓, ↓ cyclin D1 & c-Myc;
cMyc↓,
P21?, ↑ p21WAF1 protein
DR5↑, ↑ DR5 & cleaved PARP
cl‑PARP↑,
P53↑, ↑ phosphorylated p53 & p53
Mcl-1↑, ↓ Mcl-1 protein
p65↓, ↓ p65; ↓ NF-κB
NF-kB↓,
ROS↑, ↑ JNK activation ,Increase ROS activity:
JNK↑,
NRF2↑, ↑ Nrf2 & c-Jun protein activation
cJun↑,
EF-1α↓, ↓ EFGR; ↓ MAPK/PI3K pathway activity
MAPK↓,
PI3K↓,
mTORC1↓, ↓ mTORC1 function; ↑ LKB1 & cytosolic localisation
CSCs↓, Inhibit stem-like characteristics: ↓ Oct4, Nanog & Sox4 protein; ↓ STAT3;
OCT4↓,
Nanog↓,
SOX4↓,
STAT3↓,
CDK4↓, ↓ Cdk2, Cdk4 & p-pRbSer780;
p‑RB1↓,
PGE2↓, ↓ PGE2 production ↓ COX-2 ↑ β-catenin
COX2↓,
β-catenin/ZEB1↑,
IKKα↓, ↓ IKKα
HDAC↓, ↓ class I HDAC proteins; ↓ HDAC activity;
HATs↑, ↑ histone acetyltransferase (HAT) activity; ↑ histone H3 & H4
H3↑,
H4↑,
LC3II↑, ↑ LC3-II
c-Raf↓, ↓ c-RAF
SIRT3↑, ↑ Sirt3 mRNA & protein; ↓ Hif-1α protein
Hif1a↓,
ER Stress↑, ↑ ER stress signalling pathway activation; ↑ GRP78,
GRP78/BiP↑,
cl‑CHOP↑, ↑ cleaved caspase-9 & CHOP;
MMP↓, mitochondrial depolarization
PCNA↓, ↓ cyclin B1, cyclin D1, cyclin D2 & PCNA;
Zeb1↓, ↓ ZEB2 Inhibit
NOTCH3↓, ↓ Notch3/Hes1 pathway
CD133↓, ↓ CD133 & Nestin protein
Nestin↓,
ATG5↑, ↑ Atg7 protein activation; ↑ Atg5;
ATG7↑,
survivin↓, ↓ Mcl-1 & survivin protein
ChemoSen↑, honokiol potentiated the apoptotic effect of both doxorubicin and paclitaxel against human liver cancer HepG2 cells.
SOX2↓, Honokiol was shown to downregulate the expression of Oct4, Nanog, and Sox2 which were known to be expressed in osteosarcoma, breast carcinoma and germ cell tumours
OS↑, Lipo-HNK was also shown to prolong survival and induce intra-tumoral apoptosis in vivo.
P-gp↓, Honokiol was shown to downregulate the expression of P-gp at mRNA and protein levels in MCF-7/ADR, a human breast MDR cancer cell line
Half-Life↓, For i.v. administration, it has been found that there was a rapid rate of distribution followed by a slower rate of elimination (elimination half-life t1/2 = 49.22 min and 56.2 min for 5 mg or 10 mg of honokiol, respectively
Half-Life↝, male and female dogs was assessed. The elimination half-life (t1/2 in hours) was found to be 20.13 (female), 9.27 (female), 7.06 (male), 4.70 (male), and 1.89 (male) after administration of doses of 8.8, 19.8, 3.9, 44.4, and 66.7 mg/kg, respectively.
eff↑, Apart from that, epigallocatechin-3-gallate functionalized chitin loaded with honokiol nanoparticles (CE-HK NP), developed by Tang et al. [224], inhibit HepG2
BioAv↓, extensive biotransformation of honokiol may contribute to its low bioavailability.

2863- HNK,    Honokiol induces paraptosis-like cell death through mitochondrial ROS-dependent endoplasmic reticulum stress in hepatocellular carcinoma Hep3B cells
- in-vitro, Liver, Hep3B
ER Stress↑, Honokiol also enhanced ER stress, increased cellular calcium ion (Ca2+) levels, and caused mitochondrial dysfunction
Ca+2↑,
mtDam↑,
PTEN↑, Honokiol upregulated the expression of mitophagy regulators such as PTEN-induced kinase 1 and Parkin in the mitochondria
PARK2↑,
Alix/AIP‑1↓, whereas the expression of apoptosis-linked gene 2-interacting protein X (Alix), involved in suppressing paraptosis, was downregulated.
ROS↑, honokiol-induced cytotoxicity was accompanied by excessive generation of intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS).
mt-ROS↑,

2889- HNK,  doxoR,    Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice
- in-vivo, Nor, NA
*SIRT3↑, We have recently identified honokiol (HKL) as an activator of SIRT3
chemoP↑, HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin.
*cardioP↑, mice that received doxorubicin plus HKL showed preserved cardiac function, compared to doxorubicin and vehicle treated mice
mtDam↑, HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes
ROS↑,
*ROS↓, We found that cells treated with HKL suppressed doxorubicin-induced ROS levels
*MMP↑, HKL preserves mitochondrial membrane potential.

2891- HNK,    Honokiol, an Active Compound of Magnolia Plant, Inhibits Growth, and Progression of Cancers of Different Organs
- Review, Var, NA
AntiCan↑, honokiol possesses anti-carcinogenic, anti-inflammatory, anti-oxidative, anti-angiogenic as well as inhibitory effect on malignant transformation of papillomas to carcinomas in vitro and in vivo animal models without any appreciable toxicity.
Inflam↓,
antiOx↑,
selectivity↑,
*toxicity↓,
cycD1/CCND1↓, honokiol resulted in inhibition of UVB-induced expression levels of cyclins (cyclins D1, D2, and E) and CDKs in skin tumors
cycE/CCNE↓,
CDK2↓,
CDK4↓,
TumMeta↓, Honokiol Inhibits Metastatic Potential of Melanoma Cells
NADPH↓, Honokiol not only reduces the NADPH oxidase activity
MMP2↓, honokiol treatment reduces the expression of MMP-2 and MMP-9
MMP9↓,
p‑mTOR↓, honokiol caused significant downregulation of mTOR phosphorylation
EGFR↓, honokiol decreases the expression levels of total EGFR
EMT↓, honokiol effectively inhibits EMT in breast cancer cells
SIRT1↑, onokiol increases the expressions of SIRT1 and SIRT3,
SIRT3↑,
EZH2↓, depletion of EZH2 by honokiol treatment inhibited cell proliferation
Snail↓, significantly down regulates Snail, vimentin, N-cadherin expression, and upregulates cytokeratin-18 and E-cadherin expression
Vim↓,
N-cadherin↓,
E-cadherin↑,
COX2↓, honokiol as an inhibitor of COX-2 expression
NF-kB↓, inhibited transcriptional activity of NF-jB,
*ROS↓, Inhibition of UVR-induced inflammatory mediators as well as ROS by honokiol treatment contributes to the prevention of UVR-induced skin tumor development
Ca+2↑, excessive influx of cytosolic calcium ion into the mitochondria triggers dysfunction of the mitochon- drial membrane permeabilization with mitochondrial ROS induction
ROS↑,

2895- HNK,    Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity
- in-vitro, Lung, PC9
eff↑, Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation
TumCP↓,
mt-ROS↑, inhibiting mitochondrial complex ǀ, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3
Prx3↑,
mt-STAT3↓,
*toxicity∅, Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers.
selectivity↑,
ChemoSen↑, combination with standard chemotherapeutics.

5054- HPT,    Induction of Oxidative Stress by Hyperthermia and Enhancement of Hyperthermia-Induced Apoptosis by Oxidative Stress Modification
- Review, Var, NA
eff↓, However, clinical results by HT alone have not always been satisfactory
ROS↑, One of these HT-induced alterations, oxidative stress, has been attributed to the increased production of reactive oxygen spaces (ROS), and is known to play an important role as an intracellular mediator of HT-induced cell death, including apoptosis.
Apoptosis↑,

5053- HPT,  Rad,  Chemo,    Association of elevated reactive oxygen species and hyperthermia induced radiosensitivity in cancer stem-like cells
- in-vitro, Var, NA
CSCs↓, SCs were found to be more susceptible to radiation when combined with HT treatment
TumCP↓, Treated cells showed significantly reduced self-renewal, cell survival and proliferation in vitro, as well as significant reduced tumor formation in vivo.
ROS↑, Further study demonstrated that the radiosensitization effect was associated with increased intracellular reactive oxygen species (ROS) level in CSCs, confirmed by modifying redox status in CSCs bidirectionally.
RadioS↑, new strategy for improving CSCs radiosensitivity

5052- HPT,    Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells
- in-vitro, OS, U2OS
Apoptosis↑, Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells.
ROS↑, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells.
Casp3↑,
mtDam↑, Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax.
Cyt‑c↑,
Bcl-2↓,
Bcl-xL↓,
Bak↑,
BAX↓,
ER Stress↑, Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity.
Ca+2↝,
cal2↑,

5051- HPT,  doxoR,    Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells
- in-vitro, Melanoma, A375
tumCV↓, Combined treatment significantly decreased cell viability, but not in all tested conditions, suggesting that the effect depends on the drug concentration and heat treatment duration.
TumCCA↑, Combined treatment also mediated a G2/M phase arrest in both cell lines, as well as increasing ROS levels.
ROS↑,
eff↑, These findings demonstrate that hyperthermia enhances DOX effect through cell cycle arrest, oxidative stress, and apoptotic cell death.

5049- HPT,    Nanoparticle-based hyperthermia distinctly impacts production of ROS, expression of Ki-67, TOP2A, and TPX2, and induction of apoptosis in pancreatic cancer
- vitro+vivo, PC, Panc02 - vitro+vivo, PC, Bxpc-3
tumCV↓, The thermal effects were confirmed by the following observations: 1) decreased number of vital cells,
proCasp↑, 2) altered expression of pro-caspases, and
ROS↑, 3) production of reactive oxygen species, and
Ki-67↓, 4) altered mRNA expression of Ki-67, TOP2A, and TPX2.
TOP2↓, mRNA expression of the proliferation markers Ki-67, TOP2A, and TPX2 revealed a marked reduction in their expression after PANC-1 cells were treated with MH
TumVol↓, The MH treatment of tumor xenografts significantly (P≤0.05) reduced tumor volumes.

5050- HPT,    Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review
- Review, Nor, NA
*ROS↑, Heat stress was suggested to be an environmental factor responsible for stimulating ROS production because of similarities in responses observed following heat stress compared with that occurring following exposure to oxidative stress.
*SOD1↓, Heat stress was also shown to decrease superoxide dismutase 1 (SOD-1) mRNA levels, cytoplasmic SOD protein and enzyme activity, leading to the increase of ROS generation
*GSH↓, Furthermore, several studies demonstrated that heat stress results in a dramatic decrease in glutathione (GSH) levels.
other↑, Nowadays, a variety of diseases and degenerative processes such as cancer, Alzheimer’s and autoimmune diseases are mediated by oxidative stress.
HIF-1↑, heat stress activates hypoxia-inducible factor 1 (HIF-1) through ERK-NADPH oxidase-mediated ROS production, and this enhances tumour oxygenation by up-regulating HIF-1 target gene
ROS↑,

886- HPT,    Impact of hyper- and hypothermia on cellular and whole-body physiology
- Analysis, NA, NA
MMP↓,
OXPHOS↓, impaired oxidative phosphorylation
ATP↓,
ROS↑, increase reactive oxygen species (ROS) production within mitochondria,
Apoptosis↑,
Cyt‑c↑, releasing cytochrome c into the cytoplasm

4637- HT,    Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells
- in-vitro, Nor, RWPE-1 - in-vitro, Pca, LNCaP - in-vitro, Pca, 22Rv1 - in-vitro, Pca, PC3
selectivity↑, Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells.
TumCMig↓, HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3
p‑Akt↓, Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3.
ROS↑, both HT and its semisynthetic derivatives also exert a prooxidant effect
CSCs↓, previous studies suggest that HT was able to reduce cancer stem cell markers in other types of cancer, such as CD44 in breast cancer cells
CD44↓,
TumCP↓, our data demonstrate that HT, HT-Ac, and HT-Et decrease the proliferation of 22Rv1 and the proliferation and migration rate of PC-3 PCa cells in a concentration-dependent manner.

4638- HT,    Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation
- in-vitro, CRC, DLD1 - NA, NA, 1-
selectivity↑, HT exhibits preferential anti-proliferative effects on human colon cancer cells (DLD1 cells) but not on normal colon epithelial 1807 cells.
ROS↑, HT causes oxidative stress, activates the phosphoinositide 3-kinase/Akt pathway, phosphorylates FOXO3a and then downregulates FOXO3a's target genes.
Akt↑,
FOXO3↓,
Apoptosis↑, HT induces apoptotic cell death and mitochondrial dysfunction by generating ROS in colon cancer cells.

4639- HT,    Hydroxytyrosol Induces Apoptosis, Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, C4-2B
TumCP↓, Treatment of LNCaP and C4–2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation
selectivity↑, This was in contrast to HT’s ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer cells-specific effect.
TumCCA↑, HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4, and induction of inhibitory p21/p27. HT also induced apoptosis
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
P21↑,
p27↑,
Apoptosis↑, HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage and BAX/Bcl-2 ratio.
Casp↑,
cl‑PARP↑,
Bax:Bcl2↑, HT inhibits the expression of pro-survival Bcl-2, with concomitant induction of apoptosis-inducing BAX, this tilts the balance in favor of BAX in the cancer cells, marked by increased BAX/Bcl-2 ratio
p‑Akt↓, It inhibited the phosphorylation of Akt / STAT3, and induced cytoplasmic retention of NF-κB,
p‑STAT3↓,
NF-kB↓, transcriptional activity of NF-κB was considerably decreased, dose-dependently, by HT in both the cell lines
AR↓, HT downregulates AR expression
ROS↑, In colon cancer cells, HT has been shown to generate ROS leading to apoptotic cell death and mitochondrial dysfunction. Even in prostate cancer PC3 cells, there is evidence for ROS generation by HT
*BioAv↓, Despite the promising anticancer activity of HT, there have been concerns about its poor bioavailability owing to its extensive metabolism
*toxicity∅, HT is a ‘safe’ compound and can be administered at higher doses without signs of any genotoxic or mutagenic effects

4641- HT,    Hydroxytyrosol induced ferroptosis through Nrf2 signaling pathway in colorectal cancer cells
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW48
Ferroptosis↑, HT-induced ferroptosis elevates iron levels, lipid peroxidation (LPO) and reactive oxygen species (ROS), while decreasing glutathione (GSH) and mitochondrial membrane potential.
Iron↑,
lipid-P↑, increase in soluble iron pools, which in turn promoted lipid peroxidation
ROS↑,
GSH↓,
MMP↓,
GPx4↓, HT reduced the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) proteins while increasing the expression of Tfr1 protein.
TLR1↑,
eff↓, Additionally, the levels of protein expression of Nrf2 and NQO1 were reversed by two activators of Nrf2, bardoxolone (CDDO) and sulforaphane (SFN)
NRF2↓, HT induces ferroptosis by inhibiting the Nrf2 signaling pathway
ROS↑, Studies have shown that HT not only induces ROS production in tumour cells but also that its antitumor effect may be influenced by its own oxidative properties

4644- HT,    The Hydroxytyrosol Induces the Death for Apoptosis of Human Melanoma Cells
- in-vitro, Melanoma, NA
tumCV↓, hydroxytyrosol treatment remarkably reduces the cell viability inducing the death for apoptosis of melanoma cells.
Apoptosis↑,
P53↑, significant increase of p53 and γH2AX expression, a significant decrease of AKT expression and the inhibition of cell colony formation ability
γH2AX↑,
Akt↓,
ROS↑, Finally, we propose that the increased amount of intracellular reactive oxygen species (ROS) that may be related to the regulation of the pathways involved in the activation of apoptosis
DNAdam↑, cytotoxic functions of hydroxytyrosol are modulated by ROS production that could be involved in hydroxytyrosol induced DNA damage and apoptosis.

1175- IVM,  PDT,    Drug induced mitochondria dysfunction to enhance photodynamic therapy of hypoxic tumors
- in-vitro, Var, NA
Hypoxia↓,
mitResp↓,
ROS↑, the production of reactive oxygen species would be increase which, in turn, improves the efficacy of PDT against hypoxic tumors.

1920- JG,  TQ,  PLB,    Natural quinones induce ROS-mediated apoptosis and inhibit cell migration in PANC-1 human pancreatic cancer cell line
- in-vitro, PC, PANC1
ROS↑, thymoquinone, plumbagin and juglone were evaluated for their influence on reactive oxygen species (ROS) generation through 2,7-dichlorofluorescein diacetate (DCFDA) staining and they dramatically increased the intracellular ROS level in treated PANC-
TumCMig↓, inhibited PANC-1 cell migration
MMP9↓, reduced expression of matrix metalloproteinase-9 (MMP-9) in juglone-treated cells

1918- JG,    ROS -mediated p53 activation by juglone enhances apoptosis and autophagy in vivo and in vitro
- in-vitro, Liver, HepG2 - in-vivo, NA, NA
TumCG↓, JG significantly inhibited tumor growth in vivo
TumCP↓, JG effectively inhibited cell proliferation and induced apoptosis through extrinsic pathways
Apoptosis↑,
TumAuto↑, JG treatment induced autophagy flux
AMPK↑, activiting the AMPK-mTOR signaling pathway
mTOR↑,
P53↑, JG enhanced p53 activation
H2O2↑, JG enhanced the generation of hydrogen peroxide (H2O2)
ROS↑, JG caused apoptosis and autophagy via activating the ROS-mediated p53 pathway in human liver cancer cells in vitro and in vivo
toxicity↝, a slight loss in body weight was observed after JG injection (Fig. 1D), suggesting that JG might has slight side effects.
p62↓, rmarkable decrease of p62 level was observed after 30uM JG treatment
DR5↑,
Casp8↑,
PARP↑,
cl‑Casp3↑,

1927- JG,    Juglone-induced apoptosis in human gastric cancer SGC-7901 cells via the mitochondrial pathway
- in-vitro, GC, SGC-7901
Apoptosis↑, rate of apoptosis was found to increase in a dose-dependent manner
ROS↑, juglone at the same dose for 24h, the level of ROS was significantly higher
Bcl-2↓, Bcl-2 was significantly down-regulated and the expression of Bax was significantly up-regulated
BAX↑,
MMP↓, mitochondrial transmembrane potential was significantly lower
Cyt‑c↑, expression of the cytochrome c protein was significantly higher relative to the control
Casp3?, Caspase 3 was activated in a concentration-dependent manner
Bax:Bcl2↑, reduction in the Bcl-2/Bax ratio

1926- JG,    Mechanism of juglone-induced apoptosis of MCF-7 cells by the mitochondrial pathway
- in-vitro, BC, MCF-7
TumCG↓, Juglone inhibited the growth of MCF-7 cell line with an IC50 of 11.99 μM.
ROS↑, juglone-exposed cells exhibited significant elevation in intracellular ROS level
MMP↓, decrease in mitochondrial membrane potential
i-Ca+2↑, increase in intracellular Ca(2+) concentration
BAX↑, Juglone upregulated the expression of Bax, and downregulated the expression of Bcl-2, promoting the release of cytochrome C
Bcl-2↓,
Cyt‑c↑,
Casp3?, thereby upregulating the activity of caspase-3

1925- JG,    Redox regulation of mitochondrial functional activity by quinones
- in-vitro, NA, NA
other↓, Quinones are among the rare compounds successfully used as therapeutic agents to correct mitochondrial diseases and as specific regulators of mitochondrial function within cells.
ROS↑, The stimulation of ROS production by juglone and 2,5-di-tert-butyl-1,4-benzoquinone
MMP↓, dissipation of the mitochondrial membrane potential
eff↝, all the quinones, except for coenzyme Q10, decreased the mitochondrial membrane potential. Juglone, 1,4-benzoquinone, and menadione showed the most pronounced effects.

1924- JG,    Juglone triggers apoptosis of non-small cell lung cancer through the reactive oxygen species -mediated PI3K/Akt pathway
- in-vitro, Lung, A549
TumCMig↓, substantially suppressed the migration and invasion of these two lung cancer cells
TumCI↓,
TumCCA↑, juglone arrested the cell cycle, induced apoptosis, increased the cleavage of caspase 3
Apoptosis↑,
cl‑Casp3↑,
BAX↑, protein expression of Bax and Cyt c
Cyt‑c↑,
ROS↑, juglone treatment considerably increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels
MDA↑,
GPx4↓, suppressed glutathione peroxidase 4 (GPX4) and superoxide dismutase (SOD) activities
SOD↓,
PI3K↓, inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway
Akt↓,
eff↓, N-acetylcysteine (a ROS scavenger) partially reversed the positive effects of juglone in terms of migration, invasion, ROS production, apoptosis, and PI3K/Akt pathway-associated protein expression

1923- JG,    Mechanism of Juglone-Induced Cell Cycle Arrest and Apoptosis in Ishikawa Human Endometrial Cancer Cells
- in-vitro, Endo, NA
TumCP↓, juglone significantly inhibited Ishikawa cell proliferation
TumCCA↑, as shown by S phase arrest
cycA1/CCNA1↓, inactivation of cyclin A protein
ROS↑, The ROS levels increased significantly after exposure to juglone
P21↑, paralleled increases in the mRNA and protein expression of p21
CDK2↓, decreases in the levels of CDK2, cdc25A, CHK1, and cyclin A
CDK1↓,
CDC25↓,
Bcl-2↓, expression of Bcl-2 and Bcl-xL was significantly down-regulated,
Bcl-xL↓,
BAX↑, expression of Bax, Bad and cyto c was up-regulated
BAD↑,
Cyt‑c↑,

1922- JG,    Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma
- in-vitro, GBM, U87MG
tumCV↓, inhibit the proliferation of TSCs in glioma by decreasing cell viability
TumCP↓,
ROS↑, juglone could generate ROS significantly
p‑p38↑, increase p38 phosphorylation
eff↓, pretreatment with ROS scavenger or p38-MAPK inhibitor could reverse juglone-induced cytotoxicity
Apoptosis↑, Juglone could induce glioma stem-like cells apoptosis
OS↑, juglone could increase the survival time by about 23.6%(though less significant than TMZ)

1921- JG,    Juglone induces ferroptotic effect on hepatocellular carcinoma and pan-cancer via the FOSL1-HMOX1 axis
- in-vitro, PC, NA - vitro+vivo, PC, NA
TumCG↓, Juglone suppressed HCC growth via ferroptosis in vitro and in vivo
Ferroptosis↑,
ROS↑, evidenced by increased levels of iron, lipid peroxidation (LPO), reactive oxygen species (ROS), malondialdehyde (MDA)
Iron↑,
lipid-P↑,
MDA↑,
GSH↓, decreased levels of glutathione (GSH)
FOSL1↑, induce ferroptosis in pan-cancer by activating the FOSL1-HMOX1 axis
HO-1↑, HMOX1

1919- JG,    The Anti-Glioma Effect of Juglone Derivatives through ROS Generation
- in-vitro, GBM, U87MG - in-vitro, GBM, U251
ROS↑, apoptosis rates were increased after D2 or D3 treatment via ROS generation
Apoptosis↑,
eff↓, The peak of juglone could be detected in fresh solution (Molecular Weight: 174kD), while many unknown compounds could be found, and juglone itself decreased obviously after oxidation (1 week)
eff↓, NAC, a ROS scavenger, reversed the cytotoxic effect, indicating the involvement of ROS generation in the anti-glioma effect of D2 and D3

1917- JG,    Inhibition of human leukemia cells growth by juglone is mediated via autophagy induction, endogenous ROS production, and inhibition of cell migration and invasion
- in-vitro, AML, HL-60
selectivity↑, revealed significant, selective (less cytotoxicity towards normal cells) and dose-dependent inhibition of HL-60 leukemia cells
LC3I↑, significant increase in LC3-I and LC3-II
LC3II↑,
Beclin-1↑, slight increase in Beclin-I
ROS↑, Confocal microscopy revealed tremendous increase in ROS concentrations in a dose-dependent manner
tumCV↓,
Dose↝, ROS percentage was 8%, with 20 μM dose it was 25% and with 80 μM its highest value was observed. dose-dependent increase in ROS production
TumAuto↑, The growth inhibitory effects of juglone were mediated via autophagy induction, endogenous ROS production, and inhibition of cell migration and invasion.

5118- JG,    Juglone induces apoptosis and autophagy via modulation of mitogen-activated protein kinase pathways in human hepatocellular carcinoma cells
- in-vitro, HCC, HepG2
m-ROS↑, JG-induced ROS production caused oxidative damage to mitochondria and DNA
DNAdam↑,
Apoptosis↑, JG kills HepG2 cells through the induction of apoptosis.
TumAuto↑, JG triggers autophagy, which contributes to JG-induced cell death.
p38↑, The autophagic cell death was dependent on ROS generation and the activation of p38 MAPK and JNK pathways.
MAPK↑,
JNK↑,
MMP↓, closely related with loss of mitochondrial membrane potential,
LC3II↑, increased expressions of LC3-II and Beclin-1
Beclin-1↑,

5113- JG,    Juglone in Oxidative Stress and Cell Signaling
- Review, Var, NA - Review, AD, NA
ROS↑, However, being a quinone molecule, juglone could also act as a redox cycling agent and produce reactive oxygen species.
Pin1↓, Notably, juglone is an inhibitor of Pin1 (peptidyl-prolyl cis/trans isomerase) that could regulate phosphorylation of Tau, implicating potential effects of juglone in Alzheimer’s disease.
antiOx⇅, Juglone may have either pro- or antioxidant characteristics depending on the concentrations
*ROS↓, A recent study in a transgenic mouse model of Alzheimer’s disease demonstrated that the walnut supplementation can reduce oxidative damage
SMAD2↓, juglone reduces oxidative stress by inhibiting the phosphorylation of Smad2 in the kidney
GSH↓, cytotoxicity of juglone is due to two different mechanisms, namely, redox cycling and the reaction with glutathione (GSH) . toxicity of juglone is the formation of adducts, which also causes the glutathione depletion.
lipid-P↑, Juglone enhances lipid peroxidation predominantly through redox cycling
TumCCA↓, Figure3
BAX↑,
Bcl-2↓,
Casp3↑,
Casp9↑,
Ca+2↑,
Cyt‑c↑,
AntiFungal↑, Juglone may be as effective as commercially available antifungal agents including zinc undecylenate and selenium sulfide
Bacteria↓, Juglone has been shown to possess antibacterial activities
Akt↓, juglone has been shown to suppress the Akt pathway

5114- JG,    Juglone, from Juglans mandshruica Maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism
- in-vitro, AML, HL-60
ROS↑, The generation of ROS was about 2 to 8-fold as compared to control cell after treatment with juglone (2, 4 and 8 μM) for 24 h.
GSH↓, The glutathione (GSH) depletion was consistent with ROS generation after treatment with juglone.
eff↓, Reversal of apoptosis in antioxidants (NAC and catalase) pretreated cells indicated the involvement of ROS in juglone-induced apoptosis.
cl‑PARP↑, the cleavage of PARP and procaspase-3 and -9, loss of mitochondrial membrane potential (△Ψm), and release of cytochrome c (Cyt c) and Smac induced by juglon
proCasp3↑,
proCasp9↑,
MMP↓,
Cyt‑c↑,
Diablo↑,

5099- JG,    Juglone induces ferroptosis in glioblastoma cells by inhibiting the Nrf2-GPX4 axis through the phosphorylation of p38MAPK
- vitro+vivo, GBM, LN229 - vitro+vivo, GBM, T98G
Ferroptosis↑, Juglone mainly causes cell death by inducing ferroptosis
p‑MAPK↑, juglone can significantly activate the phosphorylation of p38MAPK
NRF2↓, juglone induces the ferroptosis of GBM by activating the phosphorylation of p38MAPK and negatively regulating the Nrf2-GPX4 signaling pathway.
GPx4↓,
TumPF↓, Juglone significantly inhibits the proliferation of GBM cells and induces cell apoptosis
Apoptosis↑,
ROS↑, Juglone can dose-dependently enhance the accumulation of ROS in GBM cells
GSH↓, juglone can reduce the content of GSH
lipid-P↑, lipid peroxidation
Ki-67↓, The results show that juglone significantly inhibits the expression of Ki67, GPX4, and Nrf2
TumCG↓, juglone inhibits tumor growth in vivo by inducing ferroptosis.

5098- JG,    Effects of Juglone on Antioxidant Status in Pancreatic Cancer Cell Lines
- in-vitro, PC, Bxpc-3 - in-vitro, PC, PANC1
tumCV↓, Juglone reduced the cell viability of human pancreatic cancer cells in a concentration-dependent manner
ROS↑, At now, it is found that juglone could inhibit cell proliferation and induce ROS production in pancreatic cancer cells
GSH⇅, In our study, it was observed that the application of juglone exposed in different hours caused variability in the antioxidant activity of cells.

5115- JG,    Natural Products to Fight Cancer: A Focus on Juglans regia
- Review, Var, NA
Casp3↑, In LNCaP cells, it triggered apoptosis through the intrinsic pathway, promoting the activation of caspases 3 and 9, and decreasing mitochondrial potential (ΔΨ)
Casp9↑,
MMP↓,
AR↓, At sub-toxic concentrations, it downregulated ARs and PSA expression
PSA↓,
E-cadherin↑, Juglone upregulated the expression of the epithelial marker E-cadherin while reducing the mesenchymal factors N-caderin and vimentin.
N-cadherin↓,
Vim↓,
Akt↓, Furthermore, it synergistically inhibited the Akt/glycogen synthase kinase-3β (GSK-3β)/Snail axis that would physiologically promote E-cadherin repression and EMT induction
GSK‐3β↓,
EMT↑,
TumCI↓, decreased cell invasions by 56% and 80%, respectively, on BxPC-3 and PANC-1 cell lines.
MMP9↓, Juglone significantly dropped the protein level of MMP-9 and the vascular endothelial growth factor (VEGF) reporter Phactr-1 in both cell lines, while a drop of MMP-2 was evident only on BxPC-3
VEGF↓,
MMP2↓,
TumCCA↑, juglone promoted G1 cell-cycle arrest [94,95] and ROS-driven apoptosis
ROS↑,
Apoptosis↑,
GSH↓, Glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase protein levels diminished
Catalase↓,
SOD↓,
GPx↓,
DNAdam↑, juglone cytotoxicity is, at least partially, ascribed to DNA damage
γH2AX↑, high levels of γ-H2AX were registered when juglone was tested in combination with ascorbate.
eff↑, juglone’s anticancer profile (in terms of proliferation inhibition, cytotoxicity, and ROS induction) was highly improved by ascorbate [115], revealing an interesting synergistic activity between these two compounds
BAX↑, upregulation of many proteins involved in the intrinsic and extrinsic pathway, such as Bax, Cyt-c, Fas cell surface death receptor (Fas), Fas-ligand.
Fas↑,
Pin1↓, On U251 glioblastoma cells, juglone arrested cell growth by promoting apoptosis with the involvement of peptidyl-prolyl cis/trans isomerase (Pin1) inhibition [111]. Juglone is a well-known Pin1 inhibitor

5116- JG,    Juglone, a naphthoquinone from walnut, exerts cytotoxic and genotoxic effects against cultured melanoma tumor cells
- in-vitro, Melanoma, B16-BL6
GSH↓, A significant concentration-dependent decrease in the glutathione levels and increase in dichlorofluorescein (DCF) fluorescence after juglone treatment confirmed the ability of juglone to generate intracellular reactive oxygen species.
ROS↑,
chemoPv↑, concluded that juglone could be a promising chemopreventive agent

5117- JG,    https://pubmed.ncbi.nlm.nih.gov/31283929/
- vitro+vivo, Liver, NA
TumCG↓, Here, the present results showed that JG significantly inhibited tumor growth in vivo.
TumCP↓, JG effectively inhibited cell proliferation and induced apoptosis through extrinsic pathways.
Apoptosis↑,
TumAuto↑, We also observed that JG treatment induced autophagy flux via activiting the AMPK-mTOR signaling pathway.
AMPK↑,
mTOR↑,
P53↑, JG enhanced p53 activation by increasing down-regulation of ubiquitin-mediated degradation
H2O2↑, JG enhanced the generation of hydrogen peroxide (H2O2) and superoxide anion radical (O2• -).
ROS↑, JG caused apoptosis and autophagy via activating the ROS-mediated p53 pathway in human liver cancer cells in vitro and in vivo

2351- lamb,    Anti-Warburg effect via generation of ROS and inhibition of PKM2/β-catenin mediates apoptosis of lambertianic acid in prostate cancer cells
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
proCasp3↓, LA exerted cytotoxicity, increased sub G1 population and attenuated the expression of pro-Caspase3 and pro-poly (ADP-ribose) polymerase (pro-PARP) in DU145 and PC3 cells
proPARP↓,
LDHA↓, LA reduced the expression of lactate dehydrogenase A (LDHA), glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 (PKM2) with reduced production of lactate in DU145 and PC3 cells
Glycolysis↓,
HK2↓,
PKM2↓,
lactateProd↓,
p‑STAT3↓, inhibited the expression of p-STAT3, cyclin D1, C-Myc, β-catenin, and p-GSK3β with the decrease of nuclear translocation of p-PKM2
cycD1/CCND1↓,
cMyc↓,
β-catenin/ZEB1↓,
p‑GSK‐3β↓,
ROS↑, LA generated ROS in DU145 and PC3
eff↓, while ROS scavenger NAC (N-acetyl L-cysteine) blocked the ability of LA to reduce p-PKM2, PKM2, β-catenin, LDHA, and pro-caspase3 in DU145 cells.

1100- LT,    Luteolin, a flavonoid, as an anticancer agent: A review
- Review, NA, NA
TumCP↓,
TumCCA↑,
Apoptosis↑,
EMT↓, reverse epithelial-mesenchymal transition (EMT)
E-cadherin↑,
N-cadherin↓,
Snail↓,
Vim↓,
ROS↑, Luteolin increases levels of intracellular reactive oxygen species (ROS) by activation
ER Stress↑,
mtDam↑, mitochondrial dysfunction
p‑eIF2α↝,
p‑PERK↝,
p‑CHOP↝,
p‑ATF4↝,
cl‑Casp12↝,

2906- LT,    Luteolin, a flavonoid with potentials for cancer prevention and therapy
- Review, Var, NA
*Inflam↓, anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically
AntiCan↑,
antiOx⇅, With low Fe ion concentrations (< 50 μM), luteolin behaves as an antioxidant while high Fe concentrations (>100 μM) induce luteolin's pro-oxidative effect
Apoptosis↑, induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis.
TumCP↓,
TumMeta↓,
angioG↓,
PI3K↓, , luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP)
Akt↓,
NF-kB↓,
XIAP↓, luteolin inhibits PKC activity, which results in a decrease in the protein level of XIAP by ubiquitination and proteasomal degradation of this anti-apoptotic protein
P53↑, stimulating apoptosis pathways including those that induce the tumor suppressor p53
*ROS↓, Direct evidence showing luteolin as a ROS scavenger was obtained in cell-free systems
*GSTA1↑, Third, luteolin may exert its antioxidant effect by protecting or enhancing endogenous antioxidants such as glutathione-S-transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT)
*GSR↑,
*SOD↑,
*Catalase↑,
*other↓, luteolin may chelate transition metal ions responsible for the generation of ROS and therefore inhibit lipooxygenase reaction, or suppress nontransition metal-dependent oxidation
ROS↑, Luteolin has been shown to induce ROS in untransformed and cancer cells
Dose↝, It is believed that flavonoids could behave as antioxidants or pro-oxidants, depending on the concentration and the source of the free radicals
chemoP↑, may act as a chemopreventive agent to protect cells from various forms of oxidant stresses and thus prevent cancer development
NF-kB↓, We found that luteolin-induced oxidative stress causes suppression of the NF-κB pathway while it triggers JNK activation, which potentiates TNF-induced cytotoxicity in lung cancer cells
JNK↑,
p27↑, Table 1
P21↑,
DR5↑,
Casp↑,
Fas↑,
BAX↑,
MAPK↓,
CDK2↓,
IGF-1↓,
PDGF↓,
EGFR↓,
PKCδ↓,
TOP1↓,
TOP2↓,
Bcl-xL↓,
FASN↓,
VEGF↓,
VEGFR2↓,
MMP9↓,
Hif1a↓,
FAK↓,
MMP1↓,
Twist↓,
ERK↓,
P450↓, Recently, it was determined that luteolin potently inhibits human cytochrome P450 (CYP) 1 family enzymes such as CYP1A1, CYP1A2, and CYP1B1, thereby suppressing the mutagenic activation of carcinogens
CYP1A1↓,
CYP1A2↓,
TumCCA↑, Luteolin is able to arrest the cell cycle during the G1 phase in human gastric and prostate cancer, and in melanoma cells

2912- LT,    Luteolin: a flavonoid with a multifaceted anticancer potential
- Review, Var, NA
ROS↑, induction of oxidative stress, cell cycle arrest, upregulation of apoptotic genes, and inhibition of cell proliferation and angiogenesis in cancer cells.
TumCCA↑,
TumCP↓,
angioG↓,
ER Stress↑, Luteolin induces mitochondrial dysfunction and activates the endoplasmic reticulum stress response in glioblastoma cells, which triggers the generation of intracellular reactive oxygen species (ROS)
mtDam↑,
PERK↑, activate the expression of stress-related proteins by mediating the phosphorylation of PERK, ATF4, eIF2α, and cleaved-caspase 12.
ATF4↑,
eIF2α↑,
cl‑Casp12↑,
EMT↓, Luteolin is known to reverse epithelial-to-mesenchymal transition (EMT), which is associated with the cancer cell progression and metastasis.
E-cadherin↑, upregulating the biomarker E-cadherin expression, followed by a significant downregulation of the N-cadherin and vimentin expression
N-cadherin↓,
Vim↓,
*neuroP↑, Furthermore, luteolin holds potential to improve the spinal damage and brain trauma caused by 1-methyl-4-phenylpyridinium due to its excellent neuroprotective properties.
NF-kB↓, downregulation and suppression of cellular pathways such as nuclear factor kappa B (NF-kB), phosphatidylinositol 3’-kinase (PI3K)/Akt, and X-linked inhibitor of apoptosis protein (XIAP)
PI3K↓,
Akt↑,
XIAP↓,
MMP↓, Furthermore, the membrane action potential of mitochondria depletes in the presence of luteolin, Ca2+ levels and Bax expression upregulate, the levels of caspase-3 and caspase-9 increase, while the downregulation of Bcl-2
Ca+2↑,
BAX↑,
Casp3↑,
Casp9↑,
Bcl-2↓,
Cyt‑c↑, cause the cytosolic release of cytochrome c from mitochondria
IronCh↑, Luteolin serves as a good metal-chelating agent owing to the presence of dihydroxyl substituents on the aromatic ring framework
SOD↓, luteolin further triggered an early phase accumulation of ROS due to the suppression of the activity of cellular superoxide dismutase.
*ROS↓, Luteolin reportedly demonstrated an optimal 43.7% inhibition of the accumulation of ROS, 24.5% decrease in malondialdehyde levels, and 38.7% lowering of lactate dehydrogenase levels at a concentration of 30 µM
*LDHA↑,
*SOD↑, expression of superoxide dismutase ameliorated by 73.7%, while the activity of glutathione improved by 72.3% at the same concentration of luteolin
*GSH↑,
*BioAv↓, Poor bioavailability of luteolin limits its optimal therapeutic efficacy and bioactivity
Telomerase↓, MDA-MB-231 cells with luteolin led to dose dependent arrest of cell cycle in S phase by reducing the levels of telomerase and by inhibiting the phosphorylation of NF-kB inhibitor α along with its target gene c-Myc
cMyc↓,
hTERT/TERT↓, These events led to the suppression of the expression of human telomerase reverse transcriptase (hTERT) encoding for the catalytic subunit of telomerase
DR5↑, luteolin upregulated the expression of caspase cascades and death receptors, including DR5
Fas↑, expression of proapoptotic genes such as FAS, FADD, BAX, BAD, BOK, BID, TRADD upregulates, while the anti-apoptotic genes NAIP, BCL-2, and MCL-1 experience downregulation.
FADD↑,
BAD↑,
BOK↑,
BID↑,
NAIP↓,
Mcl-1↓,
CDK2↓, expression of cell cycle regulatory genes CDK2, CDKN2B, CCNE2, CDKN1A, and CDK4 decreased on incubation with luteolin
CDK4↓,
MAPK↓, expression of MAPK1, MAPK3, MAP3K5, MAPK14, PIK3C2A, PIK3C2B, AKT1, AKT2, and ELK1 downregulated
AKT1↓,
Akt2↓,
*Beclin-1↓, luteolin led to downregulation of the expression of hypoxia-inducible factor-1α and autophagy-associated proteins, Beclin 1, and LC3
Hif1a↓,
LC3II↑, LC3-II is upregulated following the luteolin treatment in p53 wild type HepG2 cells i
Beclin-1↑, Luteolin treatment reportedly increased the number of intracellular autophagosomes, as indicated by an increased expression of Beclin 1, and conversion of LC3B-I to LC3B-II in hepatocellular carcinoma SMMC-7721 cells.

2913- LT,    Luteolin induces apoptosis by impairing mitochondrial function and targeting the intrinsic apoptosis pathway in gastric cancer cells
- in-vitro, GC, HGC27 - in-vitro, BC, MCF-7 - in-vitro, GC, MKN45
TumCP↓, Luteolin inhibited the proliferation of gastric cancer HGC-27, MFC and MKN-45 cells
MMP↓, impaired mitochondrial integrity and function by destroying the mitochondrial membrane potential,
Apoptosis↑, eventually leading to apoptosis of gastric cancer HGC-27, MFC and MKN-45 cells
ROS↑, luteolin-induced ROS accumulation in HGC-27, MFC and MKN-45 cells. HGC-27 and MFC cells were treated with luteolin (10, 40, and 70 µM) for 24 h, and MKN-45 cells were treated for 48 h
SOD↓, suggested that luteolin could induce SOD activity reduction, especially in the high dose of luteolin groups in HGC-27 and MFC cells
ATP↓, ATP content decreased, especially in the high-dose groups
Bax:Bcl2↑, luteolin significantly decreased the ratio between Bcl-2 and Bax in HGC-27, MFC, and MKN-45 cells
TumCCA↑, In addition, it is reported that luteolin could induce cell cycle arrest and apoptosis through extrinsic and intrinsic signaling pathways in MCF-7 breast cancer cell

2914- LT,    Therapeutic Potential of Luteolin on Cancer
- Review, Var, NA
*antiOx↑, As an antioxidant, Luteolin and its glycosides can scavenge free radicals caused by oxidative damage and chelate metal ions
*IronCh↑,
*toxicity↓, The safety profile of Luteolin has been proven by its non-toxic side effects, as the oral median lethal dose (LD50) was found to be higher than 2500 and 5000 mg/kg in mice and rats, respectively, equal to approximately 219.8−793.7 mg/kg in humans
*BioAv↓, One major problem related to the use of flavonoids for therapeutic purposes is their low bioavailability.
*BioAv↑, Resveratrol, which functions as the inhibitor of UGT1A1 and UGT1A9, significantly improved the bioavailability of Luteolin by decreasing the major glucuronidation metabolite in rats
DNAdam↑, Luteolin’s anticancer properties, which involve DNA damage, regulation of redox, and protein kinases in inhibiting cancer cell proliferation
TumCP↓,
DR5↑, Luteolin was discovered to promote apoptosis of different cancer cells by increasing Death receptors, p53, JNK, Bax, Cleaved Caspase-3/-8-/-9, and PARP expressions
P53↑,
JNK↑,
BAX↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
survivin↓, downregulating proteins involved in cell cycle progression, including Survivin, Cyclin D1, Cyclin B, and CDC2, and upregulating p21
cycD1/CCND1↓,
CycB/CCNB1↓,
CDC2↓,
P21↑,
angioG↓, suppress angiogenesis in cancer cells by inhibiting the expression of some angiogenic factors, such as MMP-2, AEG-1, VEGF, and VEGFR2
MMP2↓,
AEG1↓,
VEGF↓,
VEGFR2↓,
MMP9↓, inhibit metastasis by inhibiting several proteins that function in metastasis, such as MMP-2/-9, CXCR4, PI3K/Akt, ERK1/2
CXCR4↓,
PI3K↓,
Akt↓,
ERK↓,
TumAuto↑, can promote the conversion of LC3B I to LC3B II and upregulate Beclin1 expression, thereby causing autophagy
LC3B-II↑,
EMT↓, Luteolin was identified to suppress the epithelial to mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin and Wnt3 expressions.
E-cadherin↑,
N-cadherin↓,
Wnt↓,
ROS↑, DNA damage that is induced by reactive oxygen species (ROS),
NICD↓, Luteolin can block the Notch intracellular domain (NICD) that is created by the activation of the Not
p‑GSK‐3β↓, Luteolin can inhibit the phosphorylation of the GSK3β induced by Wnt, resulting in the prevention of GSK3β inhibition
iNOS↓, Luteolin in colon cancer and the complications associated with it, particularly the decreasing effect on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)
COX2↓,
NRF2↑, Luteolin has been identified to increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a crucial transcription factor with anticarcinogenic properties related
Ca+2↑, caused loss of the mitochondrial membrane action potential, enhanced levels of mitochondrial calcium (Ca2+),
ChemoSen↑, Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells
ChemoSen↓, high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [52]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer
IFN-γ↓, decreased the expression of interferon-gamma-(IFN-γ)
RadioS↑, suggested that Luteolin can act as a radiosensitizer, promoting apoptosis by inducing p38/ROS/caspase cascade
MDM2↓, Luteolin treatment was associated with increased p53 and p21 and decreased MDM4 expressions both in vitro and in vivo.
NOTCH1↓, Luteolin suppressed the growth of lung cancer cells, metastasis, and Notch-1 signaling pathway
AR↓, downregulating the androgen receptor (AR) expression
TIMP1↑, Luteolin inhibits the migration of U251MG and U87MG human glioblastoma cell lines by downregulating MMP-2 and MMP-9 and upregulating the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.
TIMP2↑,
ER Stress↑, Luteolin caused oxidative stress and ER stress in the Hep3B cells,
CDK2↓, Luteolin’s ability to decrease Akt, polo-like kinase 1 (PLK1), cyclin B1, cyclin A, CDC2, cyclin-dependent kinase 2 (CDK2) and Bcl-xL
Telomerase↓, Luteolin dose-dependently inhibited the telomerase levels and caused the phosphorylation of NF-κB and the target gene of NF-κB, c-Myc to suppress the human telomerase reverse transcriptase (hTERT)
p‑NF-kB↑,
p‑cMyc↑,
hTERT/TERT↓,
RAS↓, Luteolin was found to suppress the expressions of K-Ras, H-Ras, and N-Ras, which are the activators of PI3K
YAP/TEAD↓, Luteolin caused significant inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)
TAZ↓,
NF-kB↓, Luteolin was found to have a strong inhibitory effect on the NF-κB
NRF2↓, Luteolin-loaded nanoparticles resulted in a significant reduction in the Nrf2 levels compared to Luteolin alone.
HO-1↓, The expressions of the downstream genes of Nrf2, Ho1, and MDR1 were also reduced, where inhibition of Nrf2 expression significantly increased the cell death of breast cancer cells
MDR1↓,

2903- LT,    Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma
- in-vitro, GBM, U251 - in-vitro, GBM, U87MG - in-vivo, NA, NA
ER Stress↑, Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels.
ROS↑,
PERK↑, Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12.
eIF2α↑,
ATF4↑,
CHOP↑,
Casp12↑,
eff↓, Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis.
UPR↑, Researches indicate that abnormalities in ER function can cause ER stress, resulting in unfolded protein response (UPR),
MMP↓, integrity of mitochondrial membranes potential decreased in U87MG cells after treatment of 40 uM luteolin
Cyt‑c↑, release of cytochrome C to cytoplasm was elevated in U251MG cells
Bcl-2↓, significantly decreased the expression of anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bax in U251MG and U87MG glioblastoms cells.
BAX↑,
TumCG↓, Luteolin inhibited tumor growth in a xenograft mouse model
Weight∅, luteolin did not affect body weight, alanine aminotransferase (ALT) or aspartate transaminase (AST)
ALAT∅,
AST∅,

2922- LT,    Combination of transcriptomic and proteomic approaches helps unravel the mechanisms of luteolin in inducing liver cancer cell death via targeting AKT1 and SRC
- in-vitro, Liver, HUH7
Half-Life↝, However, after oral administration, luteolin showed relatively rapid absorption and slow elimination in rats, with a tmax (time to reach peak plasma level) of approximately 1.02 h and a t1/2 (elimination half-life) of 4.94 h, indicating that luteolin
TumCCA↑, luteolin could promote cell cycle arrest and apoptosis in HuH-7 cells
AKT1↓, Dramatic downregulation of components downstream of the AKT1-ASK2-ATF2 pathway (CycD, BCL2, CycA, etc.), the AKT1-NF-κB pathway (BCL-XL and MIP2) and the AKT1-GSK3β-β-catenin pathway (c-Myc and CCND1)
ATF2↓,
NF-kB↓,
GSK‐3β↓,
cMyc↓,
GSTs↓, expression change of NQO-1, GSTs, and TRXR1 indicated the increase in ROS
TrxR1↓,
ROS↑,

2919- LT,    Luteolin as a potential therapeutic candidate for lung cancer: Emerging preclinical evidence
- Review, Var, NA
RadioS↑, it can be used as an adjuvant to radio-chemotherapy and helps to ameliorate cancer complications
ChemoSen↑,
chemoP↑,
*lipid-P↓, ↓LPO, ↑CAT, ↑SOD, ↑GPx, ↑GST, ↑GSH, ↓TNF-α, ↓IL-1β, ↓Caspase-3, ↑IL-10
*Catalase↑,
*SOD↑,
*GPx↑,
*GSTs↑,
*GSH↑,
*TNF-α↓,
*IL1β↓,
*Casp3↓,
*IL10↑,
NRF2↓, Lung cancer model ↓Nrf2, ↓HO-1, ↓NQO1, ↓GSH
HO-1↓,
NQO1↓,
GSH↓,
MET↓, Lung cancer model ↓MET, ↓p-MET, ↓p-Akt, ↓HGF
p‑MET↓,
p‑Akt↓,
HGF/c-Met↓,
NF-kB↓, Lung cancer model ↓NF-κB, ↓Bcl-XL, ↓MnSOD, ↑Caspase-8, ↑Caspase-3, ↑PARP
Bcl-2↓,
SOD2↓,
Casp8↑,
Casp3↑,
PARP↑,
MAPK↓, LLC-induced BCP mouse model ↓p38 MAPK, ↓GFAP, ↓IBA1, ↓NLRP3, ↓ASC, ↓Caspase1, ↓IL-1β
NLRP3↓,
ASC↓,
Casp1↓,
IL6↓, Lung cancer model ↓TNF‑α, ↓IL‑6, ↓MuRF1, ↓Atrogin-1, ↓IKKβ, ↓p‑p65, ↓p-p38
IKKα↓,
p‑p65↓,
p‑p38↑,
MMP2↓, Lung cancer model ↓MMP-2, ↓ICAM-1, ↓EGFR, ↓p-PI3K, ↓p-Akt
ICAM-1↓,
EGFR↑,
p‑PI3K↓,
E-cadherin↓, Lung cancer model ↑E-cadherin, ↑ZO-1, ↓N-cadherin, ↓Claudin-1, ↓β-Catenin, ↓Snail, ↓Vimentin, ↓Integrin β1, ↓FAK
ZO-1↑,
N-cadherin↓,
CLDN1↓,
β-catenin/ZEB1↓,
Snail↓,
Vim↑,
ITGB1↓,
FAK↓,
p‑Src↓, Lung cancer model ↓p-FAK, ↓p-Src, ↓Rac1, ↓Cdc42, ↓RhoA
Rac1↓,
Cdc42↓,
Rho↓,
PCNA↓, Lung cancer model ↓Cyclin B1, ↑p21, ↑p-Cdc2, ↓Vimentin, ↓MMP9, ↑E-cadherin, ↓AIM2, ↓Pro-caspase-1, ↓Caspase-1 p10, ↓Pro-IL-1β, ↓IL-1β, ↓PCNA
Tyro3↓, Lung cancer model ↓TAM RTKs, ↓Tyro3, ↓Axl, ↓MerTK, ↑p21
AXL↓,
CEA↓, B(a)P induced lung carcinogenesis ↓CEA, ↓NSE, ↑SOD, ↑CAT, ↑GPx, ↑GR, ↑GST, ↑GSH, ↑Vitamin E, ↑Vitamin C, ↓PCNA, ↓CYP1A1, ↓NF-kB
NSE↓,
SOD↓,
Catalase↓,
GPx↓,
GSR↓,
GSTs↓,
GSH↓,
VitE↓,
VitC↓,
CYP1A1↓,
cFos↑, Lung cancer model ↓Claudin-2, ↑p-ERK1/2, ↑c-Fos
AR↓, ↓Androgen receptor
AIF↑, Lung cancer model ↑Apoptosis-inducing factor protein
p‑STAT6↓, ↓p-STAT6, ↓Arginase-1, ↓MRC1, ↓CCL2
p‑MDM2↓, Lung cancer model ↓p-PI3K, ↓p-Akt, ↓p-MDM2, ↑p-P53, ↓Bcl-2, ↑Bax
NOTCH1↓, Lung cancer model ↑Bax, ↑Cleaved-caspase 3, ↓Bcl2, ↑circ_0000190, ↓miR-130a-3p, ↓Notch-1, ↓Hes-1, ↓VEGF
VEGF↓,
H3↓, Lung cancer model ↑Caspase 3, ↑Caspase 7, ↓H3 and H4 HDAC activities
H4↓,
HDAC↓,
SIRT1↓, Lung cancer model ↑Bax/Bcl-2, ↓Sirt1
ROS↑, Lung cancer model ↓NF-kB, ↑JNK, ↑Caspase 3, ↑PARP, ↑ROS, ↓SOD
DR5↑, Lung cancer model ↑Caspase-8, ↑Caspase-3, ↑Caspase-9, ↑DR5, ↑p-Drp1, ↑Cytochrome c, ↑p-JNK
Cyt‑c↑,
p‑JNK↑,
PTEN↓, Lung cancer model 1/5/10/30/50/80/100 μmol/L ↑Cleaved caspase-3, ↑PARP, ↑Bax, ↓Bcl-2, ↓EGFR, ↓PI3K/Akt/PTEN/mTOR, ↓CD34, ↓PCNA
mTOR↓,
CD34↓,
FasL↑, Lung cancer model ↑DR 4, ↑FasL, ↑Fas receptor, ↑Bax, ↑Bad, ↓Bcl-2, ↑Cytochrome c, ↓XIAP, ↑p-eIF2α, ↑CHOP, ↑p-JNK, ↑LC3II
Fas↑,
XIAP↓,
p‑eIF2α↑,
CHOP↑,
LC3II↑,
PD-1↓, Lung cancer model ↓PD-L1, ↓STAT3, ↑IL-2
STAT3↓,
IL2↑,
EMT↓, Luteolin exerts anticancer activity by inhibiting EMT, and the possible mechanisms include the inhibition of the EGFR-PI3K-AKT and integrin β1-FAK/Src signaling pathways
cachexia↓, luteolin could be a potential safe and efficient alternative therapy for the treatment of cancer cachexi
BioAv↑, A low-energy blend of castor oil, kolliphor and polyethylene glycol 200 increases the solubility of luteolin by a factor of approximately 83
*Half-Life↝, ats administered an intraperitoneal injection of luteolin (60 mg/kg) absorbed it rapidly as well, with peak levels reached at 0.083 h (71.99 ± 11.04 μg/mL) and a prolonged half-life (3.2 ± 0.7 h)
*eff↑, Luteolin chitosan-encapsulated nano-emulsions increase trans-nasal mucosal permeation nearly 6-fold, drug half-life 10-fold, and biodistribution of luteolin in brain tissue 4.4-fold after nasal administration

2918- LT,    Luteolin inhibits melanoma growth in vitro and in vivo via regulating ECM and oncogenic pathways but not ROS
- in-vitro, Melanoma, A375 - in-vivo, Melanoma, NA - in-vitro, Melanoma, SK-MEL-28
TumCG↓, Luteolin inhibited melanoma tumor growth in vitro and in vivo.
ROS↑, Luteolin induced ROS in melanoma cells but ROS was not the cause of growth inhibition.
ECM/TCF↓, luteolin inhibited ECM pathway, oncogenic pathway and modulated immune signaling.

2917- LT,  Rad,    Luteolin acts as a radiosensitizer in non‑small cell lung cancer cells by enhancing apoptotic cell death through activation of a p38/ROS/caspase cascade
- in-vitro, Lung, NA
Bcl-2↓, Combined treatment with luteolin and IR enhanced apoptotic cell death in association with downregulation of B‑cell lymphoma 2 (Bcl‑2) and activation of caspase‑3, ‑8, and ‑9; it also induced phosphorylation of MAPK and ROS accumulation
Casp3↑,
Casp8↑,
Casp9↑,
p‑p38↑,
ROS↑,
RadioS↑, luteolin acts as a radiosensitizer by enhancing apoptotic cell death through activation of a p38/ROS/caspase cascade

2916- LT,    Antioxidative and Anticancer Potential of Luteolin: A Comprehensive Approach Against Wide Range of Human Malignancies
- Review, Var, NA - Review, AD, NA - Review, Park, NA
proCasp9↓, , by inactivating proteins; such as procaspase‐9, CDC2 and cyclin B or upregulation of caspase‐9 and caspase‐3, cytochrome C, cyclin A, CDK2, and APAF‐1, in turn inducing cell cycle
CDC2↓,
CycB/CCNB1↓,
Casp9↑,
Casp3↑,
Cyt‑c↑,
cycA1/CCNA1↑,
CDK2↓, inhibit CDK2 activity
APAF1↑,
TumCCA↑,
P53↑, enhances phosphorylation of p53 and expression level of p53‐targeted downstream gene.
BAX↑, Increasing BAX protein expression; decreasing VEGF and Bcl‐2 expression it can initiate cell cycle arrest and apoptosis.
VEGF↓,
Bcl-2↓,
Apoptosis↑,
p‑Akt↓, reduce expression levels of p‐Akt, p‐EGFR, p‐Erk1/2, and p‐STAT3.
p‑EGFR↓,
p‑ERK↓,
p‑STAT3↓,
cardioP↑, Luteolin plays positive role against cardiovascular disorders by improving cardiac function
Catalase↓, It can reduce activity levels of catalase, superoxide dismutase, and GS4
SOD↓,
*BioAv↓, bioavailability of luteolin is very low. Due to the momentous first pass effect, only 4.10% was found to be available from dosage of 50 mg/kg intake of luteolin
*antiOx↑, luteolin classically exhibits antioxidant features
*ROS↓, The antioxidant potential of luteolin and its glycosides is mainly due to scavenging activity against reactive oxygen species (ROS) and nitrogen species
*NO↓,
*GSTs↑, Luteolin may also have a role in protection and enhancement of endogenous antioxidants such as glutathione‐S‐transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT)
*GSR↑,
*SOD↑,
*Catalase↑,
*lipid-P↓, Luteolin supplementation significantly suppressed the lipid peroxidation
PI3K↓, inhibits PI3K/Akt signaling pathway to induce apoptosis
Akt↓,
CDK2↓, inhibit CDK2 activity
BNIP3↑, upregulation of BNIP3 gene
hTERT/TERT↓, Suppress hTERT in MDA‐MB‐231 breast cancer cel
DR5↑, Boost DR5 expression
Beclin-1↑, Activate beclin 1
TNF-α↓, Block TNF‐α, NF‐κB, IL‐1, IL‐6,
NF-kB↓,
IL1↓,
IL6↓,
EMT↓, Suppress EMT essentially notable in cancer metastasis
FAK↓, Block EGFR‐signaling pathway and FAK activity
E-cadherin↑, increasing E‐cadherin expression by inhibiting mdm2
MDM2↓,
NOTCH↓, Inhibit NOTCH signaling
MAPK↑, Activate MAPK to inhibit tumor growt
Vim↓, downregulation of vimentin, N‐cadherin, Snail, and induction of E‐cadherin expressions
N-cadherin↓,
Snail↓,
MMP2↓, negatively regulated MMP2 and TWIST1
Twist↓,
MMP9↓, Inhibit matrix metalloproteinase‐9 expressions;
ROS↑, Induce apoptosis, reactive oxygen development, promotion of mitochondrial autophagy, loss of mitochondrial membrane potential
MMP↓,
*AChE↓, Reduce AchE activity to slow down inception of Alzheimer's disease‐like symptoms
*MMP↑, Reverse mitochondrial membrane potential dissipation
*Aβ↓, Inhibit Aβ25‐35
*neuroP↑, reduces neuronal apoptosis; inhibits Aβ generation
Trx1↑, luteolin against human bladder cancer cell line T24 was due to induction cell‐cycle arrest at G2/M, downregulation of p‐S6, suppression of cell survival, upregulation of p21 and TRX1, reduction in ROS levels.
ROS↓,
*NRF2↑, Luteolin reduced renal injury by inhibiting XO activity, modulating uric acid transporters, as well as activating Nrf2 HO‐1/NQO1 antioxidant pathways and renal SIRT1/6 cascade.
NRF2↓, Luteolin exerted anticancer effects in HT29 cells as it inhibits nuclear factor‐erythroid‐2‐related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway
*BBB↑, Luteolin can be used to treat brain cancer due to ability of this molecule to easily cross the blood–brain barrier
ChemoSen↑, In ovarian cancer cells, luteolin chemosensitizes the cells through repressing the epithelial‐mesenchymal transition markers
GutMicro↑, Luteolin was also observed to modulate gut microbiota which reduce the number of tumors in case of colorectal cancer by enhancing the number of health‐related microbiota and reduced the microbiota related to inflammation

1715- Lyco,    Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence
- Review, Var, NA
antiOx↑, Carotenoids are well known for their potent antioxidant function in the cellular system.
ROS↑, However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis
ChemoSen↑, when carotenoids are delivered with ROS-inducing cytotoxic drugs, they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants
selectivity↑, In cancer cells with innately high intracellular ROS levels, carotenoids may act as pro-oxidants and trigger ROS-mediated apoptosis of cancer cells.
eff↓, However, under high oxygen tension conditions (e.g., in the lungs of smokers), β-carotene shows tumor-promoting effects.
Casp3↑,
Casp7↑,
Casp9↑,
P53↑,
BAX↑,
DNAdam↑,
mtDam↑, mitochondrial dysfunction
eff↑, Astaxanthin co-treatment with β-carotene and lutein (equimolar 5 µM each)

1712- Lyco,    Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair
- in-vitro, Lung, A549
ROS↓, Conclusions: Lycopene treatment at a lower dosage could inhibit smoke-induced oxidative stress and promote genome stability
ROS↑, we found that lycopene only exerted antioxidative effects at low-dosage, while such beneficial effects were diminished at high-dosage
eff↑, suggesting an increased carotenoid uptake in the cells under oxidative stress

1711- Lyco,    Nutritional Importance of Carotenoids and Their Effect on Liver Health: A Review
- Review, Var, NA
ROS↑, exposure to high doses of carotenoids has a pro-oxidant effect
Dose↓, lycopene, an intake of 5 to 7 mg per day was recommended for healthy people to maintain the circulating levels of this carotenoid, in order to combat oxidative stress and prevent chronic diseases
Dose↑, higher concentrations of lycopene (35–75 mg/day) may be required when there is a disease, such as cancer and cardiovascular diseases.
antiOx↑, main protective effect of lycopene is due to its antioxidant effect through the inactivation of ROS and the extinction of free radicals
P450↓, significant decrease in cytochrome P450 2E1
TNF-α↓, TNF-α, IL-1β, and IL-12) were also found
IL1β↓,
IL12↓,

1710- Lyco,    Lycopene: A Natural Arsenal in the War against Oxidative Stress and Cardiovascular Diseases
- Review, CardioV, NA
antiOx↓, Lycopene is a potent antioxidant that fights ROS and, subsequently, complications.
ROS↓,
BP↓, It reduces blood pressure via inhibiting the angiotensin-converting enzyme and regulating nitrous oxide bioavailability.
LDL↓, important role in lowering of LDL (low-density lipoproteins) and improving HDL (high-density lipoproteins) levels to minimize atherosclerosis
*toxicity∅, Lycopene is a natural substance that may be used in high doses as a dietary supplement without causing harm to human health or physiology
eff↑, Thermal food processing, particularly in the presence of cooking oils, causes lycopene to micellize and enhance its intestinal absorption rate by a factor of ten
ROS↑, As a pro-oxidant, lycopene may have both good and negative impacts in biological systems, as well as influence the course of human illnesses.
*Half-Life↑, Plasma lycopene has a half-life of 12–33 days in the human body
*BioAv↓, Tomato lycopene is not easily absorbed since it is integrated into the nutritional matrix.
*BioAv↑, Clinical research demonstrates that heat-processed tomato products absorb lycopene more quickly than raw sources, and that adding oil increases absorption
*antiOx↑, Lycopene’s ability to protect against oxidative stress has been established

1721- Lyco,  RES,  VitC,    Lycopene, resveratrol, vitamin C and FeSO4 increase damage produced by pro-oxidant carcinogen 4-nitroquinoline-1-oxide in Drosophila melanogaster: Xenobiotic metabolism implications.
- in-vitro, Pca, PC3 - in-vitro, Lung, A549 - in-vitro, Cerv, HeLa - in-vitro, BC, MCF-7 - in-vitro, Liver, HepG2
ROS↑, We propose that the basal levels of the XM's enzymes in the ST cross interacted with a putative pro-oxidant activity of the compounds added to the pro-oxidant effects of 4-NQO.

1720- Lyco,    Antioxidant and Pro-oxidant Activities of Carotenoids
- Review, Nor, NA
ROS↑, lycopene (50 μM) exhibited pro-oxidant effects in in vitro cellular assays with several cancer cell lines (PC-3), (A549), (HeLa), (MCF-7), (A431), and (HepG2)

1718- Lyco,    The role of carotenoids in the prevention of human pathologies
- Review, Var, NA
ROS⇅, Thus, in thymocytes, β-Carotene is an antioxidant at low oxygen pressure but a pro-oxidant at high oxygen concentrations
ROS↑, lycopene may have also prooxidant activities depending on the type of oxidants used.

1717- Lyco,    Potential Role of Carotenoids as Antioxidants in Human Health and Disease
- Review, Var, NA
antiOx↑, unique antioxidative properties.
ROS⇅, The molecular mechanisms underlying these reactions are still not fully understood, especially in the context of the anti- and pro-oxidant activity of carotenoids
ROS↑, antioxidant potential (e.g., lutein) or even leads to pro-oxidant behavior (i.e., zeaxanthin)

1716- Lyco,    Anti-inflammatory Activity of β-Carotene, Lycopene and Tri-n-butylborane, a Scavenger of Reactive Oxygen Species
- in-vitro, AML, RAW264.7
antiOx↑, carotenoids β-carotene and lycopene are antioxidants that not only quench singlet oxygen but also inhibit lipid peroxidation
lipid-P↓,
ROS↑, These findings could explain the intriguing pro-oxidant and cytotoxic activity of β-carotene.
Dose↑, new radical peaks then becoming slightly but reproducibly evident at concentrations over 10 mM

4778- Lyco,    Lycopene exerts cytotoxic effects by mitochondrial reactive oxygen species–induced apoptosis in glioblastoma multiforme
- in-vitro, GBM, GBM8401
BBB↑, lycopene penetration across the blood-brain barrier and its induction of apoptosis, inhibiting proliferation in GBM8401 and T98G GBM cells
Apoptosis↑,
TumCP↑,
P53↑, lycopene promoted p53 upregulation and suppressed cyclins B and cyclin D, leading to cell cycle arrest through ROS-activated ERK pathways.
CycB/CCNB1↓,
cycD1/CCND1↓,
TumCCA↓,
mt-ROS↑, Lycopene induced Mito-ROS accumulation in GBM cells
TumCG↓, Lycopene inhibits the cell growth of GBM cells

4781- Lyco,  5-FU,  Chemo,  Cisplatin,    Antioxidant and anti-inflammatory activities of lycopene against 5-fluorouracil-induced cytotoxicity in Caco2 cells
- in-vitro, Colon, Caco-2
chemoP↑, One such useful natural antioxidant that has been widely investigated to suppress chemotherapy induced side effects of drugs such as cisplatin is lycopene
Inflam↓, lycopene was found to significantly suppress inflammatory responses in CC cells by inhibiting pro-inflammatory cytokines expression like cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), IL-6 and tumor necrosis-α (TNF-α)
COX2↓,
IL1β↓,
IL6↓,
TNF-α↓,
ROS↑, Our results indicated the cells treatment with 60 µg/ml lycopene significantly increased ROS generation
ChemoSen↑, Furthermore, L60 and L120 seemed to enhance 5FU-induced ROS generation
SOD↓, significant increase SOD activity

4784- Lyco,    Protective effects of lycopene in cancer, cardiovascular, and neurodegenerative diseases: An update on epidemiological and mechanistic perspectives
- Review, Diabetic, NA - Review, CardioV, NA
*antiOx↑, Owing to its potent antioxidant properties, lycopene can potentially alleviate enhanced levels of proinflammatory mediators (e.g., proinflammatory cytokines IL-8, -6, and -1, and oxidized phospholipids) and prevent NF-κB activation
*IL8↓,
*IL6↓,
*IL1↓,
*NF-kB↓,
Inflam↓, graphical abstract
cycD1/CCND1↓,
MMP2↓,
MMP9↓,
Bcl-2↓,
NF-kB↓,
*Nrf1↑, normal cells
*antiOx↑,
*BDNF↑,
*neuroP↑,
*cardioP↑,
ROS↑, i) enhanced oxidative stress due to prooxidant activities of lycopene under circumstances of tumor cell
Dose↝, There are no known adverse effects from low (12 mg/day) to very high (150 mg/day) intake of dietary or formulated lycopene in a healthy population

4785- Lyco,    The Protective Anticancer Effect of Natural Lycopene Supercritical CO2 Watermelon Extracts in Adenocarcinoma Lung Cancer Cells
- in-vitro, Lung, A549
ROS↑, we found that Lyc W significantly increased the spontaneous release of ROS
NF-kB↑, We found that Lyc W significantly increased the nuclear expression of NF-kB in comparison to medium (p = 0.0289) and to Lyc G, Lyc T and Lyc S treatments
Apoptosis↑, Lyc W Induces Cell Apoptosis

4803- Lyco,    Enhanced cytotoxic and apoptosis inducing activity of lycopene oxidation products in different cancer cell lines
- in-vitro, Pca, PC3 - in-vitro, BC, MCF-7 - in-vitro, Melanoma, A431 - in-vitro, Liver, HepG2 - in-vitro, Cerv, HeLa - in-vitro, Lung, A549
tumCV↓, The decreased cell viability with depleted GSH and increased MDA levels were observed when treated with COL products than control, LYC and AOL
GSH↓,
MDA↑,
ROS↑, In addition, COL products increased ROS levels and percent apoptosis.
Apoptosis↑,

2542- M-Blu,    In Vitro Methylene Blue and Carboplatin Combination Triggers Ovarian Cancer Cells Death
- in-vitro, Ovarian, OV1369 - in-vitro, Ovarian, OV1946 - in-vitro, Nor, ARPE-19
BioAv↝, our study reveals MB’s distinct cellular uptake, with ARPE-19 absorbing 5 to 7 times more MB than OV1946 and OV1369-R2.
TumCP↓, Treatment with 50 µM MB (MB-50) effectively curtailed the proliferation of both ovarian cancer cell lines.
GlutaM↓, MB-50 exhibited the ability to quell glutaminolysis and the Warburg effect in cancer cell cultures.
Warburg↓,
OCR↑, MB-50 spurred oxygen consumption, disrupted glycolytic pathways, and induced ATP depletion in the chemo-sensitive OV1946 cell line.
Glycolysis↓,
ATP↓,
BioAv↝, The reduced permeability of cancer cell membranes, including mitochondria, suggests limited internalization of MB into their cytoplasm or mitochondria, consistent with their preference for aerobic glycolysis, a hallmark of the Warburg effect.
ROS↑, Consistent with our findings, they reported a decrease in intracellular ATP levels, which, in turn, led to increased generation of reactive oxygen species (ROS)

2541- M-Blu,    Spectroscopic Study of Methylene Blue Interaction with Coenzymes and its Effect on Tumor Metabolism
- in-vivo, Var, NA
TumCG↓, In the group receiving MB with drinking water, a decrease of the tumor growth rate, reduction of oxygenation level, and a1/a2 metabolic index were observed, which confirms the shift from glycolysis to oxidative phosphorylation.
Glycolysis↓,
OXPHOS↑,
ROS↑, The ability of MB to generate reactive oxygen species together with a small molecular size makes this dye attractive for using it as a photosensitizer in photodynamic therapy
OCR↑, MB can increase oxygen consumption, decrease glycolysis and increase glucose uptake in vitro
GlucoseCon↑,
lactateProd↓, The decrease of the lactate amount and extracellular acidification rate after MB introduction, which is reported in the literature [31], is supposed to be a secondary effect mediated by the metabolic shift towards oxidation phosphorylation as a resul

2547- M-Blu,  SDT,    The effect of dual-frequency ultrasound waves on B16F10 melanoma cells: Sonodynamic therapy using nanoliposomes containing methylene blue
- in-vitro, Melanoma, B16-BL6
tumCV↓, The dual-frequency protocols caused higher viability losses compared to the kHz and MHz sonications (P < .05).
ROS↑, SDT takes advantage of both physical effects (such as mechanical stress and cavitation) and biochemical effects (such as ROS) to cause cell damage and apoptosis and also to inhibit tumor growth
mtDam↑, MB-mediated SDT could obviously cause the cell death of ovarian cancer cells probably by inducing mitochondrial damage

2535- M-Blu,  SDT,    Apoptosis of ovarian cancer cells induced by methylene blue-mediated sonodynamic action
- in-vitro, Ovarian, HO-8910
tumCV↓, The cytotoxicity of MB-mediated SDT on HO-8910 cells after MB-mediated SDT was significantly higher than those of other treatments including ultrasound alone, MB alone and sham treatment.
ROS↑, Nuclear condensation and increased ROS levels were also found in HO-8910 cells treated by MB-mediated SDT.

2534- M-Blu,  doxoR,  PDT,    Methylene Blue-Mediated Photodynamic Therapy in Combination With Doxorubicin: A Novel Approach in the Treatment of HT-29 Colon Cancer Cells
- in-vitro, CRC, HT-29
LDH↑, present study, the results strongly suggest that the groups treated with DOX + MB + L 610/830 nm had the highest rates of LDH release
ROS↑, Several studies have shown that PDT via different mechanisms, including ROS generation, damage to cellular components (for example lipids, proteins, and nucleic acids) and, as a result, disrupting the integrity of the cell membrane

2533- M-Blu,  PDT,    Methylene blue-mediated photodynamic therapy enhances apoptosis in lung cancer cells
- in-vitro, Lung, A549
MMP↓, MB enhances PDT-induced apoptosis in association with downregulation of anti-apoptotic proteins, reduced mitochondrial membrane potential (MMP), increased phosphorylation of the mitogen-activated protein kinase (MAPK) and the generation of ROS
p‑MAPK↑,
ROS↑,
cl‑PARP↑, n MB-PDT-treated A549 cells, we observed PARP cleavage, procaspase-3 activation, downregulation of the anti-apoptotic proteins Bcl-2 and Mcl-1
Bcl-2↓,
Mcl-1↓,
eff↓, pretreatment of A549 cells with the antioxidant N-acetylcysteine (NAC) followed by MB-PDT resulted in increased cell viability and reduced proteolytic cleavage of PARP.

4517- MAG,    Mitochondrion-targeted magnolol derivatives exert synergistic anticancer activity by modulating energy metabolism and tumor microenvironment
- vitro+vivo, Var, NA
eff↑, , three derivatives of magnolol, MT1, MT2, and MTP, were synthesized by modifying the parent compound with mitochondrion-targeting triphenylphosphonium and other groups.
AntiCan↑, MTP bearing a pyridyl demonstrated remarkable anticancer activity both in vitro and in vivo
ROS↑, MTP promoted the production of reactive oxygen species, disrupted the structure and energy metabolism of mitochondria, and induced endoplasmic reticulum stress, thus triggering mitophagy and apoptosis in cancer cells.
ER Stress↑,
Apoptosis↑,

4524- MAG,    Magnolol facilitates mitochondrial-peroxisome dysfunction and induces oxeiptosis in lung cancer cells following transfer via tunneling nanotubes
- vitro+vivo, Lung, NA
ROS↑, Magnolol promotes the production of reactive oxygen species (ROS) and inhibits the antioxidant pathway in cancer cells.
antiOx↓,
mtDam↑, leading to mitochondrial dysfunction and mitocytosis

4519- MAG,    Magnolol: A Neolignan from the Magnolia Family for the Prevention and Treatment of Cancer
- Review, Var, NA
*antiOx↑, anti-oxidant [70], anti-inflammatory [71], anti-bacterial [10], anti-thrombotic or anti-platelet
*Inflam↓,
*Bacteria↓,
*AntiAg↑,
*BBB↑, MAG can easily cross the blood brain barrier
*BioAv↓, bioavailability is in the region of 10%
BAD↑, MAG increased the expression of Bad, Bcl-XS, caspases-3, -6, and -9 and c-Jun N-terminal kinases (JNK) and suppressed the expression of Bcl-xL
Casp3↑,
Casp6↑,
Casp9↑,
JNK↑,
Bcl-xL↓,
PTEN↑, MAG also induced apoptosis by enhancing the expression of PTEN and down-regulation of AKT
Akt↓,
NF-kB↓, MAG induces cell death and reduces cell proliferation by inhibition of NF-κB activity
MMP7↓, MAG inhibits cancer metastasis by reducing the expression of matrix metalloproteinase-7, -9 (MMP-7, -9) and urokinase plasminogen activator (uPA)
MMP9↓,
uPA↓,
Hif1a↓, MAG attenuated angiogenesis in vitro and in vivo which is mediated by inhibition of the expression of hypoxia-inducible factors-1α (HIF-1α) and vascular endothelial growth factor (VEGF) secretion in human bladder cancer cells
VEGF↓,
FOXO3↓, MAG downregulated the expression of transcriptional factor Forkhead box O3 (FoxO3), ubiquitin ligase, MuRF-1 and MAFbx/atrogin-1.
Ca+2↑, ↑Cytosolic free Ca (2+);
TumCCA↑, ↑Cell cycle arrest at G2/M phase, ROS, release of cyt-c,
ROS↑,
Cyt‑c↑,

3900- MCT,    Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition
- in-vitro, AD, NA
*ROS↑, CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid,
*AChE↓, AChE inhibitory activity that is 131-fold less compared to Rivastigmine.
*Aβ↓, Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31%

1899- MeJa,    Methyl jasmonate induces production of reactive oxygen species and alterations in mitochondrial dynamics that precede photosynthetic dysfunction and subsequent cell death
- in-vitro, NA, NA
ROS↑, MeJa induction of ROS production, which first occurred in mitochondria after 1 h of MeJa treatment and subsequently in chloroplasts by 3 h of treatment,
MMP↓, cessation of mitochondrial movement, the loss of mitochondrial transmembrane potential (MPT),
eff↓, treatment of protoplasts with ascorbic acid or catalase prevented ROS production, organelle change, photosynthetic dysfunction and subsequent cell death.
H2O2?, Generation of H2 O 2,

1898- MeJa,    Methyl jasmonate and its potential in cancer therapy
- Review, Var, NA
ROS↑, MeJa triggers a time-dependent production of reactive oxygen species (ROS)
selectivity↑, MeJa is a novel class of anticancer drugs that act directly and selectively against tumor cells both in vitro and in vivo, without affecting normal cells such as lymphocytes
toxicity↝, Without doubt, extensive investigation into the potential side effects of MeJa on normal human cells or animal models, and intensive examination of the selective effects (target molecules) of MeJa on cancer cells, are particularly urgent.

1776- MEL,    Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis
- Review, NA, NA
Remission↑, tumor remission rate in the MLT group was significantly higher than that in the control group
OS↑, MLT group had an overall survival rate of 28.24% (n=294/1,041), which was greatly increased compared with the control group (RR =2.07; 95% CI, 1.55–2.76; P<0.00001; I2=55%)
neuroP↑, MLT could effectively reduce the incidence of neurotoxicity
VEGF↓, by the downregulation of vascular endothelial growth factor (VEGF)
KISS1↑, MLT could suppress the metastasis of triple-negative breast cancer by inducing KISS1 expression
TumCP↓, MLT can significantly inhibit the proliferation of cancer cells
ChemoSideEff↓, while reducing the incidence of side effects in chemotherapy or radiotherapy
radioP↑, In the 20 randomized trials included, MLT was beneficial to reduce multiple side effects of radiotherapy and chemotherapy
Dose∅, mostly 20 mg/day and taken orally and taken at night, respectively
*ROS↓, Preclinical experimental research has confirmed that MLT was capable of scavenging ROS and repairing damaged DNA to exert antitumor effects
DNArepair↑,
ROS↑, The mechanisms of MLT exerting antitumor effect might involve with other pathways, such as antiangiogenesis and pro-oxidant

1779- MEL,    Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review
- Review, BC, NA
QoL↑, melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients
OS↑, Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates.
Dose∅, regular doses of 20 mg/day
antiOx↑, melatonin possesses antioxidant properties, which may help to protect cells from damage caused by free radicals
ROS↑, elimination of free radicals non-enzymatically transforms melatonin into metabolites with greater antioxidant capacity, which enabling the removal of 10 reactive species per molecule
SOD↑, melatonin upregulates various antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase
Catalase↑,
GPx↑,
Risk↓, individuals with higher melatonin levels show a lower risk of developing breast cancer, and melatonin supplementation may help inhibit the growth and spread of breast cancer cells
NK cell↑, enhance natural killer cell activity
IL1β↓, inhibit the production of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)
IL6↓,
TNF-α↓,
radioP↑, protect hematopoietic progenitor cells from radiation therapy and chemotherapy
chemoP↑,
TumVol↓, most frequent observations was the ability of melatonin to reduce tumor size
TumMeta↓, decrease the risk of metastasis
angioG↓,
ChemoSen↑, melatonin can synergistically potentiate drug cytotoxicity.
eff↑, it has been suggested that administering melatonin at the appropriate phase of the circadian cycle may enhance its anti-tumor activity and reduce the side effects of chemotherapy and radiation therapy

1778- MEL,    Melatonin: a well-documented antioxidant with conditional pro-oxidant actions
- Review, Var, NA - Review, AD, NA
*ROS↓, melatonin and its metabolic derivatives possess strong free radical scavenging properties.
*antiOx↓, potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced.
ROS↑, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (μm to mm range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant.
selectivity↑, melatonin functions as a prooxidant in cancer cells where it aids in the killing of tumor cells
Dose↑, Melatonin levels in the nucleus and mitochondria reached saturation with a lower dose of 40 mg/kg body weight, with no further accumulation under higher doses of injected melatonin
*mitResp↑, improves mitochondrial respiration and ATP production, thereby reducing electron leakage and ROS generation
*ATP↑,
*ROS↓,
eff↑, melatonin protects mitochondrial function in the brain of Alzheimer's patients through both MT1/MT2 dependent and independent mechanisms
ROS↑, Cytochrome P450 utilizes melatonin as a substrate to generate ROS in mitochondria (melatonin concentration ranges from 0.1 to 10 uM)
Dose↑, melatonin at high concentrations (10-1000uM ) was able to promote ROS generation and lead to Fas-induced apoptosis in human leukemic Jurkat cells. Concentrations of <10uM , melatonin did not induce significant ROS generation in these cancer cells
*toxicity∅, High levels of melatonin (uM to mM) did not cause cytotoxicity in several types of nontumor cells
ROS↑, lower concentrations of melatonin (0.1-10uM ), which exhibited antioxidant action in HepG2 cells within 24 hr, became pro-oxidant after 96 hr of treatment, as indicated by the increase of GSH with 24hr and depletion after 96 hr.
eff↓, Finally, a compound, chlorpromazine, which specifically interrupts the binding of melatonin to calmodulin [188], prevented melatonin-induced AA release and ROS generation;
ROS↝, It remains unknown whether the pro-oxidant action exists in vivo. the vast majority of evidence indicates that melatonin is a potent antioxidant in vivo even at pharmacological concentrations
Dose↑, decline of melatonin production with age may render it more beneficial to supplement melatonin to the aging population to improve health by reducing free radical damage
other↑, melatonin intake has the potential to improve cardiac function, inhibit cataract formation, maintain brain health, alleviate metabolic syndrome, obesity and diabetes,reduce tumorigenesis, protect tissues against ischemia

1777- MEL,    Melatonin as an antioxidant: under promises but over delivers
- Review, NA, NA
*ROS↓, uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances
*Fenton↓, reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions
*antiOx↑, credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant
*toxicity∅, uncommonly high-safety profile of melatonin also bolsters this conclusion.
*GPx↑, melatonin was found to stimulate antioxidative enzymes including glutathione peroxidase and glutathione reductase
*GSR↑,
*GSH↑, melatonin upregulates the synthesis of glutathione
*NO↓, neutralize nitrogen-based toxicants, i.e., nitric oxide
*Iron↓, Melatonin chelates both iron (III) and iron (II), which is the form that participates in the Fenton reaction to generate the hydroxyl radical
*Copper↓, copper-chelating ability of melaton
*IL1β↓, significant reductions in plasma cardiac troponin 1, interleukin 1 beta, inducible nitric oxide synthase (iNOS) and caspase 3 due to melatonin
*iNOS↓,
*Casp3↓,
*BBB↑, melatonin readily crosses the blood-brain barrier;
*RenoP↑, Published reports haveshown that the lung,231, 232 liver, 233- 235 kidney,236 pancreas,237 intestine,238 urinary bladder,239,240 corpus cavernosum,241 skeletal muscle242, 243 spinal cord244, 245 and stem cells246 are alsoprotected by melatonin.
chemoP↑, Melatonin has not been found to interfere with the efficacy of prescription drugs. Doxorubicin, if given it in combination with melatonin may allow the use of a larger dose with greater efficacy.
*Ca+2↝, Moreover, melatonin regulates free Ca2+ movement intracellularly
eff↑, elatonin was found to exaggerate the cancer inhibiting actions of pitavastatin270 and pravastatin271 against breast cancer in experimental studies
*PKCδ?, major targets by which melatonin reduces methamphetamine-related neuronal damage is due to the inhibition of the PKCδ gene
ChemoSen↑, at least some cases melatonin reduces the toxicity of these pharmacological agents in normal cells256, 289, 290 while enhancing the cancer-killing actions (also, see below) of conventional chemotherapeutic agents.256, 291-293
eff↑, TRAIL was combined with melatonin for the treatment of A172 and U87 human glioblastoma cells, however, apoptotic cell death was greatly exaggerated over that caused by TRAIL alone
Akt↓, in GBM: observed effect was related to a modulation of protein kinase c which reduced Akt activation resulting in a rise in death receptor 5 (DR5) levels;
DR5↑,
selectivity↑, The pro-oxidant action of melatonin is common in cancer cells while in normal cells the indoleamine is a powerful antioxidant.
ROS↑, cancer cells
eff↑, human lung adenocarcinoma cells (SK-LV-1) showed that melatonin also increased their sensitivity to the chemotherapy, cisplatin.

995- MEL,    Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma
- vitro+vivo, GBM, NA
LDHA↓,
MCT4↓,
lactateProd↓,
i-pH↓, decrease in intracellular pH: melatonin treatment induced a pH reversal with intracellular acidosis parallel to a downregulation in glycolysis in GBM.
ROS↑,
ATP↓,
TumCD↑, cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation
TumCCA↑, cell cycle arrest at G0/G1 in both GBM1A and QNS120 and G2/M in GBM1A
PDH↓, decrease in pyruvate dehydrogenase (PDH) expression for both cell lines at aMT 3.0 mM
Glycolysis↓,
GlucoseCon↓,
TumCG↓, in vivo

1063- MEL,    HDAC1 inhibition by melatonin leads to suppression of lung adenocarcinoma cells via induction of oxidative stress and activation of apoptotic pathways
- in-vitro, Lung, A549 - in-vitro, Lung, PC9
AntiCan↑,
TumCMig↓,
GSH↓,
Casp3↑,
Apoptosis↑,
ROS↑,
HDAC1↓,
Ac-histone H3↑,
PUMA↑,
BAX↑,
PCNA↓,
Bcl-2↓,

1204- MET,    Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer
- in-vitro, Lung, A549 - in-vitro, Lung, H1299
MDA↑,
ROS↑,
Iron↑, iron ions
GSH↓,
T-SOD↓,
Catalase↓,
GPx4↓,
xCT↓,
NRF2↓,
HO-1↓,

2251- MF,  Rad,    BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damage
- in-vitro, Lung, A549 - in-vitro, HNSCC, UTSCC15 - in-vitro, CRC, DLD1 - in-vitro, PC, MIA PaCa-2
RadioS↑, enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls
DNAdam↑,
ROS↑,
ChemoSen∅, Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab
Pyruv↓, levels of pyruvate, succinate, aspartate and adenosindiphosphate (ADP) were significantly downregulated after BEMER therapy whereas serine showed significant upregulation
ADP:ATP↓,
ROS↑, BEMER therapy increases ROS levels leading to radiosensitization via increased induction of DSBs

2241- MF,    Pulsed electromagnetic therapy in cancer treatment: Progress and outlook
- Review, Var, NA
other↝, PEMFs act on the cell, it will firstly change the cell membrane transport capacity, osmotic potential and ionic valves
p‑ERK↝, Also, it will cause changes in mitochondrial protein profile, decrease mitochondrial phosphor-ERK (extracellular-signal-regulated kinase), p53, and cytochrome c, and activate OxPhos.
P53↝,
Cyt‑c↝,
OXPHOS↑,
Apoptosis↑, PEMFs decreases cellular stress factors, increase energy demand, this series of reactions will eventually lead to apoptosis.
ROS↑, The introduction of PEFs and PEMFs can improve the penetration efficiency of ROS, not only reduce the concentration of drugs, but also reduce the irradiation dose of CAP, w

2247- MF,    Effects of Pulsed Electromagnetic Field Treatment on Skeletal Muscle Tissue Recovery in a Rat Model of Collagenase-Induced Tendinopathy: Results from a Proteome Analysis
- in-vivo, Nor, NA
*Glycolysis↓, PEMF-treated animals exhibited decreased glycolysis and increased LDHB expression, enhancing NAD signaling and ATP production
*LDHB↑,
*NAD↑,
*ATP↑,
*antiOx↑, Antioxidant protein levels increased, controlling ROS production.
*ROS↑,
*YAP/TEAD↑, upregulation of YAP and PGC1alpha and increasing slow myosin isoforms, thus speeding up physiological recovery.
*PGC-1α↑,
*TCA↑, increased in PEMF-treated injured limbs
*FAO↑,
*OXPHOS↑, Oxidative phosphorylation was increased in the muscle of injured rats that underwent PEMF treatment

2245- MF,    Quantum based effects of therapeutic nuclear magnetic resonance persistently reduce glycolysis
- in-vitro, Nor, NIH-3T3
Warburg↓, tNMR might have the potential to counteract the Warburg effect known from many cancer cells which are prone to glycolysis even under aerobic conditions.
Hif1a↓, combined treatment of tNMR and hypoxia (tNMR hypoxia) led to significantly altered HIF-1α protein levels, namely a further overall reduction in protein amounts
*Hif1a∅, Under normoxic conditions we did not find significant differences in Hif-1α mRNA and protein expression
Glycolysis↓, hypoxic tNMR treatment, driving cellular metabolism to a reduced glycolysis while mitochondrial respiration is kept constant even during reoxygenation.
*lactateProd↓, tNMR reduces lactate production and decreases cellular ADP levels under normoxic conditions
*ADP:ATP↓,
Pyruv↓, Intracellular pyruvate, which was as well decreased in hypoxic control cells, appeared to be further decreased after tNMR under hypoxia
ADP:ATP↓, tNMR under hypoxia further decreased the hypoxia induced decrease of the intracellular ADP/ATP ratio
*PPP↓, pentose phosphate pathway (PPP) is throttled after tNMR treatment, while cell proliferation is enhanced
*mt-ROS↑, tNMR under hypoxia increases mitochondrial and extracellular, but reduces cytosolic ROS
*ROS↓, but reduces cytosolic ROS
RPM↑, Because EMFs are known to affect ROS levels via the radical pair mechanism (RPM)
*ECAR↓, tNMR under normoxic conditions reduces the extracellular acidification rate (ECAR)

2244- MF,    Little strokes fell big oaks: The use of weak magnetic fields and reactive oxygen species to fight cancer
- Review, Var, NA
RPM↑, WEMFs affect multiple cellular processes through mechanisms such as the radical pair mechanism (RPM), which alters reactive oxygen species (ROS) levels, mitochondrial function, and glycolysis
Glycolysis∅, WEMF parallel to the magnetic field (does not enchance glycolysis)
ROS↑, WEMF can augment this effect by enhancing mitochondrial respiration, which increases ROS levels within cancer cells. This augmentation makes cancer cells more susceptible to treatment by promoting oxidative stress that can lead to apoptosis
ChemoSen↑, Chemotherapeutic agents, such as doxorubicin, primarily exert their effects by generating ROS to induce cell death. WEMF can augment this effect by enhancing mitochondrial respiration, which increases ROS levels
RadioS↑, Similarly, WEMF can enhance the efficacy of radiation therapy by increasing ROS production and sensitizing cancer cells to radiation-induced DNA damage
selectivity↑, primary advantage of WEMF is its non-invasive, non-ionizing nature, which minimizes collateral damage to healthy tissue.

2261- MF,    Tumor-specific inhibition with magnetic field
- in-vitro, Nor, GP-293 - in-vitro, Liver, HepG2 - in-vitro, Lung, A549
ROS↑, It enhances cell oxidative stress response and regulates apoptosis signaling pathway, changing intracellular Ca2+ concentration to induce apoptosis
Ca+2↓,
Apoptosis↑,
*selectivity↑, No signicant difference was found between the exposed 293T cell count versus the control group without magnetic exposure on the third day of exposure.
TumCG↓, Hepg2, A549 cell counts were signicantly lower than the unexposed control groups (the highest inhibition rate of Hepg2 was about 18%, and the highest inhibition rate of A549 was about 30%).
*i-Ca+2↓, Normal cells 293T showed a significant decrease in intracellular free calcium ion,
i-Ca+2↑, solid tumor cells showed no signicant change, while suspended tumor showed a slight increase in calcium ion

2260- MF,    Alternative magnetic field exposure suppresses tumor growth via metabolic reprogramming
- in-vitro, GBM, U87MG - in-vitro, GBM, LN229 - in-vivo, NA, NA
TumCP↓, proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz.
TumCG↓, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival
OS↑,
ROS↑, This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression.
SOD2↑,
eff↓, anti-cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger.
ECAR↓, decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR).
OCR↑,
selectivity↑, This suggests that AMF-induced metabolic reprogramming occurs in GBM cells but not in normal cells. Furthermore, in cancer cells, AMF decreased ECAR and increased OCR, while there were no changes in normal cells.
*toxicity∅, did not affect non-cancerous human cells [normal human astrocyte (NHA), human cardiac fibroblast (HCF), human umbilical vein endothelial cells (HUVEC)].
TumVol↓, The results showed a significant treatment effect, as assessed by tumor volume, after conducting AMF treatment five times a week for 2 weeks
PGC-1α↑, Corresponding to the rise in ROS, there was also a time-dependent increase in PGC1α protein expression post-AMF exposure
OXPHOS↑, enhancing mitochondrial oxidative phosphorylation (OXPHOS), leading to increased ROS production
Glycolysis↓, metabolic mode of cancer cells to shift from glycolysis, characteristic of cancer cells, toward OXPHOS, which is more typical of normal cells.
PKM2↓, We extracted proteins that changed commonly in U87 and LN229 cells. Among the individual proteins related to metabolism, pyruvate kinase M2 (PKM2) was found to be inhibited in both.

582- MF,  immuno,  VitC,    Magnetic field boosted ferroptosis-like cell death and responsive MRI using hybrid vesicles for cancer immunotherapy
- in-vitro, Pca, TRAMP-C1 - in-vivo, NA, NA
Fenton↑, boost, Ascorbic acid (AA, C6H8O6) can act as an electron-donor
Ferroptosis↑, HCSVs and MF efficiently inhibited TRAMP-C1 growth through ferroptosis-mediated cell death.
ROS↑, The generated ferrous ions, inducing stronger Fenton-like oxidation than ferric ions, triggered the higher accumulation of ROS, and finally inhibited tumor cell growth
TumCG↓, Collectively, it was proved that the exogenous magnetic field-boosted Fenton reaction efficiently inhibit tumor growth.
Iron↑, after 10-min MF treatment, the increase of ferrous ions was found in 0.1 h
GPx4↓, combination treatment of MF and HCSVs downregulated GPX4

587- MF,  VitC,    Effect of stationary magnetic field strengths of 150 and 200 mT on reactive oxygen species production in soybean
ROS↑,
SOD↓,
other↓, ascorbic acid content decreased

538- MF,    The extremely low frequency electromagnetic stimulation selective for cancer cells elicits growth arrest through a metabolic shift
- in-vitro, BC, MDA-MB-231 - in-vitro, Melanoma, MSTO-211H
TumCG↓, did not affect the non-malignant counterpart.
Ca+2↑,
COX2↓,
ATP↑, (ATP5B) and mitochondrial transcription (MT-ATP6)
MMP↑, significant enhancement of mitochondrial membrane potential (ΔΨm)
ROS↑, demonstrated for the first time the association of ROS production with the stimulation of the mitochondrial metabolism triggered by the electromagnetic field
OXPHOS↑,
mitResp↑, Mitochondrial respiration is increased by ELF-EMF exposure

526- MF,    Inhibition of Cancer Cell Growth by Exposure to a Specific Time-Varying Electromagnetic Field Involves T-Type Calcium Channels
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Pca, HeLa - vitro+vivo, Melanoma, B16-BL6 - in-vitro, Nor, HEK293
TumCG↓, Exposure to Thomas-EMF inhibited tumour growth in mice
Ca+2↑, exposure of malignant cells to Thomas-EMF for > 15 min promoted Ca2+ influx
selectivity↑, but did not effect non-malignant cells
*Ca+2∅, only malignant cells showed enhanced Ca2+ uptake following exposure to Thomas-EMF.
ROS↑, EMF-dependent increases in reactive oxygen species, rapid influx of Ca2+, or activation of specific signaling pathway
HSP70/HSPA5↑, Some studies have shown increased expression of HSP70, a marker of cellular stress responses, in response to EMF exposures
AntiCan↑, These observations suggest that the Thomas-EMF could provide a potential anti-cancer therapy.

527- MF,    Effects of Fifty-Hertz Electromagnetic Fields on Granulocytic Differentiation of ATRA-Treated Acute Promyelocytic Leukemia NB4 Cells
- in-vitro, AML, APL NB4
ROS↑, a significant increase in ROS levels was observed shortly after exposure to ELF-EMF
other↑, F-EMF exposure promotes ATRA-induced differentiation in APL NB4 cells and suggest the possible involvement of ROS and ERK signalling pathway in this phenomenon
p‑ERK↑, ERK1/2 phosphorylation
TumCP↓, ELF-EMF exposure decreases cellular proliferation potential

529- MF,    Low-frequency magnetic field therapy for glioblastoma: Current advances, mechanisms, challenges and future perspectives
- Review, GBM, NA
Ca+2↑, U-373MG 50 Hz, 3 mT 24 h Increased the intracellular Ca2+
ROS↑, BT115, U87, BT175 50–350 Hz, 1–58 mT 2–4 h Increased the ROS level and cell death
ChemoSen↑, A growing amount of evidence has validated that LF-MFs combined with chemotherapeutic drugs have a synergistic effect in the treatment of GBM
QoL↑, For example, researchers have discovered that LF-MFs can improve the quality of life of patients with recurrent GBM
OS↑, clinical trials have also validated the excellent therapeutic efficacy of LF-MFs in prolonging OS and improving quality of life in GBM patients

532- MF,    A 50 Hz magnetic field influences the viability of breast cancer cells 96 h after exposure
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
TumCP↓,
MMP↓, MCF-7 breast cancer cells showed a significant decrease in ΔΨM compared with control cells after 4 and 24 h of exposure only when ΔΨM was analyzed at 96 h
ROS↑, All three breast cell lines analyzed showed an increase in ROS levels compared to those in nonexposed cells after both 4 h and 24 h of 1.0 mT ELF-MF exposure
eff↝, short-term exposure (4–8 h, 0.1 mT and 1.0 mT) led to an increase in viability in breast cancer cells, while long and high exposure (24 h, 1.0 mT) led to a decrease in viability and proliferation in all cell lines.
selectivity↑, Conversely, we did not observe significant differences in MCF-10A live cell number after 0.1 mT ELF-MF cell exposure

533- MF,    Effects of extremely low-frequency magnetic fields on human MDA-MB-231 breast cancer cells: proteomic characterization
- in-vitro, BC, MDA-MB-231 - in-vitro, Nor, MCF10
TumCD↑,
necrosis↑, in normal MCF10A cells
mt-ROS↑, ELF-MF significantly increase the mitochondrial reactive oxygen species production in both MCF-10A and MDA-MB-231 cells, compared to the unexposed cell
other↑, ELF-MF exposed MCF-10A cells exhibited 53 upregulated and 189 downregulated proteins compared with control cells while exposed MDA-MB-231 cells showed 242 upregulated and 86 downregulated proteins compared with the control cells.
*STAT3↓, normal cells
STAT3↑, cancer cells

537- MF,  immuno,    Integrating electromagnetic cancer stress with immunotherapy: a therapeutic paradigm
- Review, Var, NA
Apoptosis↑,
ROS↑,
TumAuto↑,
Ca+2↑, Ca++ ion tumor-cell entry
ATP↓, ATP depletion
eff↑, In physical terms, the rate of rise in a magnetic pulse or oscillation (i.e., its “sharpness”) is conveyed as dB/dt). The EMF induced by that particular period of rise to the maximum amplitude may be more impactful on unique tumor cellular features
eff↑, The induction intensity (dB/dt) may well be more critical than the field maximum amplitude (B max) in this setting

496- MF,    Low-Frequency Magnetic Fields (LF-MFs) Inhibit Proliferation by Triggering Apoptosis and Altering Cell Cycle Distribution in Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, ZR-75-1 - in-vitro, BC, T47D - in-vitro, BC, MDA-MB-231
ROS↑, LF-MFs Enhanced the ROS Levels in MCF-7 and ZR75-1 Cells
PI3K↓, and inhibited the activities of the PI3K/AKT signaling pathways in MCF-7 and ZR-75-1 cells
Akt↓,
GSK‐3β↑, LF-MF Induced MCF-7 and ZR75-1 Cells Apoptosis by Activating GSK-3β
Apoptosis↑, LF-MF Induced Breast Cancer Cell Apoptosis
cl‑PARP↑, cleaved PARP-1
cl‑Casp3↑,
BAX↑,
Bcl-2↓,
CycB/CCNB1↓, Cyclin B1
TumCCA↑, failure of the transition from the G2 phase to M phase
p‑Akt↓,
TumCP↓, LF-MF Inhibited the Proliferation of Breast Cancer Cells
selectivity↑, The viabilities of HUVECs did not markedly reduce after exposure in LF-MF at the four selected frequencies for 6, 12, 24 or 36 h
eff↓, attenuated by ROS scavenger NAC

490- MF,    Extremely Low Frequency Magnetic Field (ELF-MF) Exposure Sensitizes SH-SY5Y Cells to the Pro-Parkinson's Disease Toxin MPP(.)
- in-vitro, Park, SH-SY5Y
ROS↑,

500- MF,    Anti-Oxidative and Immune Regulatory Responses of THP-1 and PBMC to Pulsed EMF Are Field-Strength Dependent
- in-vitro, AML, THP1
ROS↑, only in THP1 cells, not in normal cells ***
Prx6↑, 2x
DHCR24↑, 6x
IL10↑, 6x

503- MF,    Effects of acute and chronic low frequency electromagnetic field exposure on PC12 cells during neuronal differentiation
- in-vitro, NA, PC12
ROS↑,
Ca+2↑,

507- MF,    Effects of extremely low frequency electromagnetic fields on the tumor cell inhibition and the possible mechanism
- in-vitro, Liver, HepG2 - in-vitro, Lung, A549 - in-vitro, Nor, GP-293
MMP↓,
TumCG↓,
ROS↑, key to tumor growth inhibition
*Ca+2↓, Normal 293 T cells showed a significant decrease in the intracellular free calcium ion concentration.
Ca+2↑, The solid tumor cells showed no significant change, while the suspended tumor cells showed a slight increase in the calcium ion concentration
selectivity↑,
i-pH↑, In addition, the intracellular pH of A549 cells increased under the magnetic field.

508- MF,  doxoR,    Synergistic cytotoxic effects of an extremely low-frequency electromagnetic field with doxorubicin on MCF-7 cell line
- in-vitro, BC, MCF-7
ROS↑,
Apoptosis↑,
TumCCA↑, enhanced arrest of MCF-7 cells in the G0-G1 phase

509- MF,    Is extremely low frequency pulsed electromagnetic fields applicable to gliomas? A literature review of the underlying mechanisms and application of extremely low frequency pulsed electromagnetic fields
- Review, NA, NA
Ca+2↑,
TumAuto↑,
Apoptosis↑,
angioG↓,
ROS↑,

520- MF,    Exposure to a 50-Hz magnetic field induced mitochondrial permeability transition through the ROS/GSK-3β signaling pathway
- in-vitro, Nor, NA
*MPT↑, MPT induced by MF exposure was mediated through the ROS/GSK-3β signaling pathway.
*Cyt‑c↑, induced Cyt-c release
*ROS↑, cells exposed to the MF showed increased intracellular reactive oxidative species (ROS) levels and glycogen synthase kinase-3β (GSK-3β) dephosphorylation at 9 serine residue (Ser(9))
*p‑GSK‐3β↑,
*eff↓, attenuated by ROS scavenger (N-acetyl-L-cysteine, NAC) or GSK-3β inhibitor
*MMP∅, no significant effect on mitochondrial membrane potential (ΔΨm)
*BAX↓, Bax declined around 15% which was statistically significant while the total level of Bcl-2 reminded unchanged in cells
*Bcl-2∅,

4093- MF,    Low-intensity electromagnetic fields induce human cryptochrome to modulate intracellular reactive oxygen species
- in-vivo, NA, NA
*ROS↑, imaging experiments that exposure of mammalian cells to weak pulsed electromagnetic fields (PEMFs) stimulates rapid accumulation of reactive oxygen species (ROS),
*eff↑, At moderate doses, we find that reactive oxygen actively stimulates cellular repair and stress response pathways, which might account for the observed therapeutic effects to repetitive magnetic stimulation.

4092- MF,    Mechanisms and therapeutic effectiveness of pulsed electromagnetic field therapy in oncology
- Review, Var, NA
Apoptosis↑, 20 Hz; 3 mT, 60mins/day PEMFs increased apoptosis in MCF7 cells but had no effect on MCF10 cells
selectivity↑,
ROS↑, 50 Hz, 0.1–1.0 mT) for 30 min, and long‐term PEMF: undifferentiated PC12 cells increased ROS levels and decreased catalase activity
Catalase↓,
TumVol↓, 1 Hz, 100 mT, Mice exposed for 60 and 180 min daily showed a 30% and 70% tumor reduction
angioG↓, PEMFs inhibit angiogenesis in tumor tissues, suppressing tumor vascularization and reducing tumor growth, as shown by in vivo studies

4104- MF,    Effects of exposure to extremely low-frequency electromagnetic fields on spatial and passive avoidance learning and memory, anxiety-like behavior and oxidative stress in male rats
- in-vivo, NA, NA
*memory↑, Our results may allow the conclusion that exposure to ELF-EMFs can improve memory retention (but not acquisition) in the adult male rats.
*ROS↑, Although exposure to ELF-EMFs could be a factor in the development of anxious state or oxidative stress.

4103- MF,    Comparing the Effects of Long-term Exposure to Extremely Low-frequency Electromagnetic Fields With Different Values on Learning, Memory, Anxiety, and β-amyloid Deposition in Adult Rats
- in-vivo, NA, NA
*Dose↝, 1, 100, 500, and 2000 microtesla (μT), 50 Hz frequency for one h/day for two months,
*memory↑, Exposure to ELF-EMF had an anxiogenic effect on rats, promoted memory, and induced oxidative stress.
*ROS↑, exposure to the magnetic fields caused a significant increase (P<0.05) in TOS in the serum of 100, 500, and 2000 μT, compared with the control group
*MDA↑, Our results declared that the exposure to the magnetic fields caused a significant increase (P<0.05) in the levels of MDA in groups 1, 100, 500, and 2000 μT, in comparison to the control group

3457- MF,    Cellular stress response to extremely low‐frequency electromagnetic fields (ELF‐EMF): An explanation for controversial effects of ELF‐EMF on apoptosis
- Review, Var, NA
Apoptosis↑, Ding et al., 8 it was demonstrated that 24‐h exposure to 60 Hz, 5 mT ELF‐EMF could potentiate apoptosis induced by H2O2 in HL‐60 leukaemia cell lines.
H2O2↑,
ROS↑, One of the main mechanisms proposed for defining anticancer effects of ELF‐EMF is induction of apoptosis through upregulation of reactive oxygen species (ROS) which has also been confirmed by different experimental studies.
eff↑, intermittent 100 Hz, 0.7 mT EMF significantly enhanced rate of apoptosis in human hepatoma cell lines pretreated with low‐dose X‐ray radiation.
eff↑, 50 Hz, 45 ± 5 mT pulsed EMF, significantly potentiated rate of apoptosis induced by cyclophosphamide and colchicine
Ca+2↑, Over the past few years, lots of data have shown that ELF‐EMF exposure regulates intracellular Ca2+ level
MAPK↑, Mitogen‐activated protein kinase (MAPK) cascades are among the other important signalling cascades which are stimulated upon exposure to ELF‐EMF in several types of examined cells
*Catalase↑, ELF‐EMF exposure can upregulate expression of different antioxidant target genes including CAT, SOD1, SOD2, GPx1 and GPx4.
*SOD1↑,
*GPx1↑,
*GPx4↑,
*NRF2↑, Activation and upregulation of Nrf2 expression, the master redox‐sensing transcription factor may be the most prominent example in this regard which has been confirmed in a Huntington's disease‐like rat model.
TumAuto↑, Activation of autophagy, ER stress, heat‐shock response and sirtuin 3 expression are among the other identified cellular stress responses to ELF‐EMF exposure
ER Stress↑,
HSPs↑,
SIRT3↑,
ChemoSen↑, Contrarily, when chemotherapy and ELF‐EMF exposure are performed simultaneously, this increase in ROS levels potentiates the oxidative stress induced by chemotherapeutic agents
UPR↑, In consequence of ER stress, cells begin to initiate UPR to counteract stressful condition.
other↑, Since the only proven effects of ELF‐EMF exposure on cells are cellular adaptive responses, ROS overproduction and intracellular calcium overload
PI3K↓, figure 3
JNK↑,
p38↑,
eff↓, ontrarily, when cells are exposed to ELF‐EMF, a new source of ROS production is introduced in cells which can at least partially reverse anticancer effects observed with cell's treatment with melatonin.
*toxicity?, More importantly, ELF‐EMF exposure to normal cells in most cases has shown to be safe and un‐harmful.

3480- MF,    Cellular and Molecular Effects of Magnetic Fields
- Review, NA, NA
ROS↑, 50 Hz, 1 mT for 24/48/72 h SH-SY5Y (neuroblastoma Significantly increased ROS levels
*Ca+2↑, There is experimental proof that extremely low-frequency (ELF-MF) magnetic fields interact with Ca2+ channels, leading to increased Ca2+ efflux
*Inflam↓, PEMF stimulates the anti-inflammatory response of mesenchymal stem cells.
*Akt↓, nasopharyngeal carcinoma cell line. Potentially, these alterations were caused by inhibition of the Akt/mTOR signaling pathway
*mTOR↓,
selectivity↑, Ashdown and colleagues observed disruptions in the human lung cancer cell line after PMF (20 mT) exposure; in comparison, normal cells were insensitive to PMF
*memory↑, Ahmed and colleagues proved that PMF has an impact on the hippocampus, the brain region responsible for spatial orientation and memory acquisition.
*MMPs↑, In wound closure, epithelial cells, connective tissue cells, and immune cells, which promote collagen production, matrix metalloproteinase activity, growth factor release (e.g., VEGF, FGF, PDGF, TNF, HGF, and IL-1), and inflammatory environment pro
*VEGF↑,
*FGF↑,
*PDGF↑,
*TNF-α↑,
*HGF/c-Met↑,
*IL1↑,

3477- MF,    Electromagnetic fields regulate calcium-mediated cell fate of stem cells: osteogenesis, chondrogenesis and apoptosis
- Review, NA, NA
*Ca+2↑, When cells are subjected to external mechanical stimulation, voltage-gated ion channels in the cell membrane open and intracellular calcium ion concentration rises
*VEGF↑, BMSCs EMF combined with VEGF promote osteogenesis and angiogenesis
*angioG↑,
Ca+2↑, 1 Hz/100 mT MC4-L2 breast cancer cells EMF lead to calcium ion overload and ROS increased, resulting in necroptosis
ROS↑,
Necroptosis↑,
TumCCA↑, 50 Hz/4.5 mT 786-O cells ELF-EMF induce G0/G1 arrest and apoptosis in cells lines
Apoptosis↑,
*ATP↑, causing the ATP or ADP increases, and the purinergic signal can upregulate the expression of P2Y1 receptors
*FAK↑, Our research team [53] found that ELE-EMF can induce calcium oscillations in bone marrow stem cells, up-regulated calcium ion activates FAK pathway, cytoskeleton enhancement, and migration ability of stem cells in vitro is enhanced.
*Wnt↑, ability of EMF to activate the Wnt10b/β-catenin signaling pathway to promote osteogenic differentiation of cells depends on the functional integrity of primary cilia in osteoblasts.
*β-catenin/ZEB1↑,
*ROS↑, we hypothesize that the electromagnetic field-mediated calcium ion oscillations, which causes a small amount of ROS production in mitochondria, regulates the chondrogenic differentiation of cells, but further studies are needed
p38↑, RF-EMF was able to suppress tumor stem cells by activating the CAMKII/p38 MAPK signaling pathway after inducing calcium ion oscillation and by inhibiting the β-catenin/HMGA2 signaling pathway
MAPK↑,
β-catenin/ZEB1↓,
CSCs↓, Interestingly, the effect of electromagnetic fields is not limited to tumor stem cells, but also inhibits the proliferation and development of tumor cells
TumCP↓,
ROS↑, breast cancer cell lines exposed to ELE-EMF for 24 h showed a significant increase in intracellular ROS expression and an increased sensitivity to further radiotherapy
RadioS↑,
Ca+2↑, after exposure to higher intensity EMF radiation, showed a significant increase in intracellular calcium ion and reactive oxygen species, which eventually led to necroptosis
eff↓, while this programmed necrosis of tumor cells was able to be antagonized by the calcium blocker verapamil or the free radical scavenger n -acetylcysteine
NO↑, EMF can regulate multiple ions in cells, and calcium ion play a key role [92, 130], calcium ion acts as a second messenger that can activate downstream molecules such as NO, ROS

3500- MF,    Moderate Static Magnet Fields Suppress Ovarian Cancer Metastasis via ROS-Mediated Oxidative Stress
- in-vitro, Ovarian, SKOV3
ROS↑, SMFs increased the oxidative stress level and reduced the stemness of ovarian cancer cells.
CSCs↓,
CD44↓, xpressions of stemness-related genes were significantly decreased, including hyaluronan receptor (CD44), SRY-box transcription factor 2 (Sox2), and cell myc proto-oncogene protein (C-myc).
SOX2↓,
cMyc↓,
TumMeta↓, High Levels of Cellular ROS Inhibit Ovarian Cancer Cell Migration and Invasion
TumCI↓,
TumCMig↓, Moderate SMFs Increase Ovarian Cancer Cell ROS Levels and Inhibit Cell Migration
CD133↓, stemness-related genes were significantly downregulated by SMF treatment, including Sox2, Nanog, C-myc, CD44, and CD133
Nanog↓,

3470- MF,    Pulsed electromagnetic fields inhibit IL-37 to alleviate CD8+ T cell dysfunction and suppress cervical cancer progression
- in-vitro, Cerv, HeLa
TNF-α↑, PEMF treatment significantly inhibited IL-37 expression (p < 0.05), promoted inflammatory factor release (TNF-α and IL-6), and activated oxidative stress, leading to increased CC cell apoptosis
IL6↑,
ROS↑,
Apoptosis↑,
TumCP↓, Co-culture of Hela cells with CD8+ T cells under PEMF treatment showed reduced proliferation (by 40%), migration, and invasion (p < 0.05).
TumCMig↓,
TumCI↓,

3469- MF,    Pulsed Electromagnetic Fields (PEMF)—Physiological Response and Its Potential in Trauma Treatment
- Review, NA, NA
*eff↑, According to this analysis, pulse repetition frequencies higher than 100 Hz with magnet flux densities between 1 mT and 10 mT lead to the highest presence of a cellular response, although this may vary depending on the cell type and stage of growth
*eff↝, Also, repeated applications over a prolonged period of more than 10 days show a higher effect than shorter periods, while a prolonged acute exposure lasting more than 24 h seems to be less effective than an acute exposure with less than 24 h applicat
*other↑, release of Ca2+ ion and the direct activation of PEMF on voltage-gated calcium channels (VGCCs) is of great relevance.
Ca+2↑, PEMF stimulation also leads to similar membrane effects, resulting in a Ca2+ influx, which triggers further cellular signals
ROS↑, It has been proposed that the accumulation of ROS or oxidative stress may cause the upregulation of heat shock proteins (Hsp70, HIF-1), leading to cell damage.
HSP70/HSPA5↑,
*NOTCH↑, PEMF has been shown to increase the expressions of Notch4 and Hey1 during osteogenic differentiation of MSCs, suggesting that the Notch pathway, important in cellular fate and bone development, is activated by PEMF in stem cells
*HEY1↑,
*p38↑, PEMF-induced osteogenic differentiation MSCs, as well as the activation of p38 MAPK
*MAPK↑,

3468- MF,    An integrative review of pulsed electromagnetic field therapy (PEMF) and wound healing
- Review, NA, NA
*other↑, studies suggest that PEMF accelerates early stages of wound closure
*necrosis↓, By preventing necrosis, PEMF can potentially be used to reduce the incidence of ulcer formation and amputation in patients with diabetes.
*IL6↑, When gingival wounds were exposed to PEMF, one study measured an increased expression of various signalling molecules involved in proliferation including IL‑6, TGF‑β and iNOS
*TGF-β↑,
*iNOS↑,
*MMP2↑, The same study also found increased levels of MMP‑2, MCP‑1 and HO‑1 expression, all of which are thought to increase wound repair rate
*MCP1↑,
*HO-1↑,
*Inflam↓, PEMF has also been shown to reduce inflammation in chronic wounds through both intracellular and extracellular effects.
*IL1β↓, Multiple studies have measured reductions in inflammatory cytokines (IL‑1β, IL‑6, TNF‑α) following PEMF treatment
*IL6↓,
*TNF-α↓,
*BioAv↑, Electrochemotherapy mediated by PEMF was found to have a 2-fold increase in drug uptake compared to traditional electrochemotherapy in rat melanoma models
eff⇅, PEMF at 50Hz, 1mT for 1 hour had increased keratinocyte proliferation compared to control groups, while the same tissue exposed to PEMF at 60Hz, 1.5mT for 144 hours had reduced cell proliferation
DNAdam↑, At higher frequencies (6–7mT), an increase in DNA double-strand breaks, apoptosis and levels of reactive oxygen species (ROS) were measured, contributing to the inhibition of cell proliferation.
Apoptosis↑,
ROS↑,
TumCP↓,
*ROS↓, tissues exposed to lower frequencies of PEMF (1mT) had decreased ROS levels
*FGF↑, Furthermore, both diabetes-related and non-diabetes-related incision wounds had similar levels of increased FGF‑2, promoting angiogenesis and preventing necrosis in response to ischaemic injury

3464- MF,    Progressive Study on the Non-thermal Effects of Magnetic Field Therapy in Oncology
- Review, Var, NA
AntiTum↑, frequency below 300 Hz) exert anti-tumor function, independent of thermal effects
TumCG↓, Magnetic fields (MFs) could inhibit cell growth and proliferation; induce cell cycle arrest, apoptosis, autophagy, and differentiation; regulate the immune system; and suppress angiogenesis and metastasis via various signaling pathways
TumCCA↑,
Apoptosis↑,
TumAuto↑,
Diff↑,
angioG↓,
TumMeta↓,
EPR↑, MFs not only promote the absorption of chemotherapy drugs by producing small holes on the surface of cell membrane
ChemoSen↑,
ROS↑, MF treatment has been shown to promote the generation of ROS in many studies (31, 71, 72), with exposure within a 60 Hz sinusoidal MF for 48 h in induced human prostate cancer for DU145, PC3, and LNCaP apoptoses
DNAdam↑, Repetitive exposure to LF-MFs induced DNA damage and accumulation of DSBs and triggered apoptosis in Hela and MCF7 cell lines
P53↑, PMFs could trigger apoptosis cell death by upregulating the p53 level and through the mitochondrial-dependent pathway
Akt↓, LF-MFs (300 mT, 6 Hz, 24 h) also induced apoptosis by suppressing protein kinase B (Akt) signaling, activating p38 mitogen-activated protein kinase (MAPK) signaling, and caspase-9, which is the executor of the mitochondrial apoptosis pathway
MAPK↑,
Casp9↑,
VEGFR2↓, reducing the expression and activation levels of VEGFR2
P-gp↓, A combination with the SMF (8.8 m T, 12 h) decreased the expression of P-glycoprotein (P-gp) in K562 cancer cells, while adriamycin itself induced an increase

3486- MF,    Pulsed electromagnetic field potentiates etoposide-induced MCF-7 cell death
- in-vitro, NA, NA
ChemoSen↑, It is established that pulsed electromagnetic field (PEMF) therapy can enhance the effects of anti-cancer chemotherapeutic agents
tumCV↓, co-treatment with etoposide and PEMFs led to a decrease in viable cells compared with cells solely treated with etoposide.
cl‑PARP↑, PEMFs elevated the etoposide-induced PARP cleavage and caspase-7/9 activation and enhanced the etoposide-induced down-regulation of survivin and up-regulation of Bax.
Casp7↑,
Casp9↑,
survivin↓,
BAX↑,
DNAdam↑, PEMF also increased the etoposide-induced activation of DNA damage-related molecules
ROS↑, the reactive oxygen species (ROS) level was slightly elevated during etoposide treatment and significantly increased during co-treatment with etoposide and PEMF.
eff↓, Moreover, treatment with ROS scavenger restored the PEMF-induced decrease in cell viability in etoposide-treated MCF-7 cells

5241- MF,    A review on the use of magnetic fields and ultrasound for non-invasive cancer treatment
- Review, Var, NA
other↑, Magnetic fields have been found to stimulate collagen density in and around the joints, and help to trigger Ca2+ flow to the defect site resulting in faster bone healing
BloodF↑, blood microcirculation revealed that magnetic fields have strong influence on relaxation and constriction of capillary blood vessels which alters the blood flow.
Glycolysis↓, In general, the glycolysis and glucose oxidations are decreased in diabetic patients leading to lower ATP production.
ATP↓,
VEGF↓, Application of magnetic fields can significantly decrease VEGF level and therefore reduces the growth and distribution of cancer to other parts of the body
ROS↑, SMF interacts with the charged molecules (ions, proteins etc.) of biological system through several physical mechanisms and alters the activity, concentration, and life time of paramagnetic free radicals i.e. ROS (reactive oxygen species),
P-gp↓, study demonstrated that 8.8 mT SMF enhances cytotoxic potency of Adriamycin on K562 cells due to decrease in the P-gp expression
Apoptosis↑, n vitro analysis in terms of apoptosis and cell electrical properties showed that MCF7 cells are highly reactive to 3 mT flux density and normal cells (MCF10) are unaffected.
selectivity↑,
Ca+2↑, Long PMF (50 Hz, 0.1–1 mT) for 7 days Undifferentiated PC12, increased intracellular Ca+ concentration and Catalase activity.
Catalase↑,

4356- MF,    Pulsed electromagnetic fields synergize with graphene to enhance dental pulp stem cell-derived neurogenesis by selectively targeting TRPC1 channels
- in-vitro, Nor, NA
*Diff↑, brief PEMF exposure promotes in vitro differentiation by activating a TRPC1-mitochondrial axis
*TRPC1↑,
*ROS↑, PEMF-stimulated neurogenic induction of hDPSCs through their mutual capacity to activate TRPC1with subsequent ROS production.

4355- MF,    Ambient and supplemental magnetic fields promote myogenesis via a TRPC1-mitochondrial axis: evidence of a magnetic mitohormetic mechanism
- in-vitro, Nor, C2C12
*mt-OCR↑, figure 1
*mt-ROS↑, Exposure to PEMFs stimulated the production of ROS (Fig. 6A, B) and ATP
*ECAR↑, figure 6
*Dose↝, barrages of 20 × 150 μs on and off pulses for 6 ms repeated at a frequency of 15 Hz. The magnetic flux density rose to predetermined maximal level within ∼50 μs (∼17 T/s) when driving field amplitudes between 0.5 and 3 mT.
*Ca+2↑, 10 min) of C2C12 myoblasts to PEMFs (Supplemental Fig. S1A) augmented cytosolic calcium levels [intracellular [Ca2+] concentration ([Ca2+]i), blue] relative to unexposed myoblasts
*ATP↑,
*other↑, PEMF-stimulated proliferation of myoblasts
*eff↓, TRPC1 silencing precludes PEMF sensitivity.
*eff↝, revealed a magnetic efficacy window

4354- MF,  doxoR,    Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach
- in-vivo, BC, MDA-MB-231 - in-vivo, BC, MCF-7
selectivity↑, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples
Apoptosis↑,
TumCI↓, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression
tumCV↓, PEMF exposure was previously shown to impair the viability of MCF-7 breast cancer cells when administered at an amplitude of 3 mT for 1 h per day
TumVol↓, PEMF treatment alone significantly reduced tumor volume by ~-20%
eff↓, Notably, stronger PEMF exposures (5 mT) were ineffective at killing MCF-7 and MDA-MB-231 breast cancer cells
eff↑, PEMF and DOX treatments hence synergize in vitro to slow breast cancer cell growth.
ROS↑, figure 4. PEMF exposure stimulates ROS production in cancer (29, 30) and non-cancer (5, 31, 32) cells.
Ca+2↑, PEMF exposure (blue) consistently increased cytoplasmic calcium over baseline (red) and was further augmented with increasing DOX concentration
TumCMig↓, PEMF Exposure Slows the Migration and Decreases the Invasiveness of TRPC1-Overexpressing Breast Cancer Cells

2259- MFrot,  MF,    Method and apparatus for oncomagnetic treatment
- in-vitro, GBM, NA
MMP↓, Oncomagnetic patent Fig 2
Bcl-2↓,
BAX↑,
Bak↑,
Cyt‑c↑,
Casp3↑, caspase staining rises progressively until after 30 min most of the cells fluoresce positive for caspase, revealing activation of this enzyme
Casp9↑,
DNAdam↑,
ROS↑, applying the oscillating magnetic field to the tissue increases the production of reactive oxygen species (ROS )
lactateProd↑,
Apoptosis↑,
MPT↑, opening of the mitochondrial membrane permeability transition pore
*selectivity↑, repetitive magnetic stimulation has shown decreased apoptosis in non -cancerous cells .
eff↑, oncomagnetic therapy may be performed in conjunction with other forms of therapy such as with chemotherapy, other forms of radiative therapy, with drugs and prescriptions, etc
MMP↓, OMF which in turn produces rapidly fluctuating or sustained depolarizations of the mitochondrial membrane potential (MMP) in the tissue .
selectivity↑, Because normal cells have a larger amount of mitochondria, have lower demand for ATP, and are not under stress, disruption of electron flow and small amount of ROS formation and MMP depolarization does not trigger apoptosis
TCA?, decrease in Krebs cycle metabolites
H2O2↑, increase in peroxide levels in GBM cells following stimulation by the system 100 using a rotating magnet
eff↑, combine the administration of BHB , or acetoacetate , or free fatty acid, or branched chain amino acid, or cryptochrome agonist , or MGMT inhibitor, or DNA alkylating agent, or DNA methylating agent, and OMF as a more effective treatment of cancer
*antiOx↑, upregulation of antioxidant mechanisms due to the application of OMFs further protects non -cancerous cells from any ROS -mediated apoptosis
H2O2↑, The experiments showed rapid increases in the levels of superoxide and H2O2 in GBM cells
eff↓, To test whether cell death is caused by the OMF - induced increase in ROS , a potent antioxidant Trolox was used to counteract it, while measuring the decrease in GBM cell count due to 4 h exposure to OMF.
GSH/GSSG↓, GSH/GSSG ratio almost exactly half that seen in control cells
*toxicity∅, No Cytotoxic Effect in Normal Cells
OS↑, OMF -Induced Prolongation of Survival in a Mouse Xenograft Model of GBM

2258- MFrot,  MF,    EXTH-68. ONCOMAGNETIC TREATMENT SELECTIVELY KILLS GLIOMA CANCER CELLS BY INDUCING OXIDATIVE STRESS AND DNA DAMAGE
- in-vitro, GBM, GBM - in-vitro, Nor, SVGp12
TumVol↓, GBM patient reversed the progression of his recurrent tumor causing >30% reduction in its contrast-enhanced volume within 4 weeks of treatment
OS↑, Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p< 0.05, n = 10)
γH2AX↑, higher DNA damage (g-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us
DNAdam↑,
selectivity↑, Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs
ROS↑, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes
TumCD↑,
eff↑, sOMF exposure for just 2 h resulted in >40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose.
eff↓, This loss was rescued by the antioxidant Trolox

516- MFrot,  immuno,  MF,    Anti-tumor effect of innovative tumor treatment device OM-100 through enhancing anti-PD-1 immunotherapy in glioblastoma growth
- vitro+vivo, GBM, U87MG
TumCP↓,
Apoptosis↑,
TumCMig↓,
ROS↑, treatment with OM-100 led to an increase in intracellular ROS levels
PD-L1↑, upregulating PD-L1 expression, thereby enhancing the efficacy of anti-PD-1 immunotherapy
TumVol↓, in mice
eff↑, enhance the efficacy of anti‑PD‑1 immunotherapy in vivo
*toxicity∅, OM-100 did not result in noteworthy changes in the blood routine parameters (Gran, HCT, HGB, Lymph, MCH, MCV, PLT, RBC, MPV, and WBC) and biochemical indicators (ALT, AST, T-BIL, CREA, TG, TC, HDL-c, and LDL-c) in normal mice
eff↑, Particularly, there was a more pronounced response to anti-PD-1 therapy in patients whose tumors expressed PD-L1 3
*toxicity∅, OM-100 treatment in healthy mice showed no adverse effects, indicating its safety for normal tissues.
Dose↝, 24-day treatment with a magnetic field intensity of 1.066 mT and a frequency of 100 kHz (figure shows motor driven 120Hz, 7200rpm pulsed
tumCV↓, anti-tumor efficacy of OM-100 treatment, which by impairing cell viability, increasing apoptosis, inhibiting cell migration, and invasion capabilities, as well as promoting oxidative stress.
TumCI↓,

186- MFrot,  MF,    Selective induction of rapid cytotoxic effect in glioblastoma cells by oscillating magnetic fields
- in-vitro, GBM, GBM - in-vitro, Lung, NA
mt-ROS↑, Cytotoxic effects of OMF may be caused by an increase in ROS
Casp3↑, Cell death is associated with activation of caspase 3
selectivity↑, OMF induces highly selective cell death of patient derived GBM cells associated with activation of caspase 3, while leaving normal tissue cells undamaged
TumCD↑, Exposure to OMF causes cancer cell death
ETC↓, The underlying mechanism is a marked increase in ROS in the mitochondria, possibly in part through perturbation of the electron flow in the respiratory chain.
H2O2↑, Figure 6A shows rapid increases in the levels of superoxide and H 2 O 2 in GBM cells,
eff↓, we used the potent antioxidant Trolox to counteract it,
GSH↑, We tested whether GSH synthesis was upregulated as a feedback protective effect in response to OMF-induced increase in ROS. An examination of GSH levels showed that there was a 20% elevation in treated cells
MMP↓, underlying mechanism involves a marked increase in ROS, mitochondrial membrane depolarization, fragmentation of mitochondrial network and activation of caspase 3.

190- MFrot,  MF,  Chemo,    The efficacy and safety of low-frequency rotating static magnetic field therapy combined with chemotherapy on advanced lung cancer patients: a randomized, double-blinded, controlled clinical trial
- Human, Lung, NA
*IP-10/CXCL-10↑, MF group patients had higher concentrations of IP-10 and GM-CSF, and lower concentration of sTREM-1 in plasma
*GM-CSF↑, in PLASMA
*TREM-1↓, sTREM-1, in PLASMA
QoL↑, Comparing to CON group, more patients in MF group (66.7% vs 25.9%) were experiencing life quality improvement on day 21. significantly higher increase of FACT-L,TOI and LCS scores
Ca+2↑, MF treated cells were found to have higher intracellular Ca2+ concentration and Reactive Oxygen Species (ROS) reaction level, which led to higher apoptosis rates(Zhang et al. 2010;
ROS↑,
Apoptosis↑,
OS↑, median survival time for MF group and CON group was 6.7 months and 6.07 month respectively

188- MFrot,  MF,    Spinning magnetic field patterns that cause oncolysis by oxidative stress in glioma cells
- in-vitro, GBM, GBM115 - in-vitro, GBM, DIPG
ROS↑, both GBM and DIPG cells ROS generated by sOMF
SDH↓, Complex II succinate dehydrogenase
eff↓, antioxidant Trolox reverses the cytotoxic effect of sOMF on glioma cells indicating that ROS play a causal role in producing the effect
RPM↑, we hypothesized that the interaction of weak and intermediate strength magnetic fields with the RPM mechanism in the mitochondrial ETC can perturb the electron transfer process (MEP hypothesis) to generate superoxide.
eff↓, We observed that Helmholtz coil did not produce any significant increase in ROS at 2 and 4 h during stimulation or 2 h poststimulation in GBM and DIPG cells
eff↑, oscillating field alone is not sufficient to induce ROS and that the changing angle of the magnetic field axis is also required to achieve this effect.
eff↝, repeated pulse trains rising to and declining from the peak frequency with intervening pauses are sufficient to achieve near maximum level of increase in ROS
eff↝, One spinning magnet or three spinning magnets generate similar cellular ROS levels and the effect of variation of the stimulus off period.
Casp3↑, caspase 3 activation
eff↝, This indicates that the total amount of energy delivered to cancer cells is clearly not the determinant of the potency of stimulation. Instead, it appears that the longer Toff between stimuli of 750 ms in the 4-h stimulation, as opposed to 250 ms in
SOD↓, critical rise in superoxide in two types of human glioma cells (implies SOD capacity exceeded)
ETC↓, found support for the hypothesis that the sOMF-induced increase in ROS is likely due to perturbation of the electron transfer process in the mitochondrial electron transport chain (ETC)

187- MFrot,  MF,    Method for noninvasive whole-body stimulation with spinning oscillating magnetic fields and its safety in mice
- in-vivo, GBM, NA
selectivity↑, Our in vitro experiments demonstrated selective cancer cell death while sparing normal cells by sOMF-induced increase in intracellular reactive oxygen species (ROS) levels due to magnetic perturbation of mitochondrial electron transport.
ROS↑,
*ROS∅,
*toxicity∅, no significant adverse effects of chronic or acute sOMF stimulation on the health, behavior, electrocardiographic and electroencephalographic activities, hematologic profile, and brain and other tissue and organ morphology of treated mice
ETC↓, We have evidence that its mechanism of action involves alteration of electron transport in the mitochondrial respiratory chain leading to the production of reactive oxygen species (ROS)(
TumVol↓, In a case report published recently we reported that 36-day treatment with this device caused a > 30% shrinkage of the contrast-enhanced tumor volume of a left frontal GBM in a 53-year-old male patient
Dose↝, rrangement of oncoscillators generates a magnetic field strength of >1 mT (range 1 – ~100 mT) in each cage

227- MFrot,  MF,    Low Frequency Magnetic Fields Induce Autophagy-associated Cell Death in Lung Cancer through miR-486-mediated Inhibition of Akt/mTOR Signaling Pathway
- in-vivo, Lung, A549 - in-vitro, Lung, A549
TumCG↓,
miR-486↑, decreased expression of miR-486 and an increased expression of BCAP were found in tumor tissues of lung cancer patients
BCAP↓,
Apoptosis↑,
ROS↑,
TumAuto↑, miR-486 is required for LF-MFs triggered autophagy
LC3II↑,
ATG5↑,
Beclin-1↑,
p62↑, blocked p62 degradation
TumCP↓,

184- MFrot,  MF,    Rotating Magnetic Fields Inhibit Mitochondrial Respiration, Promote Oxidative Stress and Produce Loss of Mitochondrial Integrity in Cancer Cells
- in-vitro, GBM, GBM
ROS↑, sOMF
mitResp↓, Inhibit Mitochondrial Respiration
mtDam↑, Produce Loss of Mitochondrial Integrity
Dose↝, Repeated intermittent sOMF was applied for 2 hours at a specific frequency, in the 200-300 Hz frequency range, with on-off epochs of 250 or 500 ms duration.
MMP?, ROS generation has been shown to be driven, in part, by elevated mitochondrial membrane chemiosmotic potential (ΔΨ) and ubiquinol (QH2)
OCR↓, Immediately after cessation of field rotation we observe a loss of mitochondrial integrity (labeled LMI), with a very rapid increase in O2 consumption
mt-H2O2↑, We have previously demonstrated that sOMF treatment of cells generates superoxide/hydrogen peroxide in the mitochondrial matrix
eff↓, we repeated the same experiment in the presence of Trolox, which protects thiols from ROS oxidation (47). sOMF treatment of RLM in State 3u pre-treated with Trolox (15 μM), show minimal inhibition,
SDH↓, SDH Inhibition by sOMF in State 3u RLM Is Caused by ROS Generation
Thiols↓, suggest that thiol oxidation in SDH may result from sOMF.
GSH↓, Glutathione in the mitochondrial matrix can provide some protection from ROS, but after solubilizing the mitochondria, this protection is lost and the SDH becomes more sensitive to sOMF.
TumCD↑, sOMF is highly effective at killing non-dividing GBM cell cultures,
Casp3↑, caspase-3 activation 1 h after sOMF
Casp7↑, rapid activation of caspase-3/7
MPT↑, OMF-treated cell that causes near simultaneous MPT, release of cytochrome c and other apoptosis-inducing factors, resulting in caspase-3/7 activation in these GBM cells.
Cyt‑c↑,
selectivity↑, differential sensitivity to sOMF of cancer cells over ‘normal’ cells becomes apparent. rapid increase in the reactive oxygen species (ROS) in the mitochondria to cytotoxic levels only in cancer cells, and not in normal human cortical neurons
GSH/GSSG↓, increasing GSSG/GSH ratio
ETC↓, completely arrest electron transport in isolated, respiring, rat liver mitochondria and patient derived glioblastoma (GBM)

225- MFrot,  MF,    Extremely low frequency magnetic fields regulate differentiation of regulatory T cells: Potential role for ROS-mediated inhibition on AKT
- vitro+vivo, Lung, NA
MMP2↓,
MMP9↓,
FOXP3↓,
ROS↑,
p‑Akt↓,

220- MFrot,  MF,    Effect of low frequency magnetic fields on melanoma: tumor inhibition and immune modulation
- in-vitro, Melanoma, B16-F10
OS↑, prolonged the mouse survival rate
DCells↑,
T-Cell↑,
Apoptosis↑,
IL1↑,
IFN-γ↓, most of cytokines were decreased
IL10↑,
TumCG↓, grow slowed
ROS↑, Phagocyte activity, ROS release and interleukin-1β (IL-1β) production were significantly promoted after continuous exposure to 50 Hz LF-MF (1mT)
TumCP↓, LF-MF inhibits the proliferation of B16-F10 cells
TumCCA↑, the S-phase rate was significantly decreased from 40.76% to 37.24% and the G2/M-phase rate was significantly increased from 8.9% to 11.6%
ChrMod↑, Compared with control cells, the treated cells were characterized by the breaking down of chromatin (white arrow) and black granule accumulation (black arrow).
CXCL9↓, in tumor-bearing mice groups, most of cytokines were decreased after LF-MF exposure, including KC, CCL1, IFN-γ, CXCL9, CXCL12, TREM-1, CCL12, IL-1rα and IL-16.
CXCL12↓,
CD4+↑, After LF-MF exposure, the proportions of CD3+, CD3 + CD4+ and CD3 + CD8+ T cells in tumor-bearing mice were increased to 24.0%, 13.28% and 7.46%, respectively
CD8+↑,

199- MFrot,  MF,    Modulation of Cellular Response to Different Parameters of the Rotating Magnetic Field (RMF)—An In Vitro Wound Healing Study
- in-vivo, Wounds, L929 - NA, NA, HaCaT
*ROS↑,
*Ca+2↓,
*other↝, (i) WMF can evoke new tissue production/regeneration (stem cell proliferation and subsequent differentiation) due to manipulation of ROS levels and also downstream heat shock protein 70 (Hsp70) expression
*other↝, (ii) The magnetic field causes changes in membrane potential and temporary membrane permeabilization that affects sodium content and potassium-efflux or the transmembrane voltage
*other↝, (iii) The calcium gradient between the extracellular and intracellular fluid is a transduction second messenger [28], and its gradient could potentially be affected by EMFs and MFs.
*other↝, (iv) MF may induce changes in enzymatic activities (e.g., enzymes involved in mitochondrial metabolism).
*other↝, (v) MF may cause cytoskeletal organization (due to reorganization of the electrostatically negative charged actin filaments), and those changes may affect the cellular shape, endoplasmic reticulum, mitotic apparatus
*other?, vi) Finally, the RMF creates the mixing process at the micro-level and may affect the energy level; some of the selected molecules strongly influence the transfer processes between the living cells and the culture medium

198- MFrot,  MF,    Biological effects of rotating magnetic field: A review from 1969 to 2021
- Review, Var, NA
AntiCan↑, RMF can inhibit the growth of various types of cancer cells in vitro and in vivo and improve clinical symptoms of patients with advanced cancer.
breath↑, 0.4T, 7Hz RMF was applied to treat 13 advanced non-small cell lung cancer patients (2 h/day, 5 days per week, for 6–10 weeks)
Pain↓, Decreased pleural effusion (2 patients, 15.4%), remission of shortness of breath (5 patients, 38.5%), relief of cancer pain (5 patients, 38.5%), increased appetite (6 patients, 46.2%), improved physical strength (9 patients, 69.2%), regular bowel mov
Appetite↑,
Strength↑,
BowelM↑,
TumMeta↓, The same RMF (2 h/day, for 43 days) can also suppress the growth and metastasis of B16-F10 cells in vivo
TumCCA↑, The up-regulated transcription of miR-34a induced cell proliferation inhibition, cell cycle arrest, and cell senescence by targeting E2F1/E2F3, two members of E2F family which are major regulators of the cell cycle,
ETC↓, 2h exposure) effectively inhibited the growth of two types of cultured brain cancer cells, glioblastoma cells and diffuse intrinsic pontine glioma cells. They found that the mitochondrial electron transport chain was significantly disturbed by RMF,
MMP↓, which caused loss of mitochondrial integrity, decreased mitochondrial carbon flux in cancer cells, and eventual cancer cell death (Sharpe et al., 2021).
TumCD↑,
selectivity↑, same group further reported that the same RMF can also selectively kill cultured human glioblastoma and non-small cell lung cancer cells, and leave normal cells unharmed
ROS↑, Mechanistic studies revealed that RMF can increase the mitochondrial ROS level, which further activated the caspase-3 and disturbed the electron fflow in the respiratory chain pathway in cancer cells. (Helekar et al., 2021).
Casp3↑,
TumCG↓, 0.4T, 7.5Hz RMF (2 h/day, for 5 days) inhibited the growth of mouse melanoma cell line B16–F10 in vitro,
TumCCA↑, and its mechanism involved cell cycle arrest and decomposition of chromatins.
ChrMod↑,
TumMeta↓, (2 h/day, for 43 days) can also suppress the growth and metastasis of B16–F10 cells in vivo,
Imm↑, benefiting from improved immune function, including decreased regulatory T cells, increased T cells, and dendritic cells
DCells↑,
Akt↓, inhibiting the activation of the AKT pathway (Tang et al., 2016). T
OS⇅, 51 women with advanced breast cancer underwent RMF treatment. The results showed that 27 patients among them achieved signicant therapeutic effects, and there were no side-effects
toxicity↓,
QoL↑, 13 advanced non-small cell lung cancer patients the quality of life was improved in different degrees. Median survival and 1-year survival rate was 50% and 100% longer
hepatoP↑, In addition, it seems that the RMF can also attenuate liver damage in mice bearing MCF7 and GIST-T1 cells (Zha et al., 2018)
Pain↓, The results showed that the RMF treatment reduced abdominal pain by 42.9% (9/21), nausea/vomiting by 19.0% (4/21), weight loss by 52.4% (11/21), ongoing blood loss by 9.5% (2/21), improved physical strength by 23.8% (5/21) and sleep quality by 19.0%
Weight↑,
Strength↑,
Sleep↑,
IL6↓, Furthermore, decreased levels of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) and keratinocyte-derived chemokine (KC) were observed
CD4+↑, it was discovered that macrophages and dendritic cells were activated, CD4+ T and CD8+ T lymphocytes increased, and the ratio of Th17/Treg was balanced.
CD8+↑,
Ca+2↑, effects of RMF were strongly associated with increased calcium tunnel activity and intracellular Ca2+ level in CNS
radioP↑, These results suggest that RMF may be helpful to alleviate the damage of hematopoietic function caused by radiotherapy and chemotherapy
chemoP↑,
*BMD↑, 0.4T, 8Hz RMF treatment (30min/day, for 30 days) along with calcium supplement, synergistically improved bone density
*AntiAge↑, In 2019, Xu et al. reported that a 4h exposure to a 0.2T, 4Hz RMF delayed the aging of human umbilical vein endothelial cells (HUVEC)
*AMPK↑, Mechanistic research revealed that RMF treatment increased the expression of AMPK while reducing the expression of p21, p53 and mTOR.
*P21↓,
*P53↓,
*mTOR↓,
*OS↑, They also discovered that the RMF (2 h/day, for 6, 10 or 14days) can prolong the health status lifespan of Caenorhabditis elegans.
*β-Endo↑, 0.1–0.8T, 0.33Hz RMF treatment signicantly increased the β-endorphin level in the blood of rabbits and humans (23 times higher than before). Moreover, it decreased serotonin (5-HT) in brains, small intestine tissue and serum of mice.
*5HT↓,

4566- MFrot,    On the mitochondrial aspect of reactive oxygen species action in external magnetic fields
- Study, Var, NA
ROS↑, formation of reactive oxygen species requires electron leakage from the normal route in the respiratory chain.
ETC↓, leakage
selectivity↑, For all those reasons, it can be expected that coapplication of a low external magnetic field and mitochondrial inducers of reactive oxygen species should damage cancer cells without any detriment to the normal cells.

4567- MFrot,    Oncogenic pathways and the electron transport chain: a dangeROS liaison
- Review, Var, NA
ROS↑, In this review, we focus on the ETC as a source of ROS and its modulation by oncogenic pathways, which generates a vicious cycle that resets ROS levels to a higher homoeostatic set point, sustaining the cancer cell phenotype.
ETC↓, Electrons leaking from the ETC can prematurely react with oxygen, resulting in the generation of reactive oxygen species (ROS).
other↝, ETC-derived ROS are pivotal regulators of cell fate, given the central role of mitochondria in life and death.
Fenton↑, The hydroxyl radical (•OH) is a highly damaging ROS with an extremely short half-life that is generated from H2O2 in the presence of iron or copper through the Fenton reaction.
RNS↑, O2•– can also interact with nitric oxide (NO), generating the reactive nitrogen species (RNS) peroxynitrite (ONOO−), which controls signalling molecules through the nitration of tyrosine residues

4569- MFrot,    Case Report: A new noninvasive device-based treatment of a mesencephalic H3 K27M glioma
- Case Report, GBM, NA
Dose↝, treatment was for 2 hours on the first day with a 5-min break between the first and the second hour.
Dose↑, On the second day, two 2-hour sessions were conducted with a 1-hour break between the sessions.
Dose↑, 2-hour sessions was increased to three on the third day
OS↑, The longest documented survival for an adult with H3K27A brainstem DMG is 23 months (6). The patient in the present study survived for 30 months
toxicity↓, OMT was well tolerated by the patient
ETC↓, underlying mechanism of action of sOMF in DMG is analogous to that in GBM, involving disruption of electron transport in the mitochondrial respiratory chain, with release of ROS producing cancer cell oncolysis ()
ROS↑,

773- Mg,    Methyl Jasmonate-induced Increase in Intracellular Magnesium Promotes Apoptosis in Breast Cancer Cells
- in-vitro, BC, MCF-7
TRPM7↓, increase in [Mg2+]i led to decreased TRPM7 expression
ROS↑,
ER Stress↑,
MAPK↑,
ATP↓,

1892- MGO,    Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights
- Review, NA, NA
MGO↑, MG levels rise under high-glucose conditions, such as diabetes
ROS↑, MG induces protein and nucleotide modification (advanced glycation end-products, AGEs), reactive oxygen species (ROS), and apoptosis
other↝, To combat MG's cytotoxic effects, GLO1 enzymatically converts MG into the less reactive substance, d-lactate
GABA↑, MG's mechanism of action in behavior: GABAA receptor activation
other∅, GLO1 inhibition was shown to increase MG concentration and reduce anxiety-like behavior in vivo

1891- MGO,    Methylglyoxal induces mitochondria-dependent apoptosis in sarcoma
- in-vitro, SCC, NA
NADH↓, It appears that this specificity of methylglyoxal against the NADH dehydrogenase (complex I) of malignant tissue mitochondria is one very important reason for its selective anticancer property.
MMP↓, decrease in membrane potential
Cyt‑c↑, Release of cytochrome c from sarcoma tissue mitochondria.
selectivity↑, The results presented in this and the preceding paper clearly indicate that action of methylglyoxal is selective against malignant cells
Apoptosis↑, Methylglyoxal showed cytotoxicity to several malignant cells through induction of apoptosis
ROS↑, It was previously reported that methylglyoxal induced ROS generation triggered apoptosis in human Hep G2 cells
ATP↓, ATP deprivation

1997- Myr,  QC,    Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity
- in-vitro, Lung, A549
TrxR↓, Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 micromol/L, respectively
eff↑, Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition.
TumCCA↑, cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin.
eff↓, presence of superoxide dismutase diminished the inhibition dramatically
ROS↑, show that ROS played a critical role in the inhibition of TrxR by flavonoids. ...may occur as a result of their easy oxidization to flavonol semiquinone species.

1998- Myr,  CUR,    Thioredoxin-dependent system. Application of inhibitors
- Review, Var, NA
TrxR↓, myricetin, which like curcumin, can cause irreversible inhibition of TrxR activity
ROS↑, Curcumin-induced alkylation of TrxR can have effects analogous to NADPH oxidase that involve significant increases in ROS production and increased oxidative stress

116- Myrrh,    The Role of Myrrh Metabolites in Cancer, Inflammation, and Wound Healing: Prospects for a Multi-Targeted Drug Therapy
- in-vitro, AML, HL-60 - in-vitro, AML, K562 - in-vitro, BC, KAIMRC1
ROS↑, Myrrh caused a dose-dependent effect on macrophages to increase the reactive oxygen species (ROS) level
M1↑, promote their polarization to classically activated macrophages (M1) and alternatively activated macrophages (M2) phenotypes, and consequently induce apoptosis
M2 MC↑,
Apoptosis?,
BBB↝, myrrh resin extract, only compounds 3, 4, 5, and 8 are potentially not permeable to the blood-brain barrier (BBB)

1807- NarG,    A Systematic Review of the Preventive and Therapeutic Effects of Naringin Against Human Malignancies
- Review, NA, NA
AntiTum↑, antitumor ability of naringin
TumCP↓,
tumCV↓,
TumCCA↑,
Mcl-1↓,
RAS↓,
e-Raf↓, suppressing the Ras/Raf/extracellular
VEGF↓,
AntiAg↑,
MMP2↓,
MMP9↓,
TIMP2↑,
TIMP1↑,
p38↓,
Wnt↓,
β-catenin/ZEB1↑,
Casp↑,
P53↑,
BAX↑,
COX2↓,
GLO-I↓,
CYP1A1↑,
lipid-P↓,
p‑Akt↓,
p‑mTOR↓,
VCAM-1↓,
P-gp↓,
survivin↓,
Bcl-2↓,
ROS↑, ↑oxidative stress, Prostate DU145 cell line 50–250 μM
ROS↑, ↑ROS, Stomach (Gastric) AGS cell line, 1–3 mM
MAPK↑,
STAT3↓,
chemoP↑, flavonoids have excellent radical scavenging and iron-chelating properties (Kaiserová et al., 2007), and they can act as an effective modulator for DOX-induced toxicity

1799- NarG,    Naringenin as potent anticancer phytocompound in breast carcinoma: from mechanistic approach to nanoformulations based therapeutics
- Review, NA, NA
TumCCA↑, inhibition of the cell cycle
BioAv↑, oral bioavailability was determined to be 5.81%.Novel delivery strategies such as nanoparticles, liposomes, and micelles have been investigated to improve their bioavailability
Half-Life∅, researchers recorded a maximum concentration (Cmax) of 2009.51 ng/mL in 3.67 h after administration. elimination half-life was found to be 2.31 h.
TNF-α↓,
Casp8↑,
BAX↑,
Bak↑,
EGF↓,
mTOR↓,
PI3K↓,
ERK↓,
Akt↓,
NF-kB↓,
VEGF↓,
angioG↓,
antiOx↑,
EMT↓, Naringenin reduces the metastatic efficacy of breast cancer cells by EMT suppression
OS↑, Oral administration of naringenin dramatically reduced the number of metastatic tumor cells in the lungs and prolonged the lifespan of mice that had their tumors removed
MAPK↓, Naringenin inhibited the MAPK and PI3K pathways
ChemoSen↑, In MCF-7 breast cancer cells, combination therapy using NGE and tamoxifen was more effective than either drug alone
MMP9↓, downregulating the expression of MMP-9 and MMP-2
MMP2↓,
ROS↑, combination treatment increases ROS generation
ROS↑, demonstrated the antitumor effects of naringenin nanoparticles through increased ROS levels, GSH attenuation, and caspase-3 activation, which ultimately induced apoptosis
GSH↓,
Casp3↑,
ROS↑, This review concludes that naringenin can reduce carcinogenesis through pleiotropic processes such as antioxidative, apoptotic-inducing ROS generation, and cell cycle arrest

1311- NarG,  Rad,    Naringenin sensitizes lung cancer NCI-H23 cells to radiation by downregulation of akt expression and metastasis while promoting apoptosis
- in-vitro, Lung, H23
tumCV↓,
ROS↑,
Casp3↑,
p‑Akt↓,
Akt↓,
MMP2↓,
P21↓,

5253- NCL,    Niclosamide: Beyond an antihelminthic drug
- Review, Var, NA
TumCP↓, Niclosamide was found to inhibit adrenocortical carcinoma cellular proliferation, which was associated with apoptosis, reduction of epithelial-to-mesenchymal transition and β-catenin levels.
Apoptosis↑,
EMT↓,
β-catenin/ZEB1↓,
TumCG↓, Oral administration of niclosamide led to tumor growth inhibition with no observed toxicity.
toxicity↓,
Wnt↓, Lu et al. reported that niclosamide inhibits Wnt/β-catenin signaling by promoting Wnt co-receptor LRP6 degradation in breast cancer cells [11].
LRP6↓,
eff↑, niclosamide acts synergistically with a monoclonal antibody that specifically activates TRAIL death receptor 5 to inhibit tumor growth of basal-like breast cancers [12].
DR5↑,
mTORC1↓,
pH↓, Niclosamide lowered the cytoplasmic pH and may indirectly lead to inhibition of mTORC1 signaling [13]
CSCs↓, Niclosamide also was found to prevent the conversion of non-breast cancer stem cells into cancer stem cells
IL6↓, This mechanism is associated with inhibition of the IL6-JAK1-STAT3 signal transduction pathway
JAK1↓,
STAT3↓, Ren et al. identified niclosamide as a potent STAT3 inhibitor able to suppress STAT3 transcriptional activity
ChemoSen↑, niclosamide alone or in combination with cisplatin represses the growth of xenografts of cisplatin-resistant triple-negative breast cancer cells.
TumCG↓, Niclosamide inhibited growth of colon cancer cells from human patients both in vitro and in vivo, regardless of mutations in APC [24].
tumCV↓, niclosamide selectively inhibited glioblastoma cell viability [29]. Detailed mechanism studies revealed that niclosamide suppressed the Wnt, Notch, mTOR, and NF-κB signaling pathways.
NOTCH↓,
NF-kB↓,
EGFR↓, Li et al. reported that inhibition of EGFR by erlotinib, an FDA-approved therapeutic agent, led to activation of STAT3 signaling in head and neck cancer cells
ROS↑, niclosamide inhibits TNF-α-induced NF-κB–dependent reporter activity and increased the levels of reactive oxygen species (ROS) in AML cells.
RadioS↑, niclosamide enhanced radiosensitivity of the non-small cell lung cancer cell line H1299.
cFos↓, inhibit osteosarcoma cell proliferation, migration, and survival. This inhibitory effect is associated with decreased expression of c-Fos, c-Jun. E2F1, and c-Myc.
cJun↓,
E2Fs↓,
cMyc↓,
Half-Life↓, Niclosamide exhibits a short half-life (6.0 ± 0.8 h). Niclosamide was rapidly absorbed with a Tmax of less than 30 min. The Cmax is 354 ± 152 ng/mL.
BioAv↝, AUC and bioavailability were 429 ± 100 and 10%, respectively. In order to make more effective use of niclosamide, additional work needs to be done to improve its solubility, absorption and systemic bioavailability.

1271- NCL,    Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics
- vitro+vivo, Ovarian, SKOV3
Wnt/(β-catenin)↓,
mTOR↓,
STAT3↓,
NF-kB↓,
NOTCH↓,
TumCG↓,
Apoptosis↑,
MEK↓, inactivating MEK1/2-ERK1/2
ERK↓,
mitResp↓,
Glycolysis↓, aerobic glycolysis
ROS↑, abolishment of the excess ROS production with NAC (10 mM) abrogated the Niclosamide-induced cell apoptosis under glucose deprivation
JNK↑,

946- Nimb,    Nimbolide retards T cell lymphoma progression by altering apoptosis, glucose metabolism, pH regulation, and ROS homeostasis
- in-vivo, NA, NA
Apoptosis↑,
Bcl-2↓,
P53↑, up-regulated expression of p53,
cl‑Casp3↑,
Cyt‑c↑,
ROS↑, induced ROS production by suppressing the expression of antioxidant regulatory enzymes, namely superoxide dismutase and catalase
SOD↓,
Catalase↓,
Glycolysis↓,
GLUT3↓,
LDHA↓, LDHA inhibitor
MCT1↓,
NHE1↓,
ATPase↓,
CAIX↓,

4973- Nimb,    Nimbolide Exhibits Potent Anticancer Activity Through ROS-Mediated ER Stress and DNA Damage in Human Non-small Cell Lung Cancer Cells
- in-vitro, NSCLC, A549
tumCV↓, We found that NB treatment inhibits A549 cells colony formation in a dose-dependent manner.
ROS↑, Mechanistically, NB treatment increases cellular reactive oxygen species (ROS) level, leading to endoplasmic reticulum (ER) stress, DNA damage, and eventually induction of apoptosis in NSCLC cells.
ER Stress↑,
DNAdam↑,
Apoptosis↑,
eff↓, all these effects of NB were blocked by pretreatment with antioxidant glutathione (GSH), the specific ROS inhibitor.

4974- Nimb,    Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma
- in-vitro, OS, NA
Apoptosis↑, Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation.
ER Stress↑,
mtDam↑,
ROS↑,
Casp↑,
TumCMig↓, We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvβ5.
TumMeta↓,

4975- Nimb,    Nimbolide Induces Cell Apoptosis via Mediating ER Stress-Regulated Apoptotic Signaling in Human Oral Squamous Cell Carcinoma
- in-vitro, Oral, NA
Apoptosis↑, Our findings reveal that nimbolide exerts its anti-proliferative effects on OSCC cells by inducing apoptosis.
ROS↑, The nimbolide increased intracellular ROS levels and acceleration of cellular calcium accumulation, respectively promoting endoplasmic reticulum stress and cancer cell apoptosis.
Ca+2↑,
ER Stress↑,
Casp↑, nimbolide activates the caspase cascade by altering the mitochondrial membrane potential and apoptotic protein expression, thereby inhibiting the viability of tumor cells.
MMP↓,
tumCV↓,

4976- Nimb,    Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition
- vitro+vivo, PC, NA
ROS↑, Our data reveal that nimbolide induces excessive generation of reactive oxygen species (ROS), thereby regulating both apoptosis and autophagy in pancreatic cancer cells.
Apoptosis↑,
TumAuto↑,
TumCP↓, Nimbolide inhibits the proliferation of human pancreatic ductal adenocarcinoma cells
TumCMig↓, Nimbolide suppresses migration, invasion, EMT and anchorage-independent growth of pancreatic cancer cells
TumCI↓,
EMT↓,
Dose↓, All three pancreatic adenocarcinoma cell lines (HPAC, MIAPaCa-2 and PANC-1) tested were sensitive to the cytotoxic effects of nimbolide at a minimal dose of 3–5 μM
selectivity↑, Nimbolide was not highly toxic to normal pancreatic cells (hTERT HPNE) even at higher doses (10 μM).
Akt↓, Nimbolide treatment reduced the activation of AKT in pancreatic cancer cells.
eff↓, Moreover, inhibition of ROS with NAC eliminated the nimbolide-induced cell death,
BAX↑, in response to nimbolide, as did the elevated expression levels of Bax, cleaved caspase-3, and cleaved PARP and the reduced levels of Bcl-2.
cl‑Casp3↑,
cl‑PARP↑,
Bcl-2↓,

4977- Nimb,    Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis
- vitro+vivo, PC, AsPC-1 - in-vitro, PC, PANC1
SOD2↑, Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2
TumCG↓, Xenografted PDAC cells overexpressing SOD2 exhibited rapid tumor growth in vivo.
TumMeta↓, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis.
ROS↑, NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis
Apoptosis↑,
PI3K↓, Inhibition of PI3K/Akt Signaling by NB Is Caused by the Induction of ROS via SOD2 Silencing
Akt↓,
EMT↓, SOD2 Inhibits Epithelial–Mesenchymal Transition of PDAC Cells
BAX↑, silencing SOD2 increased the expression of proapoptotic markers (BAX, cleaved caspases 3 and 8, and cleaved PARP), while the expression of antiapoptotic marker BCL-2 was decreased.
cl‑Casp3↑,
cl‑Casp8↑,
cl‑PARP↑,
Bcl-2↓,

4643- OLE,  HT,    Use of Oleuropein and Hydroxytyrosol for Cancer Prevention and Treatment: Considerations about How Bioavailability and Metabolism Impact Their Adoption in Clinical Routine
- Review, Var, NA
TumCCA↑, A similar S phase cell cycle arrest was also observed for 800 μM HT, and induction of apoptosis also took place after 24 h incubation of HT-29 cells with 600 μM and 800 μM HT
Apoptosis↑,
ER Stress↑, 400 μM HT triggered endoplasmic reticulum stress in HT-29 cells, with activation of unfolded protein response,
UPR↑,
CHOP↑, increase in CHOP protein levels (responsible for ROS production and Bcl-2 downregulation) and NADPH oxidase 4 (NOX4)
ROS↑,
Bcl-2↓,
NOX4↑,
Hif1a↓, Moreover, 400 μM HT reduced HIF-1α protein levels
MMP2↓, figure 2
MMP↓,
VEGF↓,
Akt↓,
NF-kB↓,
p65↓,
SIRT3↓,
mTOR↓,
Catalase↓,
SOD2↓,
FASN↓,
STAT3↓,
HDAC2↓,
HDAC3↓,
BAD↑, figure 2 upregulated
BAX↑,
Bak↑,
Casp3↑,
Casp9↑,
PARP↑,
P53↑,
P21↑,
p27↑,
Half-Life↝, HT added to extra virgin olive oil produced a plasma peak of 3.79 ng/mL after 30 min, followed by a rapid decline in HT plasma concentration
BioAv↓, On the basis of these pieces of data, it becomes evident that cytotoxicity and anti-cancer effects of OLE and HT were recorded at concentrations largely exceeding those reachable with diet/olive oil consumption
BioAv↓, Thus, it is difficult to imagine how OLE and HT may be used as cancer-preventive/treating agents if the route of administration is ingestion.
selectivity↑, However, even at high concentrations, OLE and HT seem to be selectively cytotoxic for cancer cells, with no or negligible/minimal effects on non-cancer cells,
RadioS↑, 200 μM OLE enhanced cell radiosensitivity in vitro and in vivo after injection in BALB/C nude mice
*ROS↓, A lot of experimental data in vivo and in vitro have definitively demonstrated the ROS scavenger ability of OLE and HT, which can also act on antioxidant cellular mechanisms restoring ROS homeostasis,
*GSH↑, including promotion of the increase in reduced glutathione levels (GSH), depletion of lipid peroxidation product malondialdehyde (MDA), intensification of the expression and/or activity of detoxicating enzymes SOD, CAT, glutathione-S-transferase (GST
*MDA↓,
*SOD↑,
*Catalase↑,
*NRF2↑, and nuclear factor E2-related factor 2 (Nrf2) upregulation/transactivation,
*chemoP↑, OLE and HT have shown an important ability to mitigate the toxicity elicited by chemotherapeutic agents mainly through their largely demonstrated antioxidant and ROS scavenger activity.
*Inflam↓, OLE and HT exhibit an anti-inflammatory activity that has been demonstrated in multiple in vivo and in vitro models,
PPARγ↑, HT-dependent anti-inflammatory effect was also mediated by HT-elicited increase in protein levels of PPARγ

4626- OLE,    A Comprehensive Review on the Anti-Cancer Effects of Oleuropein
- Review, Var, NA
Risk↓, Many studies have shown that olive oil consumption reduces the incidence of cancer of any kind, particularly breast and digestive system tumors
Dose↑, Some studies suggest that 7.5 g of Ole for a 70 kg human may have an anti-tumor effect by decreasing mitosis and by increasing apoptosis [9,10], but this high dose may be impossible to achieve
TumCP↓, Ole’s anti-proliferative action has been established in numerous research using MCF-7 cell lines
NF-kB↓, Ole (100 µM) was found to suppress the nuclear factor-light-chain-enhancer of activated B (NF-kB) and its downstream targets cyclin D1 and cyclooxygenase-2 (COX2) in the MDA-MB-231 breast cancer cell line.
COX2↓,
Akt↓, Ole (100 µM) was found to suppress the nuclear factor-light-chain-enhancer of activated B (NF-kB) and its downstream targets cyclin D1 and cyclooxygenase-2 (COX2) in the MDA-MB-231 breast cancer cell line.
P53↑, Oleuropein raises the expression of the proapoptotic proteins p53 and Bax while decreasing the expression of the antiapoptotic proteins Bcl-2 and HIF-1.
BAX↑,
Bcl-2↓,
HIF-1↓,
ROS↑, Ole promotes cell damage and functions as a pro-oxidant, which contributes to cell death, according to studies on in vitro MCF-7 breast cancer cells. The activation of reactive oxygen species (ROS) is responsible for this pro-oxidant property
HO-1↑, Furthermore, an increase in the heme-oxygenase 1 (HO-1) enzyme at doses of 100 and 500 µM, which is a potent antioxidant containing thiol groups, is thought to be the mechanism by which the antioxidant action is exclusive to BPH-1 cells
chemoP↑, Ole’s antioxidant action has a chemo-protective effect, as evidenced by the fact that it slows colon cancer progression
TumCCA↑, This dual impact could lead to an increase in intracellular ROS, which could lead to cell arrest
FASN↓, Ole’s anti-cancer benefits could be attributed to its capacity to inhibit the fatty acid synthase enzyme (FASN)

4647- OLEC,    Oleocanthal, an Antioxidant Phenolic Compound in Extra Virgin Olive Oil (EVOO): A Comprehensive Systematic Review of Its Potential in Inflammation and Cancer
- Review, Var, NA
*Inflam↓, OC exhibits promising therapeutic potential against both inflammation and cancer.
AntiCan↑,
*COX2↓, OC was able to inhibit the enzymaticactivity of cyclooxigenease-2 (COX-1) and cyclooxigenease-2 (COX-2) with greater potencycompared to ibuprofen
*ROS↓, figure 3
*TNF-α↓,
*IL1β↓,
*iNOS↓,
TumCP↓, OC also effectively reduces cell proliferation and limits the production of the extracellular matrix in LX2 cells, suggesting its antifibrotic properties
*AntiAg↑, Healthy men: Anti-platelet effects
mTOR↓, Oleocanthalhas exhibited robust anti-proliferative effects in multiple breast cancer cell lines, accompanied by the downregulation of phosphorylated mTOR
STAT3↓, OC was shown to suppress STAT3 activity
ERK↓, OC was able to inhibit ERK1/2 and AKT phosphorylation and downregulate Bcl-2expression
p‑Akt↓,
Bcl-2↓,
ROS↑, OC effectively impeded the formation of cell colonies, triggered apoptosis, and incited the generation of intracellular ROS within cancer cells.
PSA↓, ↓PSA levels in mouse model

1813- Oxy,    Advances in hyperbaric oxygen to promote immunotherapy through modulation of the tumor microenvironment
- Review, Var, NA
ChemoSen↑, HBO can reduce drug resistance to chemotherapy and radiotherapy
RadioS↑,
PD-L1↓, HBO promotes immunotherapy by relieving tissue hypoxia and down-regulating PD-L1
Hif1a↓, HBO can inhibit HIF1α in tumors
ROS↑, Hyperbaric oxygen produces ROS

1814- Oxy,    Hyperbaric oxygen therapy for malignancy: a review
- Review, Var, NA
ROS↑, HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress.
SOD↑, Kaelin et al. showed a significant increase in the activity of SOD and improved survival of the skin flaps of rats exposed to HBO
OS↑,
ChemoSen↑, HBO therapy in combination with chemotherapy increases cellular uptake of certain anticancer agents and the susceptibility of cells to these agents
RadioS↑, cells to enter a proliferative stage, thus sensitizing them to radiotherapy and certain chemotherapy.
BioAv↑, Improved oxygenation improves drug delivery to hypoxic regions in the tumor

2451- PA,    The Promoting Role of HK II in Tumor Development and the Research Progress of Its Inhibitors
- Review, Var, NA
HK2↓, PA was found to significantly inhibit HK II activity in cell lysates (IC50 5.01 μm), induce mitochondrial dysfunction, ATP depletion, and ROS generation.
ATP↓,
ROS↑,

2452- PA,    Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis
- in-vitro, BC, SkBr3
HK2↓, Molecular docking and enzyme assay confirmed that PA was an inhibitor of HK2, with an IC50 of 5.01 µM.
GlucoseCon↓, PA decreased glucose uptake and lactate production
lactateProd↓,
mtDam↑, PA induced mitochondrial dysfunction, ATP depletion, and ROS generation
ATP↓,
ROS↑,
PKM2↑, The activation of PKM2 should have increased the uptake of glucose and production of lactate. However, opposite results were obtained in this study

2054- PB,    Sodium butyrate induces ferroptosis in endometrial cancer cells via the RBM3/SLC7A11 axis
- in-vitro, EC, ISH - in-vitro, EC, HEC1B
Ferroptosis↑, Sodium butyrate promotes endometrial cancer cell ferroptosis.
xCT↓, NaBu indirectly downregulates the expression of SLC7A11 by promoting the expression of RBM3, thereby promoting ferroptosis in endometrial cancer cells
RBM3↑,
HDAC↓, Butyric acid is an important histone deacetylase inhibitor
ROS↑, NaBu increased the levels of ROS, lipid ROS and intracellular Fe2 + in Ishikawa and HEC-1B cells

2055- PB,    The Effects of Butyric Acid on the Differentiation, Proliferation, Apoptosis, and Autophagy of IPEC-J2 Cells
- in-vitro, Nor, IPEC-J2
*Diff↑, 0.2-0.4 mM BT promoted the differentiation of procine jejunal epithelial (IPEC-J2) cells
*TumCP↓, BT at high concentrations inhibited the IPEC-J2 cell proliferation and induced cell cycle arrest in the G2/M phase.
*TumCCA↑,
*ROS↑, BT triggered IPEC-J2 cell apoptosis via the caspase8-caspase3 pathway accompanied by excess reactive oxygen species (ROS) and TNF-α production (0.5 mM or higher)
*Casp3↑,
*TNF-α↑,

2065- PB,  TMZ,    Inhibition of Mitochondria- and Endoplasmic Reticulum Stress-Mediated Autophagy Augments Temozolomide-Induced Apoptosis in Glioma Cells
- in-vitro, GBM, NA
eff↑, Combination of TMZ with 4-phenylbutyrate (4-PBA), an ER stress inhibitor, augmented TMZ-induced cytotoxicity by inhibiting autophagy.
ROS↑, temozolomide (TMZ), an alkylating agent for brain tumor chemotherapy, induced reactive oxygen species (ROS)
MMP↓, Mitochondrial depolarization and mitochondrial permeability transition pore (MPTP) opening were observed as a prelude to TMZ-induced autophagy
ER Stress↑, TMZ treatment triggered ER stress with increased expression of GADD153 and GRP78 proteins, and deceased pro-caspase 12 protein.
CHOP↑,
GRP78/BiP↑,
pro‑Casp12↓,
eff↝, GADD153 and GRP78 protein levels increased after treatment with TMZ and were suppressed by the ER stress modulator, 4-PB
Ca+2↝, Ca2+]i increased from 24 to 72 h, and was suppressed by 4-PBA, suggesting that the increase of calcium was induced by ER stress.

2069- PB,    Toxic and metabolic effect of sodium butyrate on SAS tongue cancer cells: role of cell cycle deregulation and redox changes
- in-vitro, Tong, NA
TumCG↓, sodium butyrate inhibited the growth of SAS tongue cancer cells by 32% and 53% at concentrations of 1 and 2mM, respectively
ROS↑, These events were concomitant with induction of intracellular reactive oxygen species (ROS) production.
P21↑, An elevation in p21 mRNA and protein level was noted in SAS cells by sodium butyrate.
CycB/CCNB1↓, decline of cyclin Bl, cdc2 and cdc25C mRNA and protein expression in SAS cells was found after exposure to sodium butyrate
cDC2↓,
CDC25↓,
eff↓, Inclusion of N-acetyl-l-cysteine (NAC) (3mM), catalase (1000 U/ml) and dimethylthiourea (DMT, 5mM), and also SOD (500 U/ml) attenuated the sodium butyrate-induced ROS production in SAS cells.
TumCCA↑, sodium butyrate is toxic and inhibits the tongue cancer cell growth via induction of cell cycle arrest and apoptosis
Apoptosis↑,

2077- PB,    Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells
- in-vitro, Liver, HUH7
miR-22↑, Intracellular expression of miR-22 was increased when the Huh 7 cells were incubated with sodium butyrate.
SIRT1↓, Over-expression of miR-22 or addition of sodium butyrate inhibited SIRT-1 expression and enhanced the ROS production
ROS↑, Butyrate induces ROS production
Cyt‑c↑, Butyrate induced apoptosis via ROS production, cytochrome c release and activation of caspase-3
Casp3↑,
eff↓, whereas addition of N-acetyl cysteine or anti-miR-22 reversed these butyrate-induced effects
TumCG↓, sodium butyrate inhibited cell growth and proliferation
TumCP↓,
HDAC↓, induces apoptosis by mediating expression of histone deacetylase (HDAC), SIRT-1, caspase 3, and NFκB
SIRT1↓,
CD44↓, Previously it was shown that butyrate significantly inhibited CD44 expression, thereby inhibiting the metastatic ability of the human colon carcinoma cells [6].
proMMP2↓, Prolonged butyrate treatment inhibited the pro-MMP-2 activation and tumor cell migration potential of HT 1080 tumor cells [7].
MMP↓, Butyrate alters mitochondrial membrane potential (ψm)
SOD↓, Butyrate inhibits super oxide dismutase

2028- PB,    Potential of Phenylbutyrate as Adjuvant Chemotherapy: An Overview of Cellular and Molecular Anticancer Mechanisms
- Review, Var, NA
HDAC↓, Phenylbutyrate is one of the first drugs encountered in cancer therapy as a histone deacetylase inhibitor (HDACI).
TumCCA↑, phenylbutyrate treatment that results in reduced proliferation and cell-cycle arrest in G1 or G2 phases.
P21↑, common sequela of phenylbutyrate treatment is the upregulation of p21,
Dose↝, In prostate cancer, phenylbutyrate at clinically achievable concentrations (0.1 mM-8 mM),
Telomerase↓, butyrate or its derivatives was also evident in several other types of cancers and was associated with loss of telomerase activity
IGFBP3↑, Upregulation of insulin-like growth factor binding protein 3 (IGFBP-3) is another unique antiproliferative mechanism of sodium butyrate in breast cancer cells
p‑p38↑, Phenylbutyrate and its derivatives upregulated p21, gelsolin, phosphorylated p38, JNK, and ERK (MAPK pathway members), Bax, caspases-3,
JNK↑,
ERK↑,
BAX↑,
Casp3↑,
Bcl-2↓, downregulated Bcl-X L , Bcl-2, cytochrome c, FAK, and survivin
Cyt‑c↝,
FAK↓,
survivin↓,
VEGF↓, Butyrate treatment reduced the level of vascular endothelial growth factor (VEGF)
angioG↓,
DNArepair↓, Inhibition of DNA Repair.
TumMeta↓,
HSP27↑, Moreover, butyrate treatment in colorectal cancer cells resulted in an acute stress response that was associated with HSP27 activation, activation of ASK1 (MAP3K) and p38 MAPK pathway consequently.
ASK1↑,
ROS↑, Also it resulted in elevated cellular levels of reactive oxygen species (ROS) in oral and tongue cancer cells.
eff↑, phenylbutyrate enhanced the cytotoxicity of temozolamide in malignant glioma cells via suppression of the endoplasmic reticulum stress revealed by the decreased expression of GRP78 and GADD153.
ER Stress↓,
GRP78/BiP↓,
CHOP↑, GADD153
AR↓, Sodium butyrate treatment of prostate cancer cells was associated with downregulation of androgen receptor
other?, lots of references in this paper.

2039- PB,    TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4‐phenylbutyrate treatment
- in-vitro, Lung, A549 - in-vitro, Nor, HEK293
TXNIP↑, TXNIP was strongly induced by NaBu (30‐ to 40‐fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells.
Casp3↑, Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production
Casp7↑,
mt-ROS↑, as well as enhanced mitochondrial superoxide production. 4PBA induced a mitochondrial superoxide‐associated cell death, while NaBu did so mainly through a TXNIP‐mediated pathway
GlucoseCon↓, both NaBu and 4PBA can decrease the glucose consumption compared to the vehicle control
TumCP↓, both inhibitors can prevent A549 cell proliferation and induce cell death
TumCD↑,
IGF-2↑, NaBu and 4PBA induce insulin‐like growth factor 2 (somatomedin A) (IGF2) 31‐fold and 48‐fold (Fig. S1 and S2), respectively.
HDAC↓, As inhibitors of HDACs, NaBu and 4PBA are capable of changing histone modifications
ROS⇅, suggests that 4PBA‐induced ROS generation might be a cell type or concentration dependent

1672- PBG,    The Potential Use of Propolis as an Adjunctive Therapy in Breast Cancers
- Review, BC, NA
ChemoSen↓, 4 human clinical trials that demonstrated the successful use of propolis in alleviating side effects of chemotherapy and radiotherapy while increasing the quality of life of breast cancer patients, with minimal adverse effects.
RadioS↑,
Inflam↓, immunomodulatory, anti-inflammatory, and anti-cancer properties.
AntiCan↑,
Dose∅, Indonesia: IC50 = 4.57 μg/mL and 10.23 μg/mL
mtDam↑, Poland: propolis induced mitochondrial damage and subsequent apoptosis in breast cancer cells.
Apoptosis?,
OCR↓, China: CAPE inhibited mitochondrial oxygen consumption rate (OCR) by reducing basal, maximal, and spare respiration rate and consequently inhibiting ATP production
ATP↓,
ROS↑, Iran: inducing intracellular ROS production, IC50 = 65-96 μg/mL
ROS↑, Propolis induced mitochondrial dysfunction and lactate dehydrogenase release indicating the occurrence of ROS-associated necrosis.
LDH↓,
TP53↓, Interestingly, a reduced expression of apoptosis-related genes such as TP53, CASP3, BAX, and P21)
Casp3↓,
BAX↓,
P21↓,
ROS↑, CAPE: inducing oxidative stress through upregulation of e-NOS and i-NOS levels
eNOS↑,
iNOS↑,
eff↑, The combination of propolis and mangostin significantly reduced the expression of Wnt2, FAK, and HIF-1α, when compared to propolis or mangostin alone
hTERT/TERT↓, downregulation of the mRNA levels of hTERT and cyclin D1
cycD1/CCND1↓,
eff↑, Synergism with bee venom was observed
eff↑, Statistically significant decrease was found in the MCF-7 cell viability 48 h after applying different combinations of cisplatin (3.12 μg/mL) and curcumin (0.31 μg/mL) and propolis (160 μg/mL)
eff↑, Nanoparticles of chrysin had significantly higher cytotoxicity against MCF-7 cells, compared to chrysin
eff↑, Propolis nanoparticles appeared to increase cytotoxicity of propolis against MCF-7 cells
STAT3↓, Chrysin also inhibited the hypoxia-induced STAT3 tyrosine phosphorylation suggesting the mechanism of action was through STAT3 inhibition.
TIMP1↓, Propolis reduced the expression of TIMP-1, IL-4, and IL-10.
IL4↓,
IL10↓,
OS↑, patients supplemented with propolis had significantly longer median disease free survival time (400 mg, 3 times daily for 10 d pre-, during, and post)
Dose∅, 400 mg, 3 times daily for 10 d pre-, during, and post
ER Stress↑, endoplasmic reticulum stress
ROS↑, upregulating the expression of Annexin A7 (ANXA7), reactive oxygen species (ROS) level, and NF-κB p65 level, while simultaneously reducing the mitochondrial membrane potential.
NF-kB↓,
p65↓,
MMP↓,
TumAuto↑, propolis induced autophagy by increasing the expression of LC3-II and reducing the expression of p62 level
LC3II↑,
p62↓,
TLR4↓, propolis downregulates the inflammatory TLR4
mtDam↑, propolis induced mitochondrial dysfunction and lactate dehydrogenase release indicating ROS-associated necrosis in MDA MB-231cancer cells
LDH↓,
ROS↑,
Glycolysis↓, inhibit the proliferation of MDA-MB-231 cells by targeting key enzymes of glycolysis, namely glycolysis-hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase muscle isozyme M2 (PKM2), and lactate dehydrogenase A (LDHA),
HK2↓,
PFK↓,
PKM2↓,
LDH↓,
IL10↓, propolis significantly reduced the relative number of CD4+, CD25+, FoxP3+ regulatory T cells expressing IL-10
HDAC8↓, Chrysin, a propolis bioactive compound, inhibits HDAC8
eff↑, combination of propolis and mangostin significantly reduced the expression of Wnt2, FAK, and HIF-1α, when compared to propolis or mangostin alone.
eff↑, Propolis also upregulated the expression of catalase, HTRA2/Omi, FADD, and TRAIL-associated DR5 and DR4 which significantly enhanced the cytotoxicity of doxorubicin in MCF-7 cells
P21↑, Chrysin, a propolis bioactive compound, inhibits HDAC8 and significantly increases the expression of p21 (waf1/cip1) in breast cancer cells, leading to apoptosis.

1673- PBG,    An Insight into Anticancer Effect of Propolis and Its Constituents: A Review of Molecular Mechanisms
- Review, Var, NA
TumCP↓, propolis-treated cells showed inhibition of cell proliferation and induction of apoptosis
Apoptosis↑,
TumCCA↑, cell cycle arrest potential against cancer cell lines
MALAT1↓, CAPE blocks the expression of the MALT1 gene to decrease the cell proliferation, invasion, and tumor growth of prostate carcinoma cells via the p53 and NF-κB signaling pathways
P53↑,
RadioS↑, Propolis capsules (400 mg, 3 times daily) is consumed for 10 days before radiotherapy, 10 days during radiation treatment, and 10 days after irradiation
OS↑, Patients who used propolis supplements had a considerably longer median disease-free lifetime.
ROS↑, Chinese propolis extract (EECP) significantly increased annexin A7 expression, ROS, NF-κB, and p65 expressions and dramatically altered the potential of mitochondrial membrane
NF-kB↓, Chrysin treatment in U937 cells (histiocytic lymphoma cells) showed induction of apoptosis by suppressing the PI3K/Akt signaling and inactivation of nuclear factor kappa B (NF-?B)/inhibitor of apoptosis (IAP)
p65↑,
MMP↓,
ROS↑, 25 to 100 μg/ml of Chinese propolis-treated cells showed increased ROS generation
MMP9↓, Cuban propolis (83 μg/ml) suppresses cell migration and invasion by inhibiting MMP-9 activity, β-catenin, vimentin expression, and decreased E-cadherin expression in human colorectal cancer
β-catenin/ZEB1↓,
Vim↓,
E-cadherin↓,
VEGF↓, Chinese red propolis and CAPE displayed a solid inhibitory effect in VEGF-mediated angiogenesis
EMT↓, Chinese propolis (12.5 μg/ml) inhibited Panc-1 cell migration by modulating the epithelial-mesenchymal transition

1674- PBG,  SDT,  HPT,    Study on the effect of a triple cancer treatment of propolis, thermal cycling-hyperthermia, and low-intensity ultrasound on PANC-1 cells
- in-vitro, PC, PANC1 - in-vitro, Nor, H6c7
tumCV↓, cell viability of a human cancer cell line PANC-1 decreased to a level 80% less than the control
ROS↑, triple treatment showed a significant accumulation of the intracellular ROS (up to a 2.1-fold increase)
eff↑, combination of TC-HT and US also promotes the anticancer effect of the heat-sensitive chemotherapy drug cisplatin on PANC-1 cells
Dose∅, moderate propolis concentration 0.3%, 10-cycles TC-HT and 2.25 MHz US with intensity 0.3 W/cm2 and duration 30 minutes were chosen to avoid the thermotoxicity on PANC-1 cells
selectivity↑, Moreover, normal cells such as the human skin cells Detroit 551 (Figure 1D) and human pancreatic duct cells H6c7 (Figure 1E) were not significantly affected by the triple treatment as well as all the other treatments.
MMP↓, ratio of the cells exhibiting MMP loss was significantly promoted to 23.3% after the double treatment of propolis + TC-HT, and it was further elevated significantly to 34.7% by employing the triple treatment.
mtDam↑, hence caused more mitochondrial dysfunction
cl‑PARP↑, PARP cleavage was further promoted significantly to a 6.2-fold increase by US in the triple treatment
p‑ERK↓, the p-ERK level was suppressed by propolis + TC-HT treatment (0.30-fold decrease), and was further down-regulated when US was introduced in the triple treatment (0.15-fold decrease)
p‑JNK↑, p-JNK and p-p38 levels both exhibited a reverse performance, which were promoted the most in the triple treatment (8.7-fold and 9.2-fold increase, respectively)
p‑p38↑,
eff↓, inhibitory effect of the triple treatment was restored by NAC
ChemoSen↑, cisplatin + TC-HT treatment significantly elevated PARP cleavage to a 3.20-fold increase. This elevation was further increased with the help of US (5.82-fold increase).

1675- PBG,    Portuguese Propolis Antitumoral Activity in Melanoma Involves ROS Production and Induction of Apoptosis
- in-vitro, Melanoma, A375 - in-vitro, Melanoma, WM983B
tumCV↓, fractions decreased cell viability
ROS↑, G18.EE and Its Fractions (n-BuOH and EtOAc) Promote Mitochondrial ROS Production in Melanoma Cells
antiOx↑, we can deduce that G18.EE may be a potential natural antioxidant value of EC50 (concentration that produces half of the maximal response) determined for the G18.EE was 10.90 ± 0.34 µg/mL
Apoptosis↑,
BAX↑, Both cell lines tested seem to display higher levels of Bax and p53, although not significant
P53↑,
Casp3↑, caspases 3 and 9 also appear to be enhanced by propolis treatments
Casp9↑,

1676- PBG,    Use of Stingless Bee Propolis and Geopropolis against Cancer—A Literature Review of Preclinical Studies
- Review, Var, NA
ROS↑, evidenced in the accumulation of reactive oxygen species (ROS)
MMP↓, reduction of mitochondrial membrane potential (Δψm)
Bcl-2↓, decreased levels of Bcl-2 proteins (antiapoptotic proteins) and AKT-3
eff↑, combination of the extract (30 µg/mL) with the antineoplastic vemurafenib (15 μM) against melanoma cells demonstrated a synergistic effect
tumCV↓, decreased cell viability for 23% of the colon cancer cells (SW620) treated with the aqueous propolis extract produced by Trigona laeviceps
TumCCA↑, antitumor activity of artepillin C is mediated by one of the following mechanisms: induction of cell cycle arrest in cancer cells, inhibition of angiogenesis, and inhibition of the oncogenic PAK1 signaling cascade
angioG↓,
PAK1↓,
HDAC1↓, negatively regulated expression of histone deacetylases (HDAC) 1 and 2
HDAC2↓,
P53↑, positive regulation of acetyl-p53 expression at the protein level
PCNA↓, negative regulation of cell-cycle-related gene expression, i.e., proliferating cell nuclear antigen (PCNA) and cyclin D1 and E1
cycD1/CCND1↓,
cycE/CCNE↓,
P21?, positively regulating the expression of the cell cycle arrest gene p21
BAX↑, Bax, Bcl-2, cleaved caspase-3, and poly(ADP-ribose) polymerase
cl‑Casp3↑,
cl‑PARP↑,
ChemoSen↑, apigenin significantly down-regulates Mcl-1 transcription and translation levels in SKOV3 and SKOV3/DDP cells, which is responsible for its cytotoxic functions and chemosensitizing effects

1684- PBG,    Antitumor Activity of Chinese Propolis in Human Breast Cancer MCF-7 and MDA-MB-231 Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vitro, Nor, HUVECs
Apoptosis?, treatment of EECP for 24 and 48 h induced both cells apoptosis obviously
ANXA7↑, EECP significantly increased ANXA7 expression and ROS level, and NF-κB p65 level
ROS↑,
NF-kB↓, EECP significantly upregulated the expression of ANXA7 and downregulated NF-?B p65 level in a dose-dependent manner
MMP↓, mitochondrial membrane potential were depressed by EECP dramatically
selectivity↑, EECP had little or small cytotoxicity on normal human umbilical vein endothelial cells (HUVECs)

1685- PBG,    Antitumor Activity of Chinese Propolis in Human Breast Cancer MCF-7 and MDA-MB-231 Cells
- in-vitro, BC, MCF-7
ANXA7↑, Exposure to EECP significantly increased ANXA7 expression and ROS level
ROS↑,
NF-kB↓, NF-κB p65 level and mitochondrial membrane potential were depressed by EECP dramatically.
MMP↓,
selectivity↑, Interestingly, EECP had little or small cytotoxicity on normal human umbilical vein endothelial cells (HUVECs)
Dose⇅, propolis plays a dual role on ROS depending on concentrations: at high concentration, it exerts a prooxidant effect; at low concentration, it can also act as an antioxidant by scavenging free radicals.
ROS⇅,

1663- PBG,    Propolis and Their Active Constituents for Chronic Diseases
- Review, Var, NA
NF-kB↓, CAPE (a bioactive constituent of propolis) was reported to have anticancer properties by inhibiting NF-κB, caspase and Fas signaling activation in MCF-7 cells
Casp↓,
Fas↓,
DNAdam↑, DNA fragmentation, CCAAT/enhancer binding protein homologous protein expression and caspase-3 activity
Casp3↑,
P53↝, Chinese propolis (EECP) and its bioactive constituents mainly persist due to regulation of the annexin A7 and p53 proteins, mitochondrial membrane potential and ROSs, as well as that inhibition of NF-κB causes apoptosis in cancer cells
MMP↝,
ROS↑, Herrera et al. and reported on the MDA-MB 231 tumor cell line, and the inhibitory effect of propolis was proposed to occur through the induction of mitochondrial dysfunction, resulting in ROS-associated necrosis
mtDam↑,
Dose?, A concentration of 100 μg/mL was able to attain 71% cytotoxicity
angioG↓, negative effect on angiogenesis, proliferation and migration of tumor cells. A concentration of 25–200 μg/mL noticeably inhibited the metastasis of breast cancer
TumCP↓,
TumCMig↓,
BAX↑,
selectivity↑, Negligible effect in fibroblasts
MMP↓, Cuban: Disturbed the mitochondrial potential, lactate dehydrogenase released, production of ROS and cell migration
LDH↓,
IL6↓, Chinese: Decreased cell tube generation, IL-6, IL-1β, TNF-α-like inflammatory mediators, glycolytic enzymes and mitochondrial potential. Promoted ROS generation
IL1β↓,
TNF-α↓,

1664- PBG,    Anticancer Activity of Propolis and Its Compounds
- Review, Var, NA
Apoptosis↑,
TumCMig↓,
TumCCA↑,
TumCP↓,
angioG↓,
P21↑, upregulating p21 and p27 expression
p27↑,
CDK1↓, thanol-extracted Cameroonian propolis increased the amount of DU145 and PC3 cells in G0/G1 phase, down-regulated cell cycle proteins (CDK1, pCDK1, and their related cyclins A and B)
p‑CDK1↓,
cycA1/CCNA1↓,
CycB/CCNB1↓,
P70S6K↓, Caffeic acid phenylethyl ester has been shown to inhibit the S6 beta-1 ribosomal protein kinase (p70S6K),
CLDN2↓, inhibition of NF-κB may be involved in the decrease of claudin-2 mRNA level
HK2↓, Chinese poplar propolis has been shown to significantly reduce the level of glycolysis at the stage of action of hexokinase 2 (HK2), phosphofructokinase (PFK), muscle isozyme pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA)
PFK↓,
PKM2↓,
LDHA↓,
TLR4↓, hinese propolis, as well as CAPE, inhibits breast cancer cell proliferation in the inflammatory microenvironment by inhibiting the Toll-like receptor 4 (TLR4) signal pathway
H3↓, Brazilian red propolis bioactive isoflavonoid, down-regulates the alpha-tubulin, tubulin in microtubules, and histone H3 genes
α-tubulin↓,
ROS↑, CAPE also affects the apoptotic intrinsic pathway by increasing ROS production
Akt↓, CAPE induces apoptosis by decreasing the levels of proteins related to carcinogenesis, including Akt, GSK3b, FOXO1, FOXO3a, NF-kB, Skp2 and cyclin D1
GSK‐3β↓,
FOXO3↓,
NF-kB↓,
cycD1/CCND1↓,
MMP↓, It was found that chrysin caused a loss of mitochondria membrane potential (MMP) while increasing the production of reactive oxygen species (ROS), cytoplasmic Ca2+ levels, and lipid peroxidation
ROS↑,
i-Ca+2↑,
lipid-P↑,
ER Stress↑, Chrysin also induced endoplasmic reticulum (ER) stress by activating unfolded protein response proteins (UPR) such as PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78)
UPR↑,
PERK↑,
eIF2α↑,
GRP78/BiP↑,
BAX↑, CAPE activated Bax protein
PUMA↑, CAPE also significantly increased PUMA expression
ROS↑, Northeast China causes cell apoptosis in human gastric cancer cells with increased production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential.
MMP↓,
Cyt‑c↑, release of cytochrome C from mitochondria to the cytoplasm is observed, as well as the activation of cleaved caspases (8, 9, and 3) and PARP
cl‑Casp8↑,
cl‑Casp8↑,
cl‑Casp3↑,
cl‑PARP↑,
eff↑, administration of Iranian propolis extract in combination with 5-fluorouracil (5-FU) significantly reduced the number of azaxymethane-induced aberrant crypt foci compared to 5-FU or propolis alone.
eff↑, Propolis may also have a positive effect on the efficacy of photodynamic therapy (PDT). enhances the intracellular accumulation of protoporphyrin IX (PpIX) in human epidermoid carcinoma cells
RadioS↑, breast cancer patients undergoing radiotherapy and supplemented with propolis had a statistically significant longer median disease-free survival time than the control group
ChemoSen↑, confirmed that propolis mouthwash is effective and safe in the treatment of chemo- or radiotherapy-induced oral mucositis in cancer patients.
eff↑, Quercetin, ferulic acid, and CAPE may also influence the MDR of cancer cells by inhibiting P-gp expression

1666- PBG,    Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer
- Review, Var, NA
ChemoSen↑, Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents
TumCCA↑, cell-cycle arrest and attenuation of cancer cells proliferation
TumCP↓,
Apoptosis↑,
antiOx↓, behave as antioxidants against peroxyl and hydroxyl radicals,
ROS↑, whereas prooxidant activity is observed in the presence of Cu2+.
COX2↑, Propolis, as well as flavonoids derived from propolis, such as galangin, is a potent COX-2 inhibitor
ER(estro)↓, Some flavonoids from propolis, such as galangin, genistein, baicalein, hesperetin, naringenin, and quercetin, suppressed the proliferation of an estrogen receptor (ER)
cycA1/CCNA1↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
CycB/CCNB1↓,
CDK2↓,
P21↑,
p27↑,
hTERT/TERT↓, leukemia cells, propolis successfully reduced hTERT mRNA expression
HDAC↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
ROS⇅, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
Dose?, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
ROS↓, By scavenging free radicals, chelating metal ions (mainly iron and copper), and stimulating endogenous antioxidant defenses, propolis and its flavonoids directly attenuate the generation of ROS
ROS↑, Romanian propolis [99], exhibits prooxidant properties at high concentrations, by mobilizing endogenous copper ions and DNA-associated copper in cells.
DNAdam↑, propolis, i.e., its polyphenolic components, may induce DNA damage in the presence of transition metal ions.
ChemoSen↑, Algerian propolis + doxorubicin decreased cell viability, prevented cell proliferation and cell cycle progression, induced apoptosis by activating caspase-3 and -9 activities, and increased the accumulation of chemotherapeutic drugs in MDA-MB-231 cel
LOX1↓, propolis components inhibited the LOX pathway
lipid-P↓, Croatian propolis improved psoriatic-like skin lesions induced by irritant agents n-hexyl salicylate or di-n-propyl disulfide by decreasing the extent of lipid peroxidation
NO↑, Taken together, propolis may increase the phagocytic index, NO production, and production of IgG antibodies
Igs↑,
NK cell↑, propolis treatment for 3 days increases the cytotoxic activity of NK cells against murine lymphoma.
MMPs↓, extracts of propolis containing artepillin C and CAPE decreased the formation of new vessels and expression of MMPs and VEGF in various cancer cells
VEGF↓,
Hif1a↓, Brazilian green propolis inhibit the expression of the hypoxia-inducible factor-1 (HIF-1) protein and HIF-1 downstream targets such as glucose transporter 1, hexokinase 2, and VEGF-A
GLUT1↓,
HK2↓,
selectivity↑, Portuguese propolis was selectively toxic against malignant cells.
RadioS↑, propolis increased the lifespan of mice that received the radiotherapy with gamma rays
GlucoseCon↓, Portuguese propolis disturbed the glycolytic metabolism of human colorectal cancer cells, as evidenced by a decrease in glucose consumption and lactate production
lactateProd↓,
eff↓, Furthermore, different pesticides or heavy metals can be found in propolis, which can cause unwanted side effects.
*BioAv↓, Due to the low bioavailability and clinical efficacy of propolis and its flavonoids, their biomedical applications remain limited.

1668- PBG,    Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms
- Review, Var, NA
antiOx↑, Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties.
Inflam↓,
AntiCan↑,
TumCP↓, primarily by inhibiting cancer cell proliferation, inducing apoptosis
Apoptosis↑,
eff↝, Depending on the bee species, geographic location, plant species, and weather conditions, the chemical makeup of propolis fluctuates significantly
MMPs↓, via inhibiting the metastatic protein expression such as MMPs (matrix metalloproteinases)
TNF-α↓, inhibit inflammatory mediators including tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-1/2 (COX ½), lipoxygenase (LOX), prostaglandins (PGs), and interleukin 1- β (IL1-β)
iNOS↓,
COX2↓,
IL1β↑,
*BioAv↓, Despite the low bioavailability of Artepillin C, a compound with a wide variety of physiological activities
BAX↑, Egyptian propolis extract revealed high apoptotic effects through an increase in BAX (pro-apoptotic protein), caspase-3, and cytochrome-c expression levels, and by a reduction in B-cell lymphoma2 (BCL2)
Casp3↑,
Cyt‑c↑,
Bcl-2↓,
eff↑, enhanced the G0/G1 cell cycle arrest induced by methotrexate
selectivity↑, Thailand propolis on normal and cancerous cells carried out by Umthong et al. found significant differences with the propolis showing cytotoxicity against cancerous but not normal cells.
P53↑, significant increases in the levels of p53 in cells treated with propolis extracts.
ROS↑, propolis induced apoptosis in the SW620 human colorectal cancer cell line through mitochondrial dysfunction caused by high production of reactive oxygen species (ROS) and caspase activation
Casp↑,
eff↑, Galangin- and chrysin-induced apoptosis and mitochondrial membrane potential loss in B16-F1 and A375 melanoma cell lines
ERK↓, Galangin- and chrysin-induced apoptosis and mitochondrial membrane potential loss in B16-F1 and A375 melanoma cell lines
Dose∅, propolis extracts at concentrations of 50 μg/mL significantly increased the levels of TRAIL in cervical tumor cell lines
TRAIL↑,
NF-kB↑, p53, NF-κB, and ROS. These molecules were found to be elevated following exposure of the cells to the alcoholic extract of the propolis
ROS↑,
Dose↑, high concentrations, propolis increased the amounts of integrin β4, ROS, and p53
MMP↓, high expression levels of these molecules, in turn, drove a decrease in mitochondrial membrane potential
DNAdam↑, propolis extract induced DNA fragmentation
TumAuto↑, CAPE, were found to induce autophagy in a breast cancer cell line (MDA-MB-231) through upregulating LC3-II and downregulating p62,
LC3II↑,
p62↓,
EGF↓, downregulation of EGF, HIF-1α, and VEGF
Hif1a↓,
VEGF↓,
TLR4↓, downregulating Toll-like receptor 4 (TLR-4), glycogen synthase kinase 3 beta (GSK3 β), and NF-κB signaling pathways
GSK‐3β↓,
NF-kB↓,
Telomerase↓, Propolis was shown to inhibit the telomerase reverse transcriptase activity in leukemia cells.
ChemoSen↑, Propolis has been shown to increase the activity of existing chemotherapeutic agents and inhibit some of their side effects
ChemoSideEff↓,

2381- PBG,    Chinese Poplar Propolis Inhibits MDA-MB-231 Cell Proliferation in an Inflammatory Microenvironment by Targeting Enzymes of the Glycolytic Pathway
- in-vitro, BC, MDA-MB-231
TumCP↓, Propolis treatment obviously inhibited MDA-MB-231 cell proliferation, migration and invasion, clone forming, and angiogenesis.
TumCMig↓,
TumCI↓,
angioG↓,
TNF-α↓, (TNF-α), interleukin (IL)-1β, and IL-6, as well as NLRP3 inflammasomes, were decreased following propolis treatment when compared with the LPS group.
IL1β↓,
IL6↓,
NLRP3↓,
Glycolysis↓, Moreover, propolis treatment significantly downregulated the levels of key enzymes of glycolysis–hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase muscle isozyme M2 (PKM2), and lactate dehydrogenase A (LDHA) in MDA-MB-231 cells
HK2↓,
PFK↓,
PKM2↓,
LDHA↓,
ROS↑, propolis increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential.
MMP↓,

2430- PBG,    The cytotoxic effects of propolis on breast cancer cells involve PI3K/Akt and ERK1/2 pathways, mitochondrial membrane potential, and reactive oxygen species generation
- in-vitro, BC, MDA-MB-231
TumCP↓, CP extract exhibited antiproliferative and cytotoxic effects on MDA MB-231 cells, what may be probably related to PI3K/Akt and ERK1/2 pathways.
TP53↓, decreased expression of apoptosis-related genes (TP53, CASP3, BAX and P21)
Casp3↓,
BAX↓,
P21↓,
ROS↑, These results suggested that CP cytotoxic effects on MDA MB-231 cells might be associated with the intracellular ROS production
eff↓, CP-induced ROS generation was reduced after cotreatment with the antioxidant NAC, which increased the percentage of viable cells, suggesting that CP-induced necrotic-related cell death could be associated with ROS production
MMP↓, Necrosis death is associated with mitochondrial dysfunction and our propolis sample reduced the MMP and increased LDH levels.
LDH↑,
ATP↓, rupture of mitochondrial membrane, loss of adenosine triphosphate (ATP),
Ca+2↑, excessive ROS production, intracellular [Ca+2] elevation, osmotic shock,

4946- PEITC,    Phenethyl Isothiocyanate Inhibits Oxidative Phosphorylation to Trigger Reactive Oxygen Species-mediated Death of Human Prostate Cancer Cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3
Apoptosis↑, inhibits growth of human cancer cells by causing apoptotic and autophagic cell death.
TumAuto↑,
ROS↑, we demonstrate that the PEITC-induced cell death is initiated by production of reactive oxygen species (ROS) resulting from inhibition of oxidative phosphorylation (OXPHOS)
OXPHOS↓,
ATP↓, , suppression of OXPHOS, and ATP depletion.
selectivity↑, These effects were not observed in a representative normal human prostate epithelial cell line (PrEC)
ETC↓, PEITC-induced cell death involving ROS production due to inhibition of complex III and OXPHOS.
eff↓, PEITC-mediated increase in CM· signal intensity in PC-3 cells was markedly suppressed in the presence of NAC
eff↓, Rho-0 Variants of LNCaP and PC-3 Cells Were Resistant to PEITC-induced Apoptosis
BAX↑, PEITC Treatment Caused Mitochondrial Translocation of Bax

4947- PEITC,    Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G0/G1   Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death
- in-vitro, Oral, HSC3
AntiCan↑, Phenethyl isothiocyanate (PEITC), an effective anticancer and chemopreventive agent, has been reported to inhibit cancer cell growth through cell-cycle arrest and induction of apoptotic events in various human cancer cells models.
chemoPv↑,
TumCG↓,
Apoptosis↑,
TumCCA↑, PEITC effectively inhibited the HSC-3 cells’ growth and caused apoptosis. PEITC induced G0/G1   phase arrest through the effects of associated protein such as p53, p21, p17, CDK2 and cyclin E,
P53↑,
P21↑,
BAX↑, triggered apoptosis through promotion of Bax and Bid expression and reduction of Bcl-2, leading to decrease the levels of mitochondrial membrane potential (ΔΨm), and followed the releases of cytochrome c, AIF and Endo G then for causing apoptosis in
BID↑,
Bcl-2↓,
MMP↓,
Cyt‑c↑,
AIF↑,
ROS↑, PEITC promoted the production of ROS (Figure 4(a)) and Ca2+ (Figure 4(c)) but decreased the levels of ΔΨm
Ca+2↑,

4948- PEITC,    Sensory acceptable equivalent doses of β-phenylethyl isothiocyanate (PEITC) induce cell cycle arrest and retard the growth of p53 mutated oral cancer in vitro and in vivo
- vitro+vivo, Oral, CAL27 - vitro+vivo, Oral, FaDu - vitro+vivo, Oral, SCC4 - vitro+vivo, Oral, SCC9
TumCD↑, In vitro, PEITC was selectively toxic to oral cancer cells (CAL-27, FaDu, SCC4, SCC 9, SCC15, SCC25 and TU138), compared to oral keratinocytes (OKF6/TERT2 and NOK/Si)
TumCG↓, In vivo, 5 and 10 mg kg−1 PEITC, equivalent to human organoleptically acceptable doses, retarded tumor growth and prolonged the survival of mice bearing p53-mutated oral cancer cells
OS↑,
ROS↑, Mechanistically, PEITC induced ROS accumulation, nuclear translocation of p53 and p21 and G1/S cell cycle arrest in vitro; increased p53 and 8-oxo-dG levels
P53↑,
P21↑,
TumCCA↑,
Ki-67↓, and decreased Ki-67 intense/mild staining ratios without TUNEL changes in vivo

4949- PEITC,    Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells
- in-vitro, Cerv, HeLa
ROS↑, Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells.
selectivity↑,
CSCs↓, PEITC treatments resulted in a reduced number of ALDHhi hCSCs in a concentration-dependent manner
Sp1/3/4↓, PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein)
P-gp↓,
ALDH↓, PEITC inhibits ALDH2 in the liver
GSH↓, The electrophilic property of PEITC has been shown to covalently interact with nucleophilic glutathione (GSH), leading to ROS-induction in cells
TumCP↓, Phenethyl Isothiocyanate Treatment Suppressed HeLa Cancer Stem Cells Proliferation and Increased Early Apoptosis
Apoptosis↑,

4950- PEITC,    Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential
- vitro+vivo, Pca, PC3
MMP↓, The PEITC-induced cell death in PC-3 cells was associated with disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria to the cytosol and generation of reactive oxygen spe
Cyt‑c↑,
Smad1↑,
Diablo↑,
ROS↑,

4951- PEITC,    ROS accumulation by PEITC selectively kills ovarian cancer cells via UPR-mediated apoptosis
- in-vitro, Ovarian, PA1 - in-vitro, Ovarian, SKOV3
ROS↑, PEITC caused increased ROS-accumulation and inhibited proliferation selectively in ovarian cancer cells, and glutathione (GSH) depletion in SKOV-3.
TumCP↓,
GSH↓, One of the generating ROS mechanisms by PEITC is a depletion of GSH
selectivity↑, However, PEITC did not cause any effect in normal ovarian epithelial cells and peripheral blood mononuclear cells
UPR↑, PEITC Induces Unfolded Protein Response, Attenuated by NAC, in Ovarian Cancer Cells
CHOP↑, The key regulator of UPR-mediated apoptosis, CHOP/GADD153 and endoplasmic reticulum resident chaperone BiP/GRP78 were parallely up-regulated
ER Stress↑,
GRP78/BiP↑,
PERK↑, with activation of two major sensors of the UPR [PERK and ATF-6 in PA-1; PERK, and IRE1α in SKOV-3) in response to ROS accumulation induced by PEITC (5 μM)
ATF6↑,
eff↓, ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the effect of PEITC on UPR signatures (P-PERK, IRE1α, CHOP/GADD153, and BiP/GRP78)
TumCG↓, PEITC Inhibits Growth of Ovarian Cancer Cells without Inhibiting the Growth of Normal PBMC Cells
Apoptosis↑, PEITC Induces Apoptotic Cell Death in Ovarian Cancer Cell Lines
toxicity↓, IC50 value of PEITC for endothelial cells was more than 100 μM, suggesting cancer cell-specific cell death by PEITC (28). PEITC is a well-known ROS inducer in cancer cells without any potential adverse effect on normal cells (

4953- PEITC,    PEITC: a natural compound effective in killing primary leukemia cells and overcoming drug resistance
- in-vitro, CLL, NA
ROS↑, Based on the recent observations that β-phenylethyl isothiocyanate (PEITC) causes significant ROS increase in cancer cells by disabling the GSH antioxidant system
GSH↓,
TumCD↓, PEITC effectively killed both F-ara-A sensitive (n=7, IC50 range: 0.5-10 µM) and resistant (n=4, IC50>50 µM,) CLL cells, with similar IC50 values of 4-8 µM.
eff↓, Antioxidant N-acetylcysteine (NAC) suppressed PEITC-induced ROS accumulation and cell death, suggesting that this compound killed CLL cells through ROS-mediated mechanism.
Mcl-1↓, PEITC treatment led to a significant decrease in MCL-1 protein without detectable change in BCL-2 protein level.
Casp3↑, PEITC induced caspase-3 activation

4954- PEITC,    Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate
- vitro+vivo, Ovarian, SKOV3
ROS↑, Here, we show that such abnormal increases in ROS can be exploited to selectively kill cancer cells using β-phenylethyl isothiocyanate (PEITC).
GSH↓, malignant cells highly sensitive to PEITC, which effectively disables the glutathione antioxidant system and causes severe ROS accumulation preferentially in the transformed cells due to their active ROS output
selectivity↑, Our study showed that PEITC has a superior selectivity compared to cisplatin. The ability to preferentially kill malignant cells is a promising feature of PEITC.
mtDam↑, Excessive ROS causes oxidative mitochondrial damage, inactivation of redox-sensitive molecules, and massive cell death.
TumCD↑,
OS↑, In vivo, PEITC exhibits therapeutic activity and prolongs animal survival.
eff↑, Furthermore, because PEITC has low toxicity in nonmalignant cells and exhibits anticancer selectivity superior to cisplatin,
*toxicity↓,
H2O2↑, t ROS induced by PEITC were mainly DCF-DA-reactive species such as hydrogen peroxide (H2O2) and nitric oxide (NO)
NO↑,
eff↓, 5 μM PEITC significantly increased DAF-FM fluorescence, which was reversed by the antioxidant N-acetyl-L-cysteine (NAC) but not by the H2O2-scavenging enzyme catalase
GPx↓, 500 μM PEITC inhibited GPX by approximately 50% and 90%, respectively. These concentrations could be achieved intracellularly when cells were incubated with 5–10 μM PEITC.
Dose↝, Interestingly, incubation of cells with 5–10 μM PEITC led to a depletion of cellular GSH, which is in the mM range. The explanation for this stoichiometric discrepancy is that PEITC can be concentrated in the cells. A
eff↑, combination of PEITC with curcumin was effective, suggesting that combination of PEITC with other agents may enhance anticancer activity.

4956- PEITC,    Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells
- vitro+vivo, Lung, A549
GSH↓, synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation
ROS↑,
mtDam↑, and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential.
mitResp↓,
MMP↓,
CSCs↓, Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549
OCT4↓, with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133.
ABC↓,
SOX2↓,
CD133↓,
CD44↓, LBL21 caused a significant decrease in various CSC biomarkers CD44, CD133, OCT4, ABCG2, SOX2, ALDH2 and NANOG in mRNA expression levels
ALDH↓,
Nanog↓,
TumCG↓, LBL21 substantially suppressed tumor growth in A549 xenograft mice

4963- PEITC,    Sensory Acceptable Equivalent Doses of β - Phenylethyl isothiocyanate (PEITC) Induce Cell Cycle Arrest and Retard Growth of p53 Mutated Oral Cancer In Vitro and In Vivo
- vitro+vivo, Oral, CAL27 - vitro+vivo, Oral, FaDu - vitro+vivo, Oral, SCC4 - vitro+vivo, Oral, SCC9
Dose↝, High doses of β - Phenethyl isothiocyanate (PEITC), a phytochemical in cruciferous vegetables are not feasible for consumption due to a strong mouth-tingling effect. This study investigated the anti-cancer effect of PEITC at sensory acceptable doses.
selectivity↑, In vitro, PEITC was selectively toxic to oral cancer cells (CAL-27, FaDu, SCC4, SCC 9, SCC15, SCC25 and TU138), compared to oral keratinocytes (OKF6/TERT2 and NOK/Si).
TumCG↓, In vivo, 5 and 10 mg/kg PEITC, equivalent to human organoleptic acceptable doses, retarded tumor growth and prolonged survival of mice bearing p53-mutated oral cancer cell - TU138 xenograft.
OS↑,
ROS↑, Mechanistically, PEITC induced ROS accumulation, nuclear translocation of p53 and p21 and G1/S cell cycle arrest in vitro; increased p53 and 8-oxo-dG levels, and decreased Ki-67 intense/mild staining ratios without TUNEL changes in vivo.
P53↑,
P21↑,
TumCCA↑,
Ki-67↓,

4922- PEITC,    Phenethyl Isothiocyanate: A comprehensive review of anti-cancer mechanisms
- Review, Var, NA
Risk↓, strong inverse relationship between dietary intake of cruciferous vegetables and the incidence of cancer.
AntiCan↑, Phenethyl isothiocyanate (PEITC) is present as gluconasturtiin in many cruciferous vegetables with remarkable anti-cancer effects.
TumCP↓, PEITC targets multiple proteins to suppress various cancer-promoting mechanisms such as cell proliferation, progression and metastasis
TumMeta↓,
ChemoSen↑, combination of PEITC with conventional anti-cancer agents is also highly effective in improving overall efficacy
*BioAv↑, ITCs are released from glucosinolates by the action of the enzyme myrosinase. The enzyme myrosinase can be activated by cutting or chewing the vegetables, but heating can destroy its activity
*other↝, Although water cress and broccoli are known to be the richest source, PEITC can also be obtained from turnips and radish
*Dose↝, In a study conducted with human volunteers, approximately 2 to 6 mg of PEITC was found to be released by the consumption of one ounce of watercress
Dose↓, significant anti-cancer effects can be achieved at micromolar concentrations of PEITC.
*BioAv↑, PEITC is highly bioavailable after oral administration. A single dose of 10–100 μmol/kg PEITC in rats resulted in bioavailability ranging between 90–114%
*Dose↝, Furthermore, about 928.5±250nM peak plasma concentration of PEITC was achieved in human subjects, after the consumption of 100g watercress.
*Half-Life↝, time to reach peak plasma concentration was observed to be 2.6h±1.1h with a t1/2 4.9±1.1h
*toxicity↝, long term studies are required to establish the safety profile of PEITC, since regular intake of PEITC can cause its accumulation resulting in cumulative effects, which could be toxic.
GSH↓, The conjugation of PEITC with intracellular glutathione and the subsequent removal of the conjugate result in depletion of glutathione and alteration in redox homeostasis leading to oxidative stress
ROS↑, PEITC-mediated generation of reactive oxygen species (ROS) is known to be a general mechanism of action leading to cytotoxic effects, especially specific to cancer cells
CYP1A1↑, PEITC on one hand causes induction of CYP1A1 and CYP1A2; however, it inhibits activity of certain CytP450 enzymes, such as CYP2E1, CYP3A4 and CYP2A3
CYP1A2↑,
P450↓,
CYP2E1↑,
CYP3A4↓,
CYP2A3/CYP2A6↓,
*ROS↓, PEITC treatment caused a significant increase in the activities of ROS detoxifying enzymes such as glutathione peroxidase1, superoxide dismutase 1 and 2. This was also confirmed in human study where subjects were administered watercress, a major sour
*GPx1↑,
*SOD1↑,
*SOD2↑,
Akt↓, PEITC inhibits Akt, a component of Ras signaling to inhibit tumor growth in several cancer types
EGFR↓, PEITC is also known to inhibit EGFR and HER2, which are important growth factors and regulators of Akt in different cancer models
HER2/EBBR2↓,
P53↑, PEITC-mediated activation of another tumor suppressor, p53 was observed in oral squamous cell carcinoma, causing G0/G1 phase arrest in multiple myeloma,
Telomerase↓, PEITC has been shown to inhibit telomerase activity in prostate and cervical cancer cells
selectivity↑, generation of reactive oxygen species (ROS), which also has been shown to be the basis of selectivity of PEITC toward cancer cells leaving normal cells undamaged [
MMP↓, ROS generation by PEITC leads to mitochondrial deregulation and modulation of proteins like Bcl2, BID, BIM and BAX, causing the release of cytochrome c into cytosol leading to apoptosis
Cyt‑c↑,
Apoptosis↑,
DR4↑, induction of death receptors and Fas-mediated apoptosis
Fas↑,
XIAP↓, PEITC-mediated suppression of anti-apoptotic proteins like XIAP and survivin, which are up-regulated in cancer cells
survivin↓,
TumAuto↑, PEITC induces autophagic cell death in cancer cells
Hif1a↓, PEITC directly or indirectly suppresses HIF1α
angioG↓, is possible that PEITC can block angiogenesis by non-hypoxic mechanisms also.
MMPs↓, Various studies with PEITC have shown suppression of invasion through inhibition of matrix metalloproteinases along with anti-metastatic effects caused by suppression of ERK kinase activity and transcriptional activity of NFkB
ERK↓,
NF-kB↓,
EMT↓, PEITC was also known to inhibit processes, such as epithelial to mesenchymal transition (EMT), cell invasion and migration, which are essential pre-requisites for metastasis
TumCI↓,
TumCMig↓,
Glycolysis↓, reduced rates of glycolysis in PEITC-treated cells and depletion of ATP lead to death in prostate cancer cells
ATP↓,
selectivity↑, PEITC (5μM) treatment suppressed glycolysis in the cancer cells, but no changes were observed in normal cells.
*antiOx↑, the antioxidant effect is achieved at very low ITC levels in normal cells as shown in various animal models
Dose↝, At higher concentrations, ITCs may generate ROS by depleting antioxidant levels. PEITC is known to cause ROS generation, which is the major mechanism of toxicity in cancer cells
other↝, There is a continuous leakage of electrons from the electron transport chain (ETC), which is major source of ROS production. PEITC causes generation of endogenous ROS by disrupting mitochondrial respiratory chain
OCR↓, PEITC also inhibits mitochondrial complex III activity and reduces the oxygen consumption rate in prostate cancer cells
GSH↓, PEITC binds to GSH and causes its depletion in cancer cells leading to ROS-induced cell damage
ITGB1↓, PEITC was found to inhibit major integrins, such as ITGB1, ITGA2 and ITGA6 in prostate cancer cells
ITGB6↓,
ChemoSen↑, Using pre-clinical studies, improved outcomes were observed when the conventional agents, such as docetaxel, metformin, vinblastine, doxorubicin and HDAC inhibitors were combined with PEITC

4924- PEITC,    Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial
- Trial, Oral, NA
QoL↑, higher proportion of participants with improved HRQOL, stable disease, and increased serum p53 levels
P53↑,
OS↑, The PFS time in the study group was significantly longer than that of the control group (p < 0.05).
Cyt‑c↝, Serum cytochrome c levels were non-significantly decreased in the study group
other↝, β-phenylethyl isothiocyanate (PEITC) is a phytochemical naturally present in cruciferous vegetables such as watercress, broccoli, wasabi, and cabbage
ROS↑, PEITC was selectively toxic to numerous types of cancer cells via reactive oxygen species, (ROS)-mediated mechanisms
selectivity↑,
P21↑, PEITC led to increased oxidative stress, nuclear translocation of p53 and p21, and cell cycle arrest in TP53-mutated oral cancer cells
TumCCA↑,
Dose↝, PEITC at 5 or 10 mg per kg body weight can slow down tumor growth and prolong the survival of cancer-bearing mice along with increased p53 expression
BioAv↑, Nutri-PEITC Jelly containing 40 mg of PEITC per day can be absorbed rapidly within a few hours and eliminated completely within 24 h
Weight↑, the Nutri-PEITC Jelly group had a significantly higher proportion of participants with improved BMI than that of the placebo control group (40% vs. 20%, p < 0.05)
chemoP↑, Therefore, Nutri-PEITC Jelly at the dose of 20 mg/day of PEITC did not inhibit the disease progression and the clinical application of this product is rather a functional food for tertiary chemoprevention than a therapy.

4918- PEITC,    Nutritional Sources and Anticancer Potential of Phenethyl Isothiocyanate: Molecular Mechanisms and Therapeutic Insights
- Review, Var, NA
Apoptosis↑, Its anticancer activities are mediated through several mechanisms, including the induction of apoptosis (programmed cell death), inhibition of cell proliferation, suppression of angiogenesis (formation of new blood vessels that feed tumors), and red
TumCP↓,
angioG↓,
TumMeta↓, reduction of metastasis (spread of cancer cells to new areas).
NF-kB↓, PEITC targets crucial cellular signaling pathways involved in cancer progression, notably the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), Protein Kinase B (Akt), and Mitogen-Activated Protein Kinase (MAPK) pathways.
Akt↓,
MAPK↓,
*BioAv↓, Isothiocyanates, including PEITC, are thermally labile, meaning they are susceptible to decomposition under heat;
ROS↑, Several studies proved that PEITC could initiate oxidative damage in the mitochondria by increasing the intracellular ROS to a highly toxic level
lipid-P↑, PEITC-induced ROS can cause lipid peroxidation of the mitochondrial membrane and, therefore, the loss of membrane integrity and the production of apoptosis-inducing factor (AIF) and apoptogenic cytochrome c (Cyt c)
AIF↑,
Cyt‑c↑,
DR4↑, PEITC can enhance TRAIL-induced apoptosis by upregulating DR4 and DR5 expression.
DR5↑,
TumCCA↑, Antiproliferative: Cell Cycle Arrest Induction
JAK↓, PEITC can hinder the activation of the JAK-STAT3 pathway,[112] decreasing the expression of MMP2 and MMP9.
STAT3↓,
MMP2↓,
MMP9↓,
PKCδ↓, efficacy of PEITC in inhibiting the protein kinase C (PKC)/MAPK pathway
Hif1a↓, PEITC can inhibit angiogenesis in cancer cells by suppressing the expression of HIF-1α
JNK↓, inhibiting the Akt pathway, activating Jun N-terminal kinase (JNK), and downregulating the Mcl-1
Mcl-1↓,
COX2↓, PEITC not only as a direct inhibitor of COX-2
MMP↓, 10 µm of PEITC caused ROS generation and mitochondrial depolarization, leading to the release of Cyt c and apoptosis mediated by activation of caspase-3, indicating that the mitochondrial membrane potential is compromised by ROS generation
Casp3↑,
ChemoSen↑, PEITC can synergize with cisplatin, doxorubicin, docetaxel, fludarabine, paclitaxel, gefitinib, or ionizing radiation to induce more pronounced apoptosis and growth inhibition in cancer than either agent alone
*BioAv↓, its low bioavailability impedes its clinical application as an oncologic treatment. PEITC is a lipophilic compound with poor water solubility, which hinders its dissolution and absorption in the gastrointestinal tract
Half-Life↓, Furthermore, rapid metabolism and elimination limit the systemic exposure of PEITC, reducing its efficacy against cancer cells.

4944- PEITC,    Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations
- in-vitro, Oral, NA
TumCG↓, PEITC was able to inhibit cell growth, arrest G2/M phase, and induce apoptosis of OSCC cells.
TumCCA↑, PEITC-induced G2/M phase arrest and apoptosis depend on the GSH redox stress- and p53-related pathway
Apoptosis↑,
ROS↑, PEITC induced reactive oxygen species and NO production, GSH depletion, and ΔΨm reduction in OSCC cells.
NO↑,
GSH↓,
MMP↓,
DNAdam↑, PEITC-induced oxidative DNA damage was associated with the activation of the ATM–Chk2–p53 pathway.
ATM↑,
Chk2↑,
P53↑,
eff↓, Pifithrin-α, NAC, or GSH, but not free radical scavengers, can reverse anticancer effects of PEITC.

4925- PEITC,    PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells
- in-vitro, OS, NA
tumCV↓, PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an IC50 value of 33.49 μM at 24 h.
TumCP↓, PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G2/M cell cycle arrest, depleted glutathione (GSH), generated reactive oxygen species (ROS)
TumCCA↑,
GSH↓,
ROS↑,
Ferroptosis↑, altered iron metabolism, and triggered multiple forms of cell death, namely ferroptosis, apoptosis, and autophagy in K7M2 cells.
Apoptosis↑,
TumAuto↑,
MAPK↑, PEITC treatment activated MAPK signaling pathway, and ROS generation was a major cause of PEITC-induced cell death.
TumCG↓, osteosarcoma mouse model, administration of PEITC (30, 60 mg/kg every day, ig, for 24 days) significantly inhibited the tumor growth
Dose⇅, but higher dose of PEITC (90 mg/kg every day) compromised its anti-osteosarcoma effect.

4927- PEITC,    Targeting ferroptosis in osteosarcoma
- Review, OS, NA
AntiCan↑, β-Phenethyl isothiocyanate (PEITC) is widely found in cruciferous vegetables and has anti-cancer potential
BioAv↑, great value in OS treatment owing to its unique biological properties such as low clearance and high bioavailability
Ferroptosis↑, mechanism of action is thought to be linked to ferroptosis
TfR1/CD71↑, uplifting the expression of transferrin receptor 1 (TfR1) and elevating the level of reactive iron.
Iron↑,
ROS↑, PEITC induced oxidative stress. Malondialdehyde (MDA) and ROS, products of lipid peroxidation, were raised and GPX4 was diminished to impair intracellular antioxidant defence systems
MDA↑,
lipid-P↑,
GPx4↓,

4932- PEITC,    Pharmacokinetics and Pharmacodynamics of Phenethyl Isothiocyanate: Implications in Breast Cancer Prevention
- Review, BC, NA
TumCCA↑, pharmacodynamics of PEITC in breast cancer that include cancer cell apoptosis by upregulation of apoptotic genes, cell cycle arrest at G2/M phase by generation of reactive oxygen species and depletion of intracellular glutathione
ROS↑,
GSH↓,
ERα/ESR1↓, downregulation of the estrogen receptor, decrease in sensitivity to estrogen, and inhibition of tumor metastasis.
TumMeta↓,
angioG↓, Inhibition of angiogenesis is one of the recently reported mechanisms of breast cancer prevention by PEITC.

4934- PEITC,    Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
GSH↓, Phenethyl isothiocyanate (PEITC) is a naturally occurring electrophile which depletes intracellular glutathione (GSH) levels and triggers accumulation of reactive oxygen species (ROS)
ROS↑,
chemoPv↑, PEITC is of considerable interest as a potential chemopreventive/chemotherapeutic agent
Apoptosis↑, PEITC readily induced apoptosis in MDA-MB-231 cells (associated with rapid activation of caspases 9 and 3, and decreased expression of BAX), MCF7 cells were relatively resistant to the apoptosis promoting effects of PEITC.
Casp9↑,
Casp3↑,
eff↓, pre-treatment of MDA-MB-231 cells with NAC rendered these cells relatively resistant to PEITC-induced apoptosis.
TumCG↓, PEITC-induced growth inhibition in human breast cancer cell lines
TumCCA↑, There was also an increase in the proportion of cells in S phase, and cells with sub-G1 DNA content, indicative of cell death, especially after 48 h.
BAX↑, An increase in BAX expression was observed at 2 h after addition of PEITC in MDA-MB-231 cells, and BAX levels further increased at 4 and 6 h (
Nrf1↑, PEITC increased NRF2 expression by ~3-fold in MDA-MB-231 cells at 4 h after treatment with PEITC. By contrast, NRF2 expression in MCF7 cells was not effected by PEITC
GSH↓, Total GSH and GSSG levels were reduced in MCF7 cells at 2 h after treatment with PEITC, but then remained at this level for the remainder of the time course
GSSG↓,
GSH/GSSG↓, By contrast, in MDA-MB-231 cells, total GSH levels decreased up to 6 h and were reduced by ~50% at this time. There was also an increase in the GSSG/GSH ratio, indicative of increasing oxidative stress.

4937- PEITC,    PEITC: Functional Compound for Primary and Tertiary Chemoprevention of Cancer
chemoPv↑, The findings highlight PEITC as a primary chemopreventive agent to prevent the initiation of carcinogenesis.
tumCV↓, Interestingly, the very same compound PEITC also shows promising effects in selectively removal of cancer cells in vitro and in vivo. T
GSH↓, The anti-cancer mechanisms are mostly mediated through glutathione conjugation and redox balance shift toward increased oxidative stress leading to cell death.
ROS↑,
*toxicity↝, it is safe at 40 mg per day in human

4940- PEITC,    Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G 0/G 1 Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death
- in-vitro, Oral, HSC3
TumCCA↑, reported to inhibit cancer cell growth through cell-cycle arrest and induction of apoptotic events in various human cancer cells models
Apoptosis↑, PEITC induced cytotoxic effects on HSC-3 cells through the induction of apoptosis, and it also related to the involvement of ROS via mitochondria-dependent signal pathways.
BAX↑, it triggered apoptosis through promotion of Bax and Bid expression and reduction of Bcl-2, leading to decrease the levels of mitochondrial membrane potential (ΔΨm)
BID↑,
Bcl-2↓,
MMP↓,
Cyt‑c↑, and followed the releases of cytochrome c, AIF and Endo G then for causing apoptosis in HSC-3 cells.
AIF↑,
tumCV↓, PEITC Induced Cell-Morphological Changes and Decreased the Percentage of Viable Cells
ROS↑, We confirmed that whether PEITC-induced apoptosis is accompanied by the production of ROS and Ca2+ . PEITC promoted the production of ROS (Figure 4(a)) and Ca2+
Ca+2↑,
CDC25↓, PEITC decreased expression of cdc25A, CDK6 and cyclin D (Figure 5(a)), CDK2 and cyclin E (Figure 5(b)) proteins but increased the levels of p15
CDK6↓,
cycD1/CCND1↓,
CDK2↓,
cycE/CCNE↓,
P53↑, but increased the levels of p15 (Figure 5(a)), p53, p27, and p21 (Figure 5(b)) that led to G 0/G 1 phase arrest in HSC-3 cells.
p27↑,
P21↑,
Casp9↑, Here, we found that PEITC promoted ROS production and decreased the levels of ΔΨm and cytochrome c release, the activation of caspase-9 and caspase-3
Casp3↑,
GRP78/BiP↑, promotion of ROS and Ca2+ production that caused ER stress which based on increasing the GRP78 and ROS,

4942- PEITC,    Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G(0)/G(1) Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death
- in-vitro, Oral, HSC3
chemoPv↑, Phenethyl isothiocyanate (PEITC), an effective anticancer and chemopreventive agent, has been reported to inhibit cancer cell growth through cell-cycle arrest and induction of apoptotic events in various human cancer cells models
TumCG↓,
TumCCA↑,
Apoptosis↑, PEITC effectively inhibited the HSC-3 cells' growth and caused apoptosis.
BAX↑, triggered apoptosis through promotion of Bax and Bid expression and reduction of Bcl-2, leading to decrease the levels of mitochondrial membrane potential (ΔΨm),
BID↑,
Bcl-2↓,
MMP↓,
Cyt‑c↑, and followed the releases of cytochrome c, AIF and Endo G then for causing apoptosis in HSC-3 cells
AIF↑,
ROS↑, PEITC promoted the production of ROS (Figure 4(a)) and Ca2+
Ca+2↑,

5183- PEITC,  Cisplatin,    Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells
- in-vitro, Cerv, HeLa - in-vitro, Nor, HaCaT
DNAdam↑, Phenethyl isothiocyanate alone was sufficient to cause nucleus condensation and fragmentation and induce apoptosis in cervical cancer cells, but evident synergistic effects were observed in combination with cisplatin
Apoptosis↑,
ChemoSen↑, Phenethyl Isothiocyanate Exerted Synergistic Effects With Cisplatin on CaSki Cells
ROS↑, phenethyl isothiocyanate treatment increased the production of intracellular ROS in a dose-dependent manner in cervical cancer cells.
mt-ROS↑, phenethyl isothiocyanate induced mitochondrial reactive oxygen species production, and activation of caspases showed that phenethyl isothiocyanate significantly activated caspase-3.
Casp↑,
Casp3↑,
selectivity↑, As the findings show, exposure of phenethyl isothiocyanate resulted in negligible toxicity to normal cells (HaCaT) up to a dose of 30 μM for 24 h
TumCP↓, Phenethyl Isothiocyanate Attenuated Cervical Cancer Cell Proliferation
tumCV↓, decreased the cervical cancer cell viability
eff↓, OS inhibitor N-acetylcysteine (NAC) on phenethyl isothiocyanate–mediated cytotoxic effects over CaSki and HeLa cells,

5186- PEITC,    Phenethyl Isothiocyanate inhibits STAT3 activation in prostate cancer cells
- in-vitro, Pca, DU145 - in-vitro, Pca, LNCaP
TumCP↓, PEITC significantly inhibited DU145 cell proliferation in a dose-dependent manner and induced the cell arrest at G2-M phase.
TumCCA↑,
STAT3↓, PEITC inhibited both constitutive and interleukin 6 (IL-6)-induced STAT3 activity in DU145 cells.
p‑JAK2↓, IL-6-stimulated phosphorylation of JAK2, an STAT3 upstream kinase, was also attenuated by PEITC.
eff↓, antioxidant reagent, N-acetyl-l-cysteine (NAC) which suppresses reactive oxygen species (ROS) generation, reversed the early inhibitory effects of PEITC on cell proliferation
TumCCA↑, PEITC Inhibits cell growth and induces G2-M phase cell cycle arrest in PCa cells
AR↓, PEITC inhibits IL-6-induced AR transcriptional activity in LNCaP cells
ROS↑, consistently suggest that PEITC induced ROS at early time of its application which in turn interfered with STAT3 activation with consequent cell growth inhibition.

5220- PG,  TMZ,    Propyl Gallate Exerts an Antimigration Effect on Temozolomide-Treated Malignant Glioma Cells through Inhibition of ROS and the NF- κ B Pathway
- in-vitro, GBM, U87MG
TumCMig↓, we demonstrated that temozolomide (TMZ) and propyl gallate (PG) combination enhanced the inhibition of migration in human U87MG glioma cells.
MMP2↓, PG can enhance the antimigration effect of TMZ through suppression of metalloproteinase-2 and metalloproteinase-9 activities, ROS generation, and the NF-κB pathway
MMP9↓,
NF-kB↓,
ROS↑, lower than TMZ, but still higher than untreated. TMZ induced an increased in ROS production by about 1.6-fold, and PG (100 μM) significantly inhibited the ROS level in TMZ treatment.
selectivity↑, PG Did Not Induce Cytotoxicity in the Normal Cell Lines.

5218- PG,    Propyl gallate inhibits hepatocellular carcinoma cell growth through the induction of ROS and the activation of autophagy
- in-vitro, HCC, Hep3B
TumCP↓, PG inhibited HCC cell proliferation in vitro and in zebrafish models in vivo in a dose- and time-dependent manner.
Apoptosis↑, PG also induced cell apoptosis and increased the number of necrotic cells in a time- and dose-dependent manner as determined using a high-content analysis system.
ROS↑, PG also increased the intracellular levels of superoxide and reactive oxidative stress as well as the formation of autophagosomes and lysosomes.
TumAuto↑, but increased the rate of the LC3-I to LC3-II conversion, suggesting autophagy induction.
cl‑Casp3↑, PG exposure increased the levels of the pro-apoptotic proteins cleaved caspase-3, cleaved PARP, Bax, and Bad and a decreased level of the anti-apoptotic protein Bcl-2.
cl‑PARP↑,
BAX↑,
BAD↑,
Bcl-2↓,
toxicity↓, PG is a generally recognized as safe (GRAS) antioxidant in foods and cosmetic products at a maximum concentration of 0.1%. It is currently used as an antioxidant to protect food from peroxides induced rancidity
hepatoP↑, It could be of therapeutic value in protecting the liver from injury, inflammation, and carcinogenesis [46–51].
GSH↓, Interestingly, PG-induced GSH depletion and cell death in leukemia cells did not occur by increasing ROS levels in leukemia cells.

1767- PG,    Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione
- in-vitro, Nor, NA
*ROS↑, PG (100–800 μM) increased the levels of total ROS and O2·− at early time points of 30–180 min and 24 h
*GSH↓, whereas PG (800–1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30–180 min.
*SOD↓, PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells
*Catalase↓,
eff↓, NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion

1769- PG,    The Anti-Apoptotic Effects of Caspase Inhibitors in Propyl Gallate-Treated Lung Cancer Cells Are Related to Changes in Reactive Oxygen Species and Glutathione Levels
- in-vitro, Lung, Calu-6 - in-vitro, Lung, A549
TumCP↓, Treatment with 800 μM PG inhibited the proliferation and induced the cell death of both Calu-6 and A549 cells at 24 h.
eff↑, Each inhibitor of pan-caspase, caspase-3, caspase-8, and caspase-9 reduced the number of dead and sub-G1 cells in both PG-treated cells at 24 h
ROS↑, ROS levels in PG-treated lung cancer cells at 24 h
GSH↓, PG augmented the number of GSH-depleted Calu-6 and A549 cells at 24 h

1764- PG,  Cu,    DNA strand break induction and enhanced cytotoxicity of propyl gallate in the presence of copper(II)
- in-vitro, Nor, GM05757
*DNAdam↑, Propyl gallate (PG), in combination with 5 uM and 10 uM CuCl2 induced extensive DNA scission
*ROS↑, the antioxidative and cytoprotective properties of propyl gallate may change to prooxidative, cytotoxic, and genotoxic properties in the presence of Cu(II).
*Dose∅, At higher than 2 uM PG in combination with 100 uM CuCl2 extensive double strand breakage was observed
*DNAdam∅, no strand break induction was observed for the combination Fe(III)/propyl gallate.

1763- PG,    Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment
- Review, NA, NA
*antiOx↑, PG alone demonstrated antioxidative and cytoprotective properties against cellular damage
*ROS↓,
*ROS↑, gained a pro-oxidative property in combination with copper (II)

1765- PG,    Enhanced cell death effects of MAP kinase inhibitors in propyl gallate-treated lung cancer cells are related to increased ROS levels and GSH depletion
- in-vitro, Lung, A549 - in-vitro, Lung, Calu-6
TumCD↑, PG induced cell death in both Calu-6 and A549 lung cancer cells at 24 h
MMP↓, accompanied by loss of mitochondrial membrane potential (MMP; ΔΨm)
ROS↑, PG increased ROS levels and caused GSH depletion in both cell lines at 24 h
GSH↓,
Dose∅, IC50 of PG was approximately 800 uM at 24 h
eff↑, All of the MAPK inhibitors tested in the present study enhanced PG-induced cell death.

1256- PI,    Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models
- in-vitro, adrenal, PHEO - in-vivo, NA, NA
Apoptosis↑,
ROS↑,
TumCMig↓,
TumCI↓,
EMT↓,
angioG↓,
Necroptosis↑,
MAPK↑,
ERK↑, 8 fold

1254- PI,  VitC,    Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS–STAT3 pathway
- in-vivo, GC, NA
STAT3⇅, PL effectively suppressed STAT3 activation while VC caused abnormal activation of STAT3.
eff↑, combination of PL and VC exhibited a stronger apoptotic effect compared with either agent alone
ROS↑, PL and VC effectively induced apoptosis of GC cells through oxidative stress.
Apoptosis↑, 15 µM PL and 3 mM VC caused more than 60% apoptosis in two GC cell lines.

5215- PI,    Piperine impairs cell cycle progression and causes reactive oxygen species-dependent apoptosis in rectal cancer cells
- in-vitro, CRC, NA
TumCCA↑, piperine inhibited cell cycle progression
Apoptosis↑, Piperine also caused HRT-18 cells to die by apoptosis
ROS↑, HRT-18 cells showed increased production of reactive oxygen species in piperine-treated cells.
eff↓, antioxidant N-acetylcysteine(NAC) reduced apoptosis in cultures of piperine-treated HRT-18 cells, indicating that piperine-induced cytotoxicity was mediated at least in part by reactive oxygen species.
BioEnh↑, Piperine has diverse physiological effects, including modulation of lipid and drug metabolism, drug bioavailability, and gastrointestinal function, and inhibition of inflammation and tumor progression

5214- PI,    Piperine induces autophagy of colon cancer cells: Dual modulation of AKT/mTOR signaling pathway and ROS production
- vitro+vivo, CRC, HCT116 - in-vitro, CRC, SW48 - in-vitro, CRC, SW-620
TumCP↓, Piperine inhibits colorectal cancer (CRC) cells proliferation both in vitro and in CRC xenograft mouse model.
TumAuto↑, Piperine inhibits CRC cells growth by promoting autophagic cell death.
Akt↓, Piperine induces autophagy by repressing the Akt/mTOR pathway in CRC cells.
mTOR↓,
ROS↑, Piperine induces ROS production in CRC cells.

5213- PI,    Induction of apoptosis by piperine in human cervical adenocarcinoma via ROS mediated mitochondrial pathway and caspase-3 activation
- in-vitro, Cerv, HeLa
Apoptosis↑, piperine exposure induces apoptosis significantly in a dose-dependent manner and inhibits the growth of HeLa cells with an increase in ROS generation,
TumCG↓,
ROS↑,
MMP↓, piperine also encourages cell death by the loss of MMP, DNA fragmentation and the activation of caspase-3
DNAdam↑,
Casp3↑,
TumCCA↑, Growth inhibition of HeLa cells was found to be associated with G2/M phase arrest and sub-G1 accumulation.
*Inflam↓, Piperine possesses multifunctional pharmacological properties such as anti-inflammatory, antioxidant, antidiarrheal, hypolipidemic, hepato-protective, anti-mutagenic, antimicrobial and anti-carcinogenic activities
*antiOx↓,
*hepatoP↑,
ChemoSen↑, Dietary piperine has been shown to increase the therapeutic effect of docetaxel against castration-resistant prostate cancer in xenograft animal models
CSCs↓, Piperine has inhibited the growth of breast carcinoma by targeting the renewal of cancer stem cells

1940- PL,    Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
ROS↑, demonstrated that PL induced ROS accumulation in scratched LN229 cells.
GSH↓, reduced glutathione
p38↑, activated p38 and JNK, increased IκBα
JNK↑,
IKKα↑,
NF-kB↓, suppressed NFκB in LN229 cells after scratching
eff↓, All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC).

1946- PL,  PI,    Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling
- in-vitro, Liver, NA
eff↑, Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 μM).
toxicity↓, Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU.
TrxR↓, Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP
ROS↑,
MMP↓,
p38↑, Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways.
Akt↓,
mTOR↓,

1947- PL,    Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer
- in-vitro, GC, SGC-7901 - in-vitro, GC, NA
TrxR1↓, In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden
ROS↑, PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells
ER Stress↑, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells
mtDam↑,
selectivity↑, known to selectively kill tumor cells while sparing their normal counterparts. PL treatment did not cause a significant increase in ROS levels in normal GES-1 cells
NO↑, we found that nitric oxide was also induced by PL in gastric cancer cells
TumCCA↑, PL treatment significantly induced G2/M cell cycle arrest in human gastric cancer SGC-7901, BGC-823 and KATO III cells.
mt-ROS↑, mitochondrial ROS, were involved in the PL-induced cell death in gastric cancer cells.
Casp9↑, Notably, caspase-9 activity was significantly elevated after PL treatment in SGC-7901 cells
Bcl-2↓, PL treatment dose-dependently decreased the expression of antiapoptotic proteins Bcl-2 and Bcl-xL, but induced the cleavage of poly (ADP-ribose) polymerase (PARP)
Bcl-xL↓,
cl‑PARP↑,
eff↓, Pre-incubation with GSH attenuated these effects confirming their linkage to PL-induced oxidative stress
lipid-P↑, PL dose-dependently increased the level of lipid peroxidation product (MDA), a marker of ROS, in tumor tissues

1948- PL,  born,    Natural borneol serves as an adjuvant agent to promote the cellular uptake of piperlongumine for improving its antiglioma efficacy
- in-vitro, GBM, NA
selectivity↑, Piperlongumine (PL) can selectively inhibit the proliferation of various cancer cells by increasing reactive oxygen species (ROS) level to cause a redox imbalance in cancer cells rather than in normal cells.
ROS↑, combination of NB and PL significantly induced higher levels of ROS
BioAv↓, clinical application of PL is limited by its poor cellular uptake.
BioAv↑, NB obviously promoted the cellular uptake of PL with a 1.3-fold increase in the maximum peak concentration and an earlier peak time of 30 min in C6 glioma cells.
Apoptosis↑, increased apoptosis and enhanced G2/M cycle arrest of C6 glioma cells, compared to PL alone administration.
TumCCA↑,
eff↑, NB-enhanced antiglioma efficacy of PL without side effects was confirmed in tumor-bearing mice, which was attributed to the improved cellular uptake of PL.

1949- PL,    Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor
- in-vitro, CRC, HCT116 - in-vitro, Cerv, HeLa
TrxR↓, piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR.
selectivity↑, selective killing effect between normal and cancer cells.
ROS↑, ZC0101 had the ability to promote cellular ROS accumulation
IDO1↓, because of 4-phenylimidazole

1950- PL,    Increased Expression of FosB through Reactive Oxygen Species Accumulation Functions as Pro-Apoptotic Protein in Piperlongumine Treated MCF7 Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, Lung, A549
selectivity↑, Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells,
ROS↑, by accumulation of reactive oxygen species (ROS)
SETBP1↓, PL downregulates SETDB1 expression
cl‑Casp9↑, enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death.
eff↓, ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL.
FOSB↑, Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PL treatment dramatically increased FosB promoter activity up to 9-fold

1951- PL,    Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation
- in-vitro, Lung, A549
ROS↑, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death.
lipid-P↑,
MMP↓,
TumCCA↑,
TrxR↓, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR
eff↑, For example, curcumin [15] and PL [16], characterized with the Michael acceptor, could irreversibly inhibit thioredoxin reductase (TrxR), and the adduct triggers ROS generation.

1952- PL,  5-FU,    Piperlongumine induces ROS accumulation to reverse resistance of 5-FU in human colorectal cancer via targeting TrxR
- in-vivo, CRC, HCT8
ROS↑, PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM).
TrxR↓,
eff↑, enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts.
p‑Akt↓, promoting inhibition of Akt phosphorylation,

1953- PL,    Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation
- in-vitro, Lung, A549 - in-vitro, Nor, WI38
ROS↑, Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS).
selectivity↑, 15-fold selectivity toward A549 cells over normal WI-38 cells.
TrxR↓, selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation.
TumCCA↑, S-phase arrest
GSH?, PL-CL sharply decreased the GSH levels of A549 cells in a dose- and time-dependent fashion (Figure 5A) but barely changed the GSH levels of WI-38 cells
H2O2↑, significant accumulation of ROS (O2.- and H2O2)

1938- PL,    Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation
- Study, PSA, NA - in-vivo, NA, NA
ROS↑, In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential.
Apoptosis↑,
MMP↓,
TumCCA↑, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation.
DNAdam↑,
STAT3↓, inhibition of STAT3 and Akt signaling was observed
Akt↓,
PCNA↓, decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression
Ki-67↓,
cycD1/CCND1↓,
Bcl-2↓,
K17↓, Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly
HDAC↓, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1–4) and class II (HDAC6)
ROS↑, PPL at 5 and 10 µM concentration increased the reactive oxygen species (ROS) levels and a marked increase in oxidative stress were observed when combined with H2O2
*IL1β↓, Topical IMQ prominently induced the levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, IL-17, IL-22, and transforming growth factor (TGF)-β, while PPL significantly suppressed these levels
*IL6↓,
*TNF-α↓,
*IL17↓,
*IL22↓,

1945- PL,  SANG,    The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer
- in-vitro, Lung, A549
toxicity∅, Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells.
Apoptosis↑, PL and SAN increased apoptosis and favored metastasis inhibition.
TumMeta↓,
ROS↑, PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).
TumCCA↑, Combination on aCell Cycle Phases Distribution

1944- PL,    Piperlongumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress
- in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2
ER Stress↑, PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells
TrxR1↓, PL treatment reduces TrxR1 activity and tumor cell burden in vivo
ROS↑, and increasing intracellular ROS levels
eff↓, Interestingly, pretreatment with NAC, a specific ROS inhibitor, for 2 h apparently suppressed PL-induced increases in ROS levels
Bcl-2↓, PL treatment decreased the levels of the antiapoptotic proteins Bcl-2 and procaspase3 and increased the levels of the proapoptotic proteins Bax and cleaved caspase-3 in a dose-dependent manner.
proCasp3↓,
BAX↓,
cl‑Casp3↑,
TumCCA↑, PL Induces ROS-Dependent G2/M Cell Cycle Arrest in HCC Cells
p‑PERK↑, PL increased the expression of p-PERK and ATF4 in a dose-dependent manner.
ATF4↑,
TumCG↓, PL Inhibits HUH-7 Xenograft Tumor Growth Accompanied by Increased ROS Levels and Decreased Trxr1 Activity
lipid-P↑, PL treatment increased the levels of the product of lipid peroxidation (MDA) in tumor tissues ( Figure 6H ), suggesting increased ROS levels
selectivity↑, In normal cells, TrxR1 can protect against oxidant stress

1943- PL,    Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells
- in-vitro, GBM, NA - in-vivo, NA, NA
selectivity↑, Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells.
ROS↑,
selectivity↑, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs
Prx4↓, Piperlongumine Inactivates PRDX4 in HGG Cells
*Prx4∅,
ER Stress↑, Moreover, piperlongumine exacerbated intracellular ER stress
CHOP↑, We found that piperlongumine treatment rapidly and substantially increased CHOP protein levels in all 4 HGG sphere cultures
UPR↑, As with CHOP, other UPR protein levels were also increased upon piperlongumine treatment

1942- PL,    Piperlongumine inhibits antioxidant enzymes, increases ROS levels, induces DNA damage and G2/M cell cycle arrest in breast cell lines
- in-vitro, BC, MCF-7
ROS↑, PLN increased ROS levels and expression of the SOD1 antioxidant enzyme
SOD1↑,
Trx1↓, PLN inhibited the expression of the antioxidant enzymes catalase, TRx1, and PRx2.
Catalase↓,
PrxII↓,
ROS↑, ability of PLN to inhibit antioxidant enzyme expression was associated with the oxidative stress response
GADD45A↑, upregulated the levels of GADD45A mRNA and p21 protein.
P21↑,
DNAdam↑, In response to elevated ROS levels and DNA damage induction, the cells were arrested at the G2/M phase
TumCCA↑, arrested at the G2/M phase

1941- PL,    Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer
- in-vitro, HNSCC, NA
selectivity↑, Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells.
eff↑, Piperlongumine increased cisplatin-induced cytotoxicity in HNC cells in a synergistic manner in vitro and in vivo.
ROS↑, Piperlongumine selectively increases ROS accumulation in HNC cells
toxicity↑, PL markedly induced death in cancer cells, while the viability of normal cells was affected only minimally at the highest concentration (15 μM) tested
GSH↓, PL decreased GSH levels and increased GSSG levels in HNC cells (Figure 2 and Supplementary Figure S1); however, PL did not increase GSSG levels in normal HOK-1 cells
GSSG↑,
*GSSG∅, however, PL did not increase GSSG levels in normal HOK-1 cells
cl‑PARP↑, PL increased the levels of PARP and PUMA proteins regardless of p53 status
PUMA↑,
GSTP1/GSTπ↓, PL regulates ROS by targeting GSTP1, a direct negative regulator of JNK [22, 23], and thereby increases JNK phosphorylation
ChemoSen↑, Piperlongumine increases the cytotoxicity of cisplatin in HNC cells in vitro and in vivo

1939- PL,    Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP
- in-vitro, HCC, HepG2 - in-vitro, HCC, HUH7 - in-vivo, NA, NA
TumCMig↓, PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway
TumCI↓,
ER Stress↑, Piperlongumine induces ER stress-responses which preferentially suppresses HCC cell migration/invasion
selectivity↑, PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 μM while PL at much lower concentrations only suppressed HCC cell migration/invasion
tumCV↓,
ROS↑, Piperlongumine induces ROS accumulation to exert its anti-cancer effects on HCC cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in HepG2 or Huh7 cells at 1 h of PL treatment
eff↓, Pre-treatment of NAC or GSH completely reversed PL-induced cell death in Huh7 cells (Fig. 3E) and HepG2 cells
Ca+2↑, concentration of cytoplasmic free Ca2+ was prominently increased at 3 h of PL treatment in a dose-dependent manner (0-20 μM)
MAPK↑, Piperlongumine activates MAPKs signaling pathways which preferentially suppress HCC migration
CHOP↑, These evidences demonstrated that PL activated ER-MAPKs-CHOP axis signaling pathways via ROS-dependent mechanisms.
Dose↝, Notably, PL at a much lower concentration (1.5 mg/kg) showed a comparable anticancer effect in HCC-bearing mice and increasing PL concentration did not significantly enhance its anticancer effects

2649- PL,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
AntiCan↑, investigated for its anticancer activity in various cancer types, including hematological cancers, colorectal, gastric, lung, breast, prostate, and oral cancers, melanoma, and glioma
ROS↑, Its in vitro anticancer activity can be attributed to induction of ROS through increased glutathione disulfide levels, decreased glutathione levels
GSH↓,
TrxR↓, inhibition of thioredoxin reductase (TrxR), an enzyme which reduces thioredoxin, a redox protein that protects against oxidative stress
Trx↓,
Apoptosis↑, PPL-mediated ROS accumulation further leads to ROS-mediated apoptosis
TumCCA↑, G1 or G2/M cell cycle arrest
ER Stress↑, ER stress
DNAdam↑, oxidative DNA damage
ChemoSen↑, PPL was reported to sensitize head and neck, gastric, and liver cancers to cisplatin [18], oxaliplatin [19], and sorafenib [20], respectively
BioAv↓, Additionally, its poor aqueous solubility and bioavailability limit its therapeutic potential

2966- PL,    A strategy to improve the solubility and bioavailability of the insoluble drug piperlongumine through albumin nanoparticles
- in-vitro, LiverDam, NA
*Half-Life↑, pharmacokinetic properties of PL-BSA-NPs were shown that PL-BSA-NPs could maintain a certain level of blood drug concentration for a long time, thus demonstrating the sustained release and increased bioavailability of PL.
*BioAv↑,
eff↑, antitumor activity of the PL-BSA-NPs and found that PL can significantly inhibit HepG2 cell proliferation, and that PL-BSA-NPs enhanced the inhibitory effect of PL on this proliferative effect.
ROS↑, t PL can destroy liver cancer cells by increasing ROS levels.

2969- PL,    Piperlongumine induces autophagy by targeting p38 signaling
- in-vitro, OS, U2OS - in-vitro, Cerv, HeLa
p38↑, PL stimulates the activation of p38 protein kinase through ROS-induced stress response
ROS↑, PL for 4 h led to 6- to 11-fold increases of the ROS levels in the cells
GPx1∅, PL treatment only marginally reduced antioxidant enzyme, glutathione peroxidase 1 (GPX1) expression, and had no effect on SOD and catalase levels in U2OS/GFP-LC3
SOD∅,
Catalase∅,

2968- PL,  Chit,    Preparation of piperlongumine-loaded chitosan nanoparticles for safe and efficient cancer therapy
- in-vitro, GC, AGS
eff↑, The PL-CSNPs showed efficient cytotoxicity against human gastric carcinoma (AGS) cells via dramatic increase of intracellular ROS leading to cell apoptosis
Dose↝, Chitosan was mixed with NaTPP at a 4 : 1 weight ratio.
ROS↑, n contrast, the cells treated with PL–CSNPs and free PL indicated a signicant increase in intracellular ROS (
BioAv↑, Chitosan has been intensively explored for biocompatible drug carriers due to high biodegradability and low toxicity.

2973- PL,    The Natural Alkaloid Piperlongumine Inhibits Metastatic Activity and Epithelial-to-Mesenchymal Transition of Triple-Negative Mammary Carcinoma Cells
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, 4T1
MMP2↓, Piperlongumine-treated MDA-MB-231 cells showed reduced motility/invasiveness, decreased MMP2 and MMP9 expression,
MMP9↓,
IL6↓, increased miR-200c expression, reduced IL-6 synthesis, decreased expression of ZEB1 and Slug, increased E-cadherin expression, and epithelial-like morphology.
E-cadherin↑,
ROS↑, ROS accumulated in piperlongumine-treated cells,
EMT↓, Piperlongumine Suppresses EMT
Zeb1↓, EMT-promoting ZEB1 and Slug transcription factors was significantly downregulated
Slug↓,
TumMeta↓, sub-cytotoxic dose of piperlongumine prevented metastasis in a mouse model of TNBC
selectivity↑, capacity to induce apoptosis in cancer cells while sparing normal cells
MMP2↓, Low dose piperlongumine also suppressed the expression of MMP2 and MMP9,
GSH↓, The resulting depletion of ROS-scavenging GSH would be expected to cause oxidative stress due to the accumulation of intracellular ROS

2956- PL,    Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis
- in-vitro, PC, NA
ROS↑, Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels.
Ferroptosis↓, at least in part, the induction of ferroptosis,. requires the accumulation of ROS in an iron-dependent manner
GSH↓, Since we actually found that PL markedly depleted GSH (Fig. 1H), these results suggest that PL may inhibit GPX activity.
GPx↓,
cl‑PARP∅, PL did not induce the expression of typical apoptotic markers, such as cleaved PARP and cleaved caspase-3
cl‑Casp3∅,
eff↑, PL (15 uM) plus CN-A resulted in a further increase in the population of ROS-positive cells
eff↑, SSZ enhances the PL-induced ferroptotic death of pancreatic cancer cells.

2940- PL,    Piperlongumine Induces Reactive Oxygen Species (ROS)-dependent Downregulation of Specificity Protein Transcription Factors
- in-vitro, PC, PANC1 - in-vitro, Lung, A549 - in-vitro, Kidney, 786-O - in-vitro, BC, SkBr3
ROS↑, characterized as an inducer of reactive oxygen species (ROS)
TumCP↓, 5-15 μM piperlongumine inhibited cell proliferation and induced apoptosis and ROS,
Apoptosis↑,
eff↓, these responses were attenuated after cotreatment with the antioxidant glutathione
Sp1/3/4↓, Piperlongumine also downregulated expression of Sp1, Sp3, Sp4
cycD1/CCND1↓, and several pro-oncogenic Sp-regulated genes including cyclin D1, survivin, cMyc, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (cMet)
survivin↓,
cMyc↓,
EGFR↓,
cMET↓,

2941- PL,    Selective killing of cancer cells by a small molecule targeting the stress response to ROS
- in-vivo, BC, MDA-MB-231 - in-vitro, OS, U2OS - in-vitro, BC, MDA-MB-453
ROS↑, . Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death
Apoptosis↑,
selectivity↑, but it has little effect on either rapidly or slowly dividing primary normal cells
*ROS∅, In contrast, PL did not cause an increase in ROS levels in normal cells
GSH↓, lead to a decrease in GSH and an increase in GSSG levels in cancer cells
GSSG↑,
H2O2↑, we found that hydrogen peroxide and nitric oxide, but not superoxide anion, were among the ROS species induced by PL in cancer cells
NO↑,
Half-Life?, 0.8 hrs

2942- PL,    Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems
- in-vitro, CRC, CT26 - in-vitro, CRC, DLD1 - in-vivo, CRC, CT26
ROS↑, known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis
GSH↓, PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase
TrxR↓,
RadioS↑, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells
DNAdam↑, inked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration
TumCCA↑,
mitResp↓,
GSTs↓, PL proved to perturb GSH system by inhibition of glutathione S-transferase (GST) that catalyzes the conjugation of GSH with its substrate
OS↑, delays tumor growth and improves the survival rate of tumor-bearing mice.

2943- PL,    Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin
- in-vitro, CRC, HCT116 - in-vitro, Lung, A549 - in-vitro, BC, MCF-7
TrxR1?, known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells.
TumCD↑,
ROS↑, Piperlongumine Induces ROS-Dependent Cancer Cell Death but Not Ferroptosis
GSH↓, we found that piperlongumine decreased the cellular GSH contents
eff↑, Piperlongumine Enhances Erastin-Induced Cancer Cells Death

2944- PL,    Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells
- in-vitro, Thyroid, IHH4 - in-vitro, Thyroid, 8505C - in-vivo, NA, NA
ROS↑, it is selectively toxic to cancer cells by generating reactive oxygen species (ROS)
selectivity↑,
tumCV↓, Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction.
TumCCA↑,
Apoptosis↑,
ERK↑, activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL
Akt↓,
mTOR↓,
neuroP↑, neuroprotective, and anticancer properties
Bcl-2↓, induces the downregulation of Bcl2 expression and the activation of caspase-3, poly (ADP-ribose) polymerase (PARP), and JNK
Casp3↑,
PARP↑,
JNK↑,
*toxicity↓, several whole-animal models, and it is highly safe when used in vivo
eff↓, Pre-treatment with N-acetylcysteine (NAC; a selective ROS scavenger) significantly reduced PL-mediated ROS activation
TumW↓, tumor weight in the PL (10 mg/kg) treatment group significantly decreased when compared with that in the control group

2945- PL,    Piperlongumine induces ROS mediated cell death and synergizes paclitaxel in human intestinal cancer cells
- in-vitro, CRC, HCT116
ROS↑, Piperlongumine (PL) kills intestinal cancer cells by elevating ROS levels.
SMAD4↑, PL significantly up-regulates SMAD4 expression, leading to apoptosis in cancer cells.
ChemoSen↑, PL with Paclitaxel can be a better option for chemotherapy.
P53↑, Remarkably, P53, P21, BAX, and SMAD4 were significantly upregulated after PL treatment whereas; BCL2 and SURVIVIN were down-regulated.
P21↑,
BAX↑,
Bcl-2↓,
survivin↓,
TumCMig↓, Piperlongumine suppresses migration of cancer cell

2946- PL,    Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent
- Review, Var, NA
ROS↑, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cycD
GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
DNAdam↑,
ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
eff↑, encapsulation of piperlongumine in another biocompatible natural polymer, chitosan, has been found to result in pH-dependent piperlongumine release and to enhance cytotoxicity via efficient intracellular ROS accumulation against human gastric carcin
p‑Akt↓, Fig 2
mTOR↓,
GSK‐3β↓,
β-catenin/ZEB1↓,
HK2↓, iperlongumine treatment decreases cell proliferation, single-cell colony-formation ability, and HK2-mediated glycolysis in NSCLC cells via inhibiting the interaction between HK2 and voltage-dependent anion channel 1 (VDAC1)
Glycolysis↓,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Casp7↑,
cl‑PARP↑,
TrxR↓, piperlongumine (4 or 12 mg/kg/day for 15 days) administration significantly inhibits increase in tumor weight and volume with less TrxR1 activity in SGC-7901 cell
ER Stress↑,
ATF4↝,
CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
NF-kB↓, piperlongumine treatment (2.5–5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-κB
cycD1/CCND1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
CDK4↓,
CDK6↓,
p‑RB1↓,
RAS↓, piperlongumine downregulates the expression of Ras protein
cMyc↓, inhibiting the activity of other related proteins, such as Akt/NF-κB, c-Myc, and cyclin D1 in DMH + DSS induced colon tumor cells
TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
NRF2↑, Nrf2) activation has been found to mediate the upregulation of heme oxygenase-1 (HO-1) in piperlongumine treated MCF-7 and MCF-10A cells
HO-1↑,
PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-κB, and Twist downregulation;
MDR1↓,
MRP1↓,
survivin↓,
Twist↓,
AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6, and YY1.
Sp1/3/4↓,
STAT1↓,
STAT6↓,
SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
XBP-1↑,
P21↑,
eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
COX2↓,
IL6↓,
MMP9↓,
TumMeta↓,
TumCI↓,
ICAM-1↓,
CXCR4↓,
VEGF↓,
angioG↓,
Half-Life↝, The analysis of the plasma of piperlongumine treated mice (50 mg/kg) after intraperitoneal administration, 1511.9 ng/ml, 418.2 ng/ml, and 41.9 ng/ml concentrations ofplasma piperlongumine were found at 30 minutes, 3 hours, and 24 hours, respecti
BioAv↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine

2947- PL,    Piperlongumine: the amazing amide alkaloid from Piper in the treatment of breast cancer
- Review, Var, NA
TumCP↓, exhibits potent activity against various cancer cell proliferation
Apoptosis↑, Apoptosis, cell cycle arrest, increased ROS generation
TumCCA↑,
ROS↑,

2949- PL,    Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
selectivity↑, Piperlongumine (PL) selectively kills GBM cells but not normal astrocytes.
ROS↑, PL kills GBM cells via ROS accumulation
JNK↑, JNK and p38 activation contributes to PL’s cytotoxicity in GBM cells.
p38↑,
GSH↓, PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells.
eff↓, Antioxidant N-acetyl-l-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells.

2950- PL,    Overview of piperlongumine analogues and their therapeutic potential
- Review, Var, NA
AntiAg↑, PL has been shown to exert in vitro antiplatelet aggregation effect induced by agonists such as collagen, adenosine 50-diphosphate (ADP), arachidonic acid (AA) and thrombin.
neuroP↑, Neuroprotective activity of PL and its derivatives
Inflam↓, Anti-inflammatory activity of PL and its derivatives
NO↓, production of NO and PGE2 was significantly inhibited after the treatment of PL.
PGE2↓,
MMP3↓, PL also significantly suppressed the production of MMP-3 and MMP-13
MMP13↓,
TumCMig↓, PL inhibited the proliferation, induced the apoptosis and reduced the migration and invasion of RA FLS by activating the p38, JNK, NF-kB and STAT3 pathways
TumCI↓,
p38↑,
JNK↑,
NF-kB↑,
ROS↑, PL has been reported to selectively induce apoptotic by ROS accumulation in cancer cells via different molecular mechanisms.
FOXM1↓, PL inhibited proteasome including suppression of FOXM1
TrxR1↓, induction of ROS by directly inhibiting thioredoxin reductase 1 (TrxR1) activity
GSH↓, Wang et al. demonstrated that PL could inhibit both glutathione and thioredoxin and thus induce ROS elevation,
Trx↓,
cMyc↓, downregulation of c-Myc and LMP1 and the Caspase-3-dependent apoptosis of Burkitt lymphoma cells in vitro.
Casp3↑,
Bcl-2↓, PL could downregulate Bcl-2 and Mcl-1 and decrease the expression of STAT-3
Mcl-1↓,
STAT3↓, Bharadwaj et al. identified PL as a direct STAT3 inhibitor
AR↓, Golovine et al. demonstrated for the first time that PL rapidly reduced the androgen receptor protein level of prostate cancer cells
DNAdam↑, inducing DNA damage,

2953- PL,    Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished TH17 but Enhanced Treg Differentiation
- in-vitro, Nor, NA
*ROS↑, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs.
*GSTA1↓,
eff↝, promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished TH17 but enhanced Treg cell differentiation.
*toxicity↓, In the present study, we found that PL was not toxic to primary human T cells, as opposed to the malignant T leukemia line Jurkat
ROS↑, Similar to primary human T cells, the ROS levels in Jurkat leukemia cells also increased significantly after PL treatment
*Hif1a↓, PL strongly inhibits the expression of HIF-1α in a dose-dependent manner starting already at a concentration of 1 μM PL

2952- PL,    Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization
- in-vitro, Bladder, T24/HTB-9 - in-vivo, Bladder, NA
TumCP↓, PL significantly suppressed bladder cancer cell proliferation, the transition of G2/M phase to next phase, migration/invasion in vitro and bladder cancer growth/development in vivo
TumCCA↑,
TumCMig↓,
TumCI↓,
ROS↑, PL markedly elevated reactive oxygen species (ROS)
Slug↓, PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, β-catenin, ZEB1 and N-Cadherin.
β-catenin/ZEB1↓,
Zeb1↓,
N-cadherin↓,
F-actin↓, decreased F-actin intensity in bladder cancer cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in T24 cells at 3 h of PL treatment
EMT↓, PL inhibited epithelial mesenchymal transition
CLDN1↓, The decline of Claudin-1 and ZO-1 upon PL treatment
ZO-1↓,

2961- PL,    Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis
- in-vitro, ESCC, KYSE-30
Pyro↑, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells
TumCP↓,
TumCMig↓,
TumCI↓,
ASC↑, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS.
cl‑Casp1↑,
NLRP3↑,
GSDMD↑,
ROS↑,
NRF2↓, PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.
TXNIP↑,

2958- PL,    Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity
- in-vitro, Oral, HSC3
TumCP↓, proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner.
lipid-P↑, Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment.
ROS↑,
DNMT1↑, expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased.
FTH1↓,
GPx4↓,
eff↓, effect of PL on OSCC cells can be reversed by iron scavengers and antioxidants
GSH↓, PL can inhibit the synthesis of intracellular GSH to induce ferroptosis
Ferroptosis↑,
MDA↓, content of MDA decreased

2957- PL,    Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells
- in-vitro, BC, MCF-7
TumCP↓, We found that PL decreased MCF-7 cell proliferation and migration.
TumCMig↓,
TumCCA↑, PL induced G2/M phase cell cycle arrest.
ROS↑, PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion
H2O2↑,
GSH↓,
IKKα↓, PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65.
NF-kB↓,
P21↑, PL significantly increased p21 mRNA levels.
eff↓, PL significantly decreased cellular GSH levels, while in cells pre-treated with NAC, the GSH levels were similar to those observed in control cells

2954- PL,    The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy
- Review, Var, NA
NRF2↑, PL significantly increased ROS levels and protein glutathionylation with a concomitant elevation in Nrf-2 expression
ROS↑, PL selectively destroyed hepatocellular carcinoma cells rather than normal hepatocytes via ROS–endoplasmic reticulum (ER)–MAPK–CHOP axis,
ER Stress↑,
MAPK↑,
CHOP↑,
selectivity↑, PL selectively killed human breast cancer MCF-7 cells instead of human MCF-10A breast epithelial cells
Keap1↝, PL directly interacted with Kelch-like ECH-associated protein-1 (Keap1), which resulted in Nrf-2-mediated HO-1 expression
HO-1↑,
Ferroptosis↑, pancreatic cancer cell death mainly via the induction of ROS-mediated ferroptosis

2004- PLB,    Plumbagin Inhibits Proliferative and Inflammatory Responses of T Cells Independent of ROS Generation But by Modulating Intracellular Thiols
- in-vivo, Var, NA
TumCP↓, Plumbagin inhibited activation, proliferation, cytokine production, and graft-versus-host disease in lymphocytes and inhibited growth of tumor cells
TumCG↓,
NF-kB↓, by suppressing nuclear factor-κB (NF-κB)
ROS↑, Plumbagin was also shown to induce reactive oxygen species (ROS) generation in tumor cells via an unknown mechanism
GSH↓, Plumbagin depleted glutathione (GSH) levels that led to increase in ROS generation
eff↓, production by plumbagin was abrogated by thiol antioxidants but not by non-thiol antioxidants confirming that thiols but not ROS play an important role in biological activity of plumbagin.
i-Thiols↓, Plumbagin depleted intracellular thiols (mainly GSH)
GSH/GSSG↓, plumbagin also induced GSH to GSSG conversion
*GSH↓, In this report, for the first time we show GSH depletion as a source of ROS generation in normal lymphocytes following plumbagin treatment.
*ROS↑, plumbagin-induced increase in ROS levels in lymphocytes

2006- PLB,    Plumbagin induces apoptosis in human osteosarcoma through ROS generation, endoplasmic reticulum stress and mitochondrial apoptosis pathway
- in-vitro, OS, MG63 - in-vitro, Nor, hFOB1.19
tumCV↓, Plumbagin reduced cell viability in osteosarcoma cells but not normal bone cells
selectivity↑,
mtDam↑, Plumbagin induced cell apoptosis by mitochondrial dysfunction, which in turn promoted Ca2+ release and endoplasmic reticulum (ER)‑stress
Ca+2↓,
ER Stress↑,
ROS↑, plumbagin improved reactive oxygen species (ROS) generation
Casp3↑, apoptotic cascades activated caspase‑3 and caspase‑9 to elicit apoptosis response
Casp9↑,
Apoptosis↑,
eff↓, Moreover, plumbagin-induced apoptosis was reversed by pretreating with ROS scavenger N-acetyl cysteine (NAC), NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and H2O2 scavenging enzyme (catalase)

2005- PLB,    Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2)
- in-vivo, Nor, EL4 - in-vitro, AML, Jurkat
JNK↑, Plumbagin induced persistent activation of JNK
Cyt‑c↑, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway
FasL↑,
BAX↑,
ROS↑, plumbagin has been reported to induce ROS in normal as well as in tumor cells
*ROS↑, induce ROS in normal as well as in tumor cells
MKP1↓, plumbagin induced oxidative stress may suppress MKP activity in lymphoma cells leading to sustained JNK activation resulting in apoptosis.
MKP2↓,
selectivity∅, Plumbagin induced cell death in EL4(normal) cells and Jurkat cells
tumCV↑, cell viability dramatically decreased with increasing concentrations of plumbagin (0.05-2.5uM) when incubated for 24 or 48 h
Cyt‑c↑, Bax dependent cytochrome c release and apoptosome complex formation is followed by the cleavage of pro-caspase-3
Casp3↑,
GSH/GSSG↓, progressive decrease in GSH/GSSG ratio in tumor cells following plumbagin treatment
ROS↑, simultaneous increase in the levels of intracellular ROS was observed in both these cell lines which remained high up to 4 h indicating an increase in oxidative stress in tumor cells
mt-ROS↑, While we observed low basal mtROS levels in untreated cells, plumbagin treatment resulted in a significant increase in mtROS levels
*ROS↑, both cell lines, meaning normal EL4 cells too
eff↓, NAC, GSH and PEG-catalase were able to abrogate plumbagin induced ROS and cell death.

5163- PLB,    Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells
- in-vitro, SCC, SCC25
TumCP↓, PLB inhibited cell proliferation, activated death receptor-mediated apoptotic pathway,
NRF2↓, PLB induces intracellular ROS generation and regulates redox homeostasis via suppressing Nrf2-mediated oxidative signaling pathway in SCC25 cells
TumCCA↑, PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis
EMT↓, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells.
CSCs↓,
eff↓, Of note, N-acetyl-l-cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness a
ROS↑, PLB on ROS generation-related molecules
CycB/CCNB1↓, PLB induces G2/M arrest in SCC25 cells via downregulation of cyclin B1, CDK1/cdc2, and cdc25
CDK1↓,
CDK2↓,
CDC25↓,
Vim↓, PLB inhibited the expression of vimentin in a concentration- and time-dependent manner
OCT4↓, PLB significantly decreased the expression level of Oct-4, Sox-2, Nanog, and Bmi-1.
SOX2↓,
Nanog↓,
BMI1↓,
NQO1↓, The expression levels of NQO1, GST, and HSP90 were all markedly decreased
GSTA1↓,
HSP90↓,
toxicity↓, PLB exhibits anticancer activities with minimal side effect in vitro and in vivo,

5162- PLB,    Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells
- vitro+vivo, Melanoma, A172
TumCG↓, Plumbagin exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis.
TumCCA↑,
Apoptosis↑,
P21↑, Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C.
CycB/CCNB1↓,
cycA1/CCNA1↓,
CDC2↓,
CDC25↑,
Bax:Bcl2↑, Plumbagin triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activation
Casp9↑,
ROS↑, generation of ROS is a critical mediator in plumbagin-induced cell growth inhibition.
JNK↑, Plumbagin increased the activation of apoptosis signal-regulating kinase 1, JNK and extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38
ERK↑,
eff↓, antioxidants vitamin C and catalase significantly decreased plumbagin-mediated c-Jun N-terminal kinase (JNK) activation and apoptosis.

5161- PLB,    Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells
- in-vitro, SCC, SCC25
TumCCA↑, PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells
Apoptosis↑,
TumAuto↑,
Bcl-2↓, PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl)
Bcl-xL↓,
BAX↑, while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells
PI3K↓, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and p38 mitogen-activated protein kinase (p38 MAPK)
Akt↓,
mTOR↓,
GSK‐3β↓,
MAPK↓,
ROS↑, PLB induced intracellular reactive oxygen species (ROS) generation
eff↓, and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC).
CDC2↓, PLB downregulates the expression of Cdc2 and cyclin B1 while upregulating the expression of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells
CycB/CCNB1↓,
P21↑,
p27↑,
P53↑,
Casp9↑, this activates caspase 9 and caspase 3 in a positive feedback manner.
Casp3↑,

5159- PLB,    Plumbagin treatment leads to apoptosis in human K562 leukemia cells through increased ROS and elevated TRAIL receptor expression
- in-vitro, AML, K562
tumCV↓, Plumbagin exposure led to a significant reduction in cell viability and the induction of apoptosis.
Apoptosis↑,
ROS↑, plumbagin treatment led to elevated levels of ROS.
eff↓, Plumbagin-induced apoptosis was inhibited by N-acetyl L-cysteine (NAC) and PEG-catalase
DR4↑, plumbagin exposure led to elevated expression of DR4 and DR5 and increased killing through soluble TRAIL.
DR5↑,
TRAIL↑,

5158- PLB,    Plumbagin induces reactive oxygen species, which mediate apoptosis in human cervical cancer cells
- in-vitro, Cerv, ME-180
TumCG↓, plumbagin inhibits the growth of ME-180 cells in a concentration and time-dependent manner.
ROS↑, The cytotoxic effect of plumbagin induced cell death is through the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis
Apoptosis↑,
MMP↓, plumbagin caused loss of mitochondrial membrane potential (DeltaPsi(m)),
DNAdam↑, DNA fragmentation
Cyt‑c↑, lumbagin-induced apoptosis involved release of mitochondrial cytochrome c and apoptosis inducing factor (AIF)
AIF↑,
Casp3↑, plumbagin-mediated activation of caspase-3 and -9
Casp9↑,
eff↓, Our results also show that pretreatment of ME-180 cells with NAC blocks plumbagin-induced loss of DeltaPsi(m) and subsequent release of cytochrome c, AIF, and caspase-9 and -3 activation,

2651- PLB,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
ROS↑, Various studies have shown that plumbagin is a potent inducer of ROS
TrxR↓, The mechanism underlying ROS induction by plumbagin has predominantly been attributed to inhibition of the antioxidant enzymes TrxR
GSR↓, and glutathione reductase
ER Stress↓, mediates its anticancer effect by inducing ER stress-mediated apoptosis
TumCCA↑, S/G2 and G2/M cell cycle arrest
MMP↓, and mitochondrial membrane depolarization in an ROS-dependent manner
NF-kB↓, plumbagin was found to inhibit the NF-κB [57], PI3K/AKT/mTOR [58] and MKP1/2 [59] pathways in non-small cell lung cancer, bladder cancer, and lymphoma,
PI3K↓,
Akt↓,
mTOR↓,
MKP1↓,
MKP2↓,
ChemoSen↑, improve the efficacy of existing chemotherapeutic strategies

4968- PSO,    Psoralidin: emerging biological activities of therapeutic benefits and its potential utility in cervical cancer
- in-vitro, Cerv, NA
*Inflam↓, showing anti-inflammatory, anti-oxidant, estrogenic, neuroprotective, anti-diabetic, anti-depressant, antimicrobial, and anti-tumor activities substantiate its promising biological effects.
*antiOx↑,
*neuroP↑,
*AntiDiabetic↑,
*Bacteria↓,
AntiTum↑,
CSCs↓, Its capacity to effectively target cancer stem cells (CSCs) in general adds to its therapeutic potential.
ROS↑, Psoralidin carries out its anti-cancer activity by inducing oxidative stress, autophagy, and apoptosis.
TumAuto↑,
Apoptosis↑,
ChemoSen↑, This unique characteristic suggests its potential to be used as an adjunct molecule in combination with existing treatment to enhance the efficacy of chemo/radiotherapy for treating CaCx.
RadioS↑,
BioAv↓, low bioavailability and intestinal efflux limit the use of psoralidin in clinical applications
*cardioP↑, Psoralidin demonstrated cardioprotective effects.
*ROS↓, Furthermore, psoralidin administration resulted in a decrease in ROS levels and lactate dehydrogenase (LDH) release, indicating reduced oxidative stress and cellular damage in the heart.
*LDH↓,
TumCP↓, LNCaP Induction of apoptosis ↓Cell proliferation ↑TRAIL
TRAIL⇅,
TumCMig↓, PC-3, PzHPV-7, C4-2B 5–20 µM ↓Cell proliferation, ↓Migration, Invasion ROS generation
EMT↓, RWPE-1, xenograft mice 4 µM ↓Cell proliferation, Induction of apoptosis, Autophagy induction, EMT Inhibition ↓NF-кB signaling
NF-kB↓,
P53↑, HepG2 64 µM Induction of apoptosis ↑p53
Casp3↑, figure 4
NOTCH↓,
CSCs↓, Anti-CSC activity
angioG↓, Anti-angiogenesis
VEGF↓, it inhibited angiogenesis by downregulating the expression of pro-angiogenic molecules VEGF, Ki67, and CD31
Ki-67↓,
CD31↓,
TRAILR↑, psoralidin treatment induced the activation of death receptors 1 (DR 1) and DR 2 after 48 h of treatment
MMP↓, Psoralidin significantly increased the loss of ΔΨm, affecting a large percentage of cancer cells (58.38% ± 1.41%) and causing a major disruption of the mitochondrial membrane potential.
BioAv↓, hydrophobic nature, inadequate pharmacokinetic profile of psoralidin, and intestinal efflux, which hampers its clinical application
BioAv↑, bioavailability of psoralidin significantly improved with a value of 339% w.r.t to reference through its nanoencapsulation (NCs) using chitosan and Eudragit S100

4966- PSO,    Psoralidin induces pyroptosis in both tumor cells and macrophages as well as enhances nature killer cell cytotoxicity to suppress hepatocellular carcinoma
- vitro+vivo, HCC, HepG2
Pyro↑, Psoralidin induced pyroptosis and GSDME cleavage in HepG2 and Hepa1–6 cells
TumCG↓, Psoralidin suppressed HCC growth, inducing tumor cell pyroptosis and enhancing the tumor infiltration of T cells and NK cells.
mt-ROS↑, psoralidin induced mitochondrial reactive oxygen species (ROS) production, leading to caspase-3 activation and subsequent GSDME cleavage.
Casp3↑,
cl‑GSDME↑,
IL1β↑, leading to the secretion of interleukin (IL)-1β and IL-18, which promoted natural killer (NK) cell activation
IL18↑,
NK cell↑,

5157- PTL,    An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells
- vitro+vivo, AML, NA
CSCs↓, previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells.
selectivity↑,
BioAv↓, However, PTL has relatively poor pharmacologic properties that limit its potential clinical use.
BioAv↑, we generated a family of PTL analogs designed to improve solubility and bioavailability. 70% oral bioavailability
ROS↑, activities of DMAPT include induction of oxidative stress responses, inhibition of NF-κB, and activation of p53.
NF-kB↓,
P53↑,

5156- PTL,    Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells
- in-vitro, AML, NA
NADPH↑, parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway
PPP↑, Metabolomic analyses reveal increased PPP activity for NADPH production in PTL-treated AML cells. compensatory mechanisms
NRF2↑, activation of the Nrf2-mediated oxidative stress response pathway. compensatory mechanisms
ROS↑,
CSCs↓, parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells
selectivity↑,
other↝, combined with 2-deoxyglucose (D) and temsirolimus (T), drugs chosen for their ability to inhibit the PPP and the Nrf-2 mediated anti-oxidant response, respectively

5155- PTL,    Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases
- in-vitro, Liver, HepG2 - in-vitro, Nor, MEF - in-vitro, Cerv, HeLa - in-vitro, BC, MDA-MB-453
JAK↓, We found that parthenolide was a potent inhibitor of JAKs.
ROS↑, Parthenolide also induced reactive oxygen species (ROS), but the increased ROS did not seem to contribute to the inhibition of JAK/STAT3 signaling.
TumCMig↓, parthenolide inhibited the IL-6-induced cancer cell migration and preferentially inhibited the growth of cancer cells that had constitutively activated STAT3
TumCG↓,
STAT3↓, We identified parthenolide (PN) (Figure 1A) as a STAT3 pathway inhibitor

1996- PTL,    Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells
- in-vitro, CRC, COLO205
Apoptosis↑, parthenolide has shown to induce apoptosis in cancer cells
GSH↓, Parthenolide rapidly depleted intracellular thiols, including both free glutathione (GSH) and protein thiols.
ROS↑, ncreases in intracellular reactive oxygen species (ROS) and calcium levels
Ca+2↑,
GRP78/BiP↑, Increased expression of GRP78 protein, a marker for endoplasmic reticulum stress was also detected
ER Stress↑,
eff↓, pretreatment with N-acetylcysteine, a precursor of GSH synthesis, protected the cells from parthenolide-induced thiol depletion, ROS production, cytosolic calcium increase and completely blocked parthenolide-induced apoptosis.
eff↑, pretreatment of buthionine sulfoximine, an inhibitor of GSH synthesis sensitized the cell to apoptosis
Thiols↓, Parthenolide rapidly depleted intracellular thiols

1984- PTL,    Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells
- in-vitro, Cerv, HeLa
AntiCan↑, PTL demonstrates potent anticancer efficacy in numerous types of malignant cells,
TrxR1↓, PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2)
TrxR2↓,
ROS↑, elicit reactive oxygen species-mediated apoptosis in HeLa cells
Apoptosis↑,
eff↓, blocked by pretreatment of the cells with NAC
eff↑, depletion of cellular GSH by pretreatment of the cells with BSO enhances the cytotoxicity of PTL

1985- PTL,    KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Effects of Parthenolide in Normal and Cancer Cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145 - in-vitro, Nor, PrEC - in-vivo, NA, NA
ROS↑, parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase
NADPH↑,
RadioS↑, In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury
radioP↑, DMAPT, the water soluble prodrug of parthenolide, is a promising agent for selectively enhancing the sensitivity of prostate cancer cells to radiation while protecting normal tissues from damage caused by radiation.
Trx↓, causes oxidation of thioredoxin (TrX) in prostate cancer cells
*ox-Keap1↑, three normal cell lines, parthenolide increased the oxidized form of Keap1 but decreased the reduced form of Keap1
ox-Keap1↓, results from the three cancer cell lines appeared to be completely opposite to results observed in normal cells treated with parthenolide
rd-Keap1↑, in vivo results show that parthenolide decreased the oxidized form of Keap1 but increased the reduced form of Keap1 in the tumors
*NRF2↑, Oxidization of Keap1 leads to activation of the Nrf2 pro-survival pathway in normal cells. Nrf2 pathway is a major mechanism by which parthenolide protects normal cells against radiation injury
NRF2∅, but no changes were observed in the three cancer cell lines.
NF-kB↓, It has been reported that parthenolide is a potent inhibitor of NF-κB

1986- PTL,    Modulation of Cell Surface Protein Free Thiols: A Potential Novel Mechanism of Action of the Sesquiterpene Lactone Parthenolide
- in-vitro, NA, NA
JNK↑, parthenolide mediated activation of JNK
ROS↑, parthenolide induced generation of intracellular reactive oxygen species
eff↓, Parthenolide Cytotoxicity Is Blocked by Thiol Antioxidants
NF-kB↓, parthenolide has been shown to induce malignant cell death by inhibiting NFκB activation and/or activating JNK
Trx↓, thioredoxin pull-down

1987- PTL,  Rad,    A NADPH oxidase dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Nor, PrEC
selectivity↑, parthenolide (PN), a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells.
RadioS↑,
ROS↑, oxidative stress in PC3 cells but not in PrEC cells
*ROS∅, oxidative stress in PC3 cells but not in PrEC cells
NADPH↑, In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, MnSOD, CAT
Trx↓,
PI3K↑,
Akt↑,
p‑FOXO3↓, downregulation of FOXO3a targets, antioxidant enzyme manganese superoxide dismutase (MnSOD) and catalase
SOD2↓, MnSOD
Catalase↓,
radioP↑, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells
*NADPH∅, Parthenolide activates NADPH oxidase in PC3 cells but not in PrEC cells
*GSH↑, increases glutathione (GSH) in PrEC cells(normal cells)
*GSH/GSSG↑, GSH/GSSG ratio is not significantly changed by parthenolide in PC3 cells but is increased 2.4 fold in PrEC cells (normal cells)
*NRF2↑, The induction of GSH may be due to the activation of the Nrf2/ARE (antioxidant/electrophile response element) pathway

1988- PTL,    Parthenolide Induces ROS-Mediated Apoptosis in Lymphoid Malignancies
- in-vitro, lymphoma, NCI-H929
NF-kB↓, Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor.
ROS↑, parthenolide promoted cell death by apoptosis with significant ROS increase
GSH↓, GSH decrease combined with a ΔΨmit reduction across all studied cell line
MMP↓,
GPx1↓, parthenolide significantly decreased GPX1 expression

1989- PTL,    Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties
- Review, Var, NA
eff↑, therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT).
NF-kB↓, these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs
STAT↓,
ROS↑, increasing intracellular reactive oxygen species (ROS) production
Inflam↓, anti-inflammatory action of PN has been widely considered a consequence of its inhibitory effect on the transcription factors belonging to NF-κB family
Wnt↓, PN was recently shown to inhibit Wnt signaling by decreasing the levels of the transcription factors TCF4/LEF1
TCF-4↓,
LEF1↓,
GSH↓, Wen et al., who found that PN-induced apoptosis in hepatoma cells was accompanied with depletion of glutathione (GSH), generation of ROS, reduction of mitochondrial transmembrane potential and activation of caspases.
MMP↓,
Casp↑,
eff↓, These effects were effectively abrogated by the antioxidant N-acetyl-l-cysteine (NAC) and enhanced by the GSH synthesis inhibitor buthionine sulfoximine (BSO) confirming the role of oxidative stress in PN-induced apoptosis
CSCs↓, several studies showing the effect of PN in reducing the presence of CSCs in solid and hematological tumors

1991- PTL,    A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability
- in-vitro, Liver, HUH7
TumCCA↑, PTL stimulated cell cycle arrest at the G1 phase, induced apoptosis, and decreased the stemness of LCSCs
Apoptosis↑,
CSCs↓,
ROS↑, PTL caused the production of ROS and the reduction of oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential (MMP) levels of LCSCs
OXPHOS↓, PTL inhibited OXPHOS levels
MMP↓,
SLC25A1↓, PTL decreased SLC25A1 expression at the mRNA level
IDH2↓, inhibition of SLC25A1 synergistically decreased the expression of IDH2

1992- PTL,    Parthenolide induces ROS-dependent cell death in human gastric cancer cell
- in-vitro, BC, MGC803
TumCCA↑, Parthenolide induced cell cycle arrest at the G1 and S stages.
Casp↑, Parthenolide-induced caspase-dependent apoptosis and necroptosis were caused by the activation of RIP, RIP3 and MLKL
Apoptosis↑,
Necroptosis↑,
RIP1↓,
RIP3↑,
MLKL↑,
ROS↑, MGC-803 cells showed a response to ROS and oxidative stress after PN treatment.
eff↓, ROS and cytotoxicity induced by PN were significantly attenuated by a ROS scavenger catalase.

1993- PTL,    Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer
- in-vitro, Cerv, HeLa
tumCV↓, Parthenolide inhibits HeLa cell viability in a dose dependent-manner and was confirmed by MTT assay.
TumAuto↑, Parthenolide (6 µM) induces mitochondrial-mediated apoptosis and autophagy by activation of caspase-3, upregulation of Bax, Beclin-1, ATG5, ATG3
Casp3↑,
BAX↑,
Beclin-1↑,
ATG3↑,
ATG5↑,
Bcl-2↓, and down-regulation of Bcl-2 and mTOR
mTOR↓,
PI3K↓, inhibits PI3K and Akt expression through activation of PTEN expression.
Akt↓,
PTEN↑,
ROS↑, parthenolide induces generation of reactive oxygen species that leads to the loss of mitochondrial membrane potential
MMP↓,

1983- PTL,    Targeting thioredoxin reductase by micheliolide contributes to radiosensitizing and inducing apoptosis of HeLa cells
- in-vitro, Cerv, HeLa
eff↑, micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL
TrxR↓, MCL-targeted inhibition of TrxR
ROS↑, promotes oxidative stress-mediated HeLa cell apoptosis
RadioS↑, sensitizes ionizing radiation (IR) treatment

1237- PTS,    Pterostilbene induces cell apoptosis and inhibits lipogenesis in SKOV3 ovarian cancer cells by activation of AMPK-induced inhibition of Akt/mTOR signaling cascade
- in-vitro, Ovarian, SKOV3
TumCMig↓,
TumCI↓,
MDA↑,
ROS↑,
BAX↑,
Casp3↑,
Bcl-2↓,
SREBP1↓,
FASN↓,
AMPK↓,
p‑AMPK↑,
p‑P53↑,
p‑TSC2↑,
p‑Akt↓,
p‑mTOR↓,
p‑S6K↓, p-S6K1
p‑4E-BP1↓,

5033- PTS,    Involvement of the Nrf2 Pathway in the Regulation of Pterostilbene-Induced Apoptosis in HeLa Cells via ER Stress
- in-vitro, Cerv, HeLa
ER Stress↑, Pte trigged ER stress by redox homeostasis imbalance, which was negatively regulated by a following activation of Nrf2.
ROS↑,
NRF2↑,
TumCP↓, Pte inhibits the proliferation of HeLa cells
GSH/GSSG↓, The results showed that treatment with Pte consistently reduced the GSH/GSSG ratio, indicating an intracellular redox homeostasis shift toward oxidation

4692- PTS,    Pterostilbene Suppresses both Cancer Cells and Cancer Stem-Like Cells in Cervical Cancer with Superior Bioavailability to Resveratrol
- in-vitro, Cerv, HeLa
TumCG↓, Pterostilbene more effectively inhibited the growth and clonogenic survival, as well as metastatic ability of HeLa adherent cells than those of resveratrol.
TumMeta↓,
TumCCA↑, including cell cycle arrest at S and G2/M phases, induction of ROS-mediated caspase-dependent apoptosis, and inhibition of matrix metalloproteinase (MMP)-2/-9 expression
ROS↑,
Apoptosis↑,
MMP2↓,
MMP9↓,
CD133↓, more potent inhibition of the expression levels of stemness markers, such as CD133, Oct4, Sox2, and Nanog, as well as signal transducer and activator of transcription 3 signaling
OCT4↓,
SOX2↓,
Nanog↓,
STAT3↓,
CSCs↓, Potent Inhibitory Activity of Pterostilbene against the Growth and Migration of Cervical CSCs

4689- PTS,    Pterostilbene Suppresses both Cancer Cells and Cancer Stem-Like Cells in Cervical Cancer with Superior Bioavailability to Resveratrol
eff↑, Pterostilbene more effectively inhibited the growth and clonogenic survival, as well as metastatic ability of HeLa adherent cells than those of resveratrol.
TumCCA↑, including cell cycle arrest at S and G2/M phases, induction of ROS-mediated caspase-dependent apoptosis, and inhibition of matrix metalloproteinase (MMP)-2/-9 expression.
ROS↑,
MMP2↓,
MMP9↓,
CSCs↓, Notably, pterostilbene exhibited a greater inhibitory effect on the tumorsphere-forming and migration abilities of HeLa cancer stem-like cells compared to resveratrol.
CD133↓, more potent inhibition of the expression levels of stemness markers, such as CD133, Oct4, Sox2, and Nanog, as well as signal transducer and activator of transcription 3 signaling.
OCT4↓,
SOX2↓,
Nanog↓,
STAT3↓,
BioAv↑, superior bioavailability to resveratrol.
TumCI↓, Both resveratrol and pterostilbene resulted in a significant reduction in the invasiveness of HeLa cells
ROS↑, Pterostilbene more prominently elevated the production of ROS in comparison with resveratrol at the indicated doses
Apoptosis↑, Pterostilbene Exhibited Better Capacity for Inducing Cell Cycle Arrest and Apoptosis of Cervical CSCs Compared to Resveratrol

3930- PTS,    A Review of Pterostilbene Antioxidant Activity and Disease Modification
- Review, Var, NA - Review, adrenal, NA - Review, Stroke, NA
*BioAv↑, It has increased bioavailability in comparison to other stilbene compounds. pterostilbene was shown to have 80% bioavailability compared to 20% for resveratrol making it potentially advantageous as a therapeutic agent
*antiOx↑, Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits.
*neuroP↑, anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes.
*Inflam↓,
*ROS↓, pterostilbene reduces oxidative stress (OS) and production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) and superoxide anion (O2 −), which are implicated in the initiation and pathogenesis of several disease processes
*H2O2↓,
*GSH↑, pterostilbene have shown increased expression of the antioxidants catalase, total glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD).
*GPx↑,
*GSR↑,
*SOD↑,
TumCG↓, pterostilbene inhibit breast cancer in vitro and in vivo
PTEN↑, rats fed the blueberry diet exhibited higher mammary branching, increased nuclear immunoreactivity of tumor suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN)
HGF/c-Met↓, blueberry extract significantly decreased human-growth-factor (HGF-) induced activation of the PI3 K/AkT/NK-κB pathway, which is implicated in breast carcinogenesis
PI3K↓,
Akt↓,
NF-kB↓,
TumMeta↓, inhibited the metastatic potential of breast cancer cells in vitro by inhibiting HGF-induced cell migration and matrix metalloproteinase-(MMP-) 2 and MMP-9 activity.
MMP2↓,
MMP9↓,
Ki-67↓, blueberry extract produced smaller tumors with decreased expression of Ki-67, a marker of cell proliferation, and increased expression of caspase-3, an apoptosis marker
Casp3↑,
MMP↓, increased mitochondrial depolarization,
H2O2↑, pterostilbene treatment increased GPx antioxidant activity and the production of H2O2 and singlet oxygen indicating a mechanism of ROS-induced apoptosis
ROS↑,
ChemoSen↑, pterostilbene treatment produced a synergistic inhibitory effect when combined with the chemotherapy drug Tamoxifen, demonstrating clinical potential in the treatment of breast cancer
*cardioP↑, blueberries, and pterostilbene alike, exhibit protective effects against cardiovascular disease possibly due to induction of antioxidant enzymes.
*CDK2↓, Pterostilbene also produced downregulation of the cell-cycle mediators, cyclin-dependent kinase (CDK)-2, CDK-4, cyclin E, cyclin D1, retinoblastoma (Rb), and proliferative cell nuclear antigen (PCNA), all of which promote unchecked VSMC proliferation
*CDK4↓,
*cycE/CCNE↓,
*cycD1/CCND1↓,
*RB1↓,
*PCNA↓,
*CREB↑, The authors found that treatment with blueberry extract decreased dopamine- (DA-) induced upregulation of the oxidative mediators, CREB and pPKCγ, indicating a significant antioxidant effect
*GABA↑, blueberry-fed aged rats had significant improvements in GABA potentiation and increased GSH compared to aged controls
*memory↑, 1- or 2-month blueberry diet showed significantly higher object memory recognition compared to control rats
*IGF-1↑, supplementation with blueberry extract was shown to enhance hippocampal plasticity and increase levels of insulin-like growth factor (IGF-) 1, IGF-2, and ERK resulting in improved spatial memory
*ERK↑,
TIMP1↑, increased endogenous tissue inhibitors of metalloproteinases (TIMPs)
BAX↑, ↑Bax, ↑cytochrome C, ↑Smac/Diablo, ↑MnSOD
Cyt‑c↑,
Diablo↑,
SOD2↑,

3929- PTS,    New Insights into Dietary Pterostilbene: Sources, Metabolism, and Health Promotion Effects
- Review, Var, NA - Review, Arthritis, NA
*NRF2↑, PTS activates the Nrf2 pathway,
*BioAv↑, , PTS has been documented to exhibit an increased bioavailability compared to other stilbene compounds
*ROS↓, Various evidence has demonstrated the effect of PTS in countering oxidative damage and inflammation, imparting preventive and therapeutic benefits in experimental disease models
*Inflam↓,
*HO-1↑, major downstream targets activated following PTS administration were antioxidative enzymes, including HO 1, SOD, catalase, and GPX
*SOD↑,
*Catalase↑,
*GPx↑,
*lipid-P↓, reducing lipid peroxidation in STZ-induced diabetic mice.
*hepatoP↑, figure 4
*neuroP↑,
*iNOS↓, PTS inhibited the transcriptional expression of augmented iNOS levels and moderated the inhibition of COX-2 in a concentration-dependent manner
*COX2↓,
TumMeta↓, PTS in combination with quercetin at 20 mg/kg/day inhibited the metastatic activity in B16-F10 melanoma by reducing the adhesion of B16-F10 cells to the endothelium and also downregulated the levels of Bcl-2 in cancerous cells
SOD2↓, PTS was identified to reduce HCC proliferation through a reduction in SOD2 and the induction of ROS-mediated mitochondrial apoptotic pathways
ROS↑,
TumCI↓, PTS was reported to suppress the invasion and growth of HCC by down-regulating the expression of Metastasis-Associated Protein 1 (MTA1) and histone deacetylase 1 (HDAC1) while upregulating the acetylation of the tumor suppressor protein PTEN
TumCG↓,
HDAC1↓,
PTEN↑,
BP↓, highly purified trans-PTS patented by Chromadex, Irvine, CA, has been proven to significantly reduce blood pressure in adults
*GutMicro↑, PTS significantly reduced paw swelling, the arthritic score, and body weight. Interestingly, it also helped restore the healthy gut microbiota ecosystem by reducing the relative abundance of Helicobacter, Desulfovibrio, Lachnospiraceae, and Mucispiri

3924- PTS,    Effect of resveratrol and pterostilbene on aging and longevity
- Review, AD, NA - Review, Stroke, NA
*antiOx↓, Firstly, pterostilbene act as an antioxidant against various free radicals,
*ROS↑, reducing ROS production
*SOD↑, as well as increasing SOD and glutathione (GSH) activation via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in neuronal cells [44].
*GSH↑,
*NRF2↑, by activating Nrf2
*MDA↓, pterostilbene reduced malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), aconitase-2 and 8-hydroxydeoxyguanosine (8-OHdG) level;
*HNE↓,
*Inflam↓, Pterostilbene has been reported as a potential anti- inflammatory agent
*MAPK↓, pterostilbene inhibited mitogen-activated protein kinase (MAPK) activation and the production of pro-inflammatory cytokine (interleukin-6 [IL-6] and TNF-a)
*IL6↓,
*TNF-α↓,
*HO-1↑, through upregulating heme oxygenase-1 (HO-1) to prevent hypoxic-ischemic brain injury in neonatal rats
*cardioP↑, beneficial health effects of resveratrol and pterostilbene on cardioprotection, neuroprotection
*neuroP↑,
*CRM↑, as a calorie restriction mimic
*NLRP3↓, nhibiting pro-inflammatory cytokine such as IL-1b and NLRP3 inflammasome activation,

3344- QC,    Quercetin induced ROS production triggers mitochondrial cell death of human embryonic stem cells
- in-vitro, Nor, hESC
mt-ROS↑, mitochondrial reactive oxygen species (ROS), strongly induced by QC in human embryonic stem cells (hESCs) but not in human dermal fibroblasts (hDFs), were responsible for QC-mediated hESC’s cell death.
selectivity↑,
P53↑, . Increased p53 protein stability and subsequent mitochondrial localization by QC treatment triggered mitochondrial cell death only in hESCs.
ROS⇅, QC acts either as a pro-oxidant to be cytotoxic to cancer cells with active proliferation [8, 10] or as an anti-oxidant [9], depending on the cell models,

3353- QC,    Quercetin triggers cell apoptosis-associated ROS-mediated cell death and induces S and G2/M-phase cell cycle arrest in KON oral cancer cells
- in-vitro, Oral, KON - in-vitro, Nor, MRC-5
tumCV↓, reduced the vitality of KON cells and had minimal effect on MRC cells.
selectivity↑, Owing to the appropriate dosages of quercetin needed to treat these diseases, normal cells do not exhibit any overtly harmful side effects.
TumCCA↑, quercetin increased the percentage of dead cells and cell cycle arrests in the S and G2/M phases.
TumCMig↓, quercetin inhibited KON cells’ capacity for migration and invasion in addition to their effects on cell stability and structure
TumCI↓,
Apoptosis↑, inducing apoptosis and preventing metastasis, quercetin was found to downregulate the expression of BCL-2/BCL-XL while increasing the expression of BAX.
TumMeta↓,
Bcl-2↓,
BAX↑,
TIMP1↑, TIMP-1 expression was upregulated while MMP-2 and MMP-9 were downregulated.
MMP2↓,
MMP9↓,
*Inflam↓, anti-inflammatory, anti-cancer, antibacterial, antifungal, anti-diabetic, antimalarial, neuroprotective, and cardioprotective properties.
*neuroP↑,
*cardioP↑,
p38↓, MCF-7 cells, quercetin successfully decreased the expression of phosphor p38MAPK, Twist, p21, and Cyclin D1
MAPK↓,
Twist↓,
P21↓,
cycD1/CCND1↓,
Casp3↑, directly aided by the significant increase in caspase-3 and − 9 levels and activities
Casp9↑,
p‑Akt↓, High quercetin concentrations also caused an inhibition of Akt and ERK phosphorylation
p‑ERK↓,
CD44↓, reduced cell division and triggered apoptosis, albeit to a lesser degree in CD44+/CD24− cells.
CD24↓,
ChemoSen↑, combination of quercetin and doxorubicin caused G2/M arrest in T47D cells, and to a lesser amount in cancer stem cells (CSCs) that were isolate
MMP↓, (lower levels of ΔΨ m), which is followed by the release of Cyto C, AIF, and Endo G from mitochondria, which causes apoptosis and ultimately leads to cell death.
Cyt‑c↑,
AIF↑,
ROS↑, Compared to the control group, quercetin administration significantly raised ROS levels at 25, 50, 100, 200, and 400 µg/mL.
Ca+2↑, increased production of reactive oxygen species and Ca2+, decreased levels of mitochondrial membrane potential (ΔΨ m),
Hif1a↓, Quercetin treatment resulted in a considerable downregulation of HIF-1α, VEGF, MMP2, and MMP9 mRNA and protein expression levels in HOS cells.
VEGF↓,

3348- QC,    Quercetin and iron metabolism: What we know and what we need to know
- Review, NA, NA
*IronCh↑, Quercetin alleviates iron overload induced by various pathologies as a natural iron chelator.
*ROS↓, Quercetin's iron-chelating property and direct scavenging action against ROS (reactive oxygen species) are believed to be the essence of its antioxidant activity.
*AntiAg↑,
*Fenton↓, Cheng and Breen (Cheng and Breen, 2000) found that quercetin suppressed the Fenton reaction by forming a Fe-quercetin-ATP complex.
*lipid-P↓, quercetin effectively decreases iron deposition, and it alleviates lipid peroxidation as well as protein oxidation in the livers, kidneys and hearts of iron-dextran-overloaded mice.
*hepatoP↑, quercetin acts as a reliable liver protector to prevent iron-provoked oxidative damage
*RenoP↑, modulation of iron by quercetin has been shown to prevent glycerol-induced acute myoglobinuric renal failure
HIF-1↑, in both human prostate adenocarcinoma cell lines (LNCaP, DU-145, and PC-3 cell lines) and HeLa cells, quercetin treatment appears to induce HIF-1/2αaccumulation, which may give rise to some undesirable consequences in cases such as cancer treatment
ROS↑, The redox status of quercetin determines whether it can undergo oxido-reductive activation and then be subjected to the iron-involved redox cycling of the Fenton reaction to produce substantial amounts of ROS.

3355- QC,    Quercetin exhibits cytotoxicity in cancer cells by inducing two-ended DNA double-strand breaks
- in-vitro, Cerv, HeLa
DNAdam↑, Quercetin induced DNA double-strand break
ROS↑, Reactive oxygen species accumulated in quercetin-treated HeLa cells.
*antiOx↑, antioxidant properties
TOP2↓, Quercetin inhibits Top2 in vitro (Quercetin does not act as a Top2 poison)
γH2AX↑, quercetin concentrations of 50, 100 or 150 μM, γH2AX fluorescence was noticeably observed

3368- QC,    The potential anti-cancer effects of quercetin on blood, prostate and lung cancers: An update
- Review, Var, NA
*Inflam↓, quercetin is known for its anti-inflammatory, antioxidant, and anticancer properties.
*antiOx↑,
*AntiCan↑,
Casp3↓, Quercetin increases apoptosis and autophagy in cancer by activating caspase-3, inhibiting the phosphorylation of Akt, mTOR, and ERK, lessening β-catenin, and stabilizing the stabilization of HIF-1α.
p‑Akt↓,
p‑mTOR↓,
p‑ERK↓,
β-catenin/ZEB1↓,
Hif1a↓,
AntiAg↓, Quercetin have revealed an anti-tumor effect by reducing development of blood vessels. I
VEGFR2↓, decrease tumor growth through targeting VEGFR-2-mediated angiogenesis pathway and suppressing the downstream regulatory component AKT in prostate and breast malignancies.
EMT↓, effects of quercetin on inhibition of EMT, angiogenesis, and invasiveness through the epidermal growth factor receptor (EGFR)/VEGFR-2-mediated pathway in breast cancer
EGFR↓,
MMP2↓, MMP2 and MMP9 are two remarkable compounds in metastatic breast cancer (28–30). quercetin on breast cancer cell lines (MDA-MB-231) and showed that after treatment with this flavonoid, the expression of these two proteinases decreased
MMP↓,
TumMeta↓, head and neck (HNSCC), the inhibitory effect of quercetin on the migration of tumor cells has been shown by regulating the expression of MMPs
MMPs↓,
Akt↓, quercetin by inhibiting the Akt activation pathway dependent on Snail, diminishing the expression of N-cadherin, vimentin, and ADAM9 and raising the expression of E-cadherin and proteins
Snail↓,
N-cadherin↓,
Vim↓,
E-cadherin↑,
STAT3↓, inhibiting STAT3 signaling
TGF-β↓, reducing the expression of TGF-β caused by vimentin and N-cadherin, Twist, Snail, and Slug and increasing the expression of E-cadherin in PC-3 cells.
ROS↓, quercetin exerted an anti-proliferative role on HCC cells by lessening intracellular ROS independently of p53 expression
P53↑, increasing the expression of p53 and BAX in hepatocellular carcinoma (HepG2) cell lines through the reduction of PKC, PI3K, and cyclooxygenase (COX-2)
BAX↑,
PKCδ↓,
PI3K↓,
COX2↓,
cFLIP↓, quercetin by inhibiting PI3K/AKT/mTOR and STAT3 pathways, decreasing the expression of cellular proteins such as c-FLIP, cyclin D1, and c-Myc, as well as reducing the production of IL-6 and IL-10 cytokines, leads to the death of PEL cells
cycD1/CCND1↓,
cMyc↓,
IL6↓,
IL10↓,
Cyt‑c↑, In addition, quercetin induced c-cytochrome-dependent apoptosis and caspase-3 almost exclusively in the HSB2 cell line
TumCCA↑, Exposure of K562 cells to quercetin also significantly raised the cells in the G2/M phase, which reached a maximum peak in 24 hours
DNMTs↓, pathway through DNA demethylation activity, histone deacetylase (HDAC) repression, and H3ac and H4ac enrichment
HDAC↓,
ac‑H3↑,
ac‑H4↑,
Diablo↑, SMAC/DIABLO exhibited activation
Casp3↑, enhanced levels of activated caspase 3, cleaved caspase 9, and PARP1
Casp9↑,
PARP1↑,
eff↑, green tea and quercetin as monotherapy caused the reduction of levels of anti-apoptotic proteins, CDK6, CDK2, CYCLIN D/E/A, BCL-2, BCL-XL, and MCL-1 and an increase in expression of BAX.
PTEN↑, Quercetin upregulates the level of PTEN as a tumor suppressor, which inhibits AKT signaling
VEGF↓, Quercetin had anti-inflammatory and anti-angiogenesis effects, decreasing VGEF-A, NO, iNOS, and COX-2 levels
NO↓,
iNOS↓,
ChemoSen↑, quercetin and chemotherapy can potentiate their effect on the malignant cell
eff↑, combination with hyperthermia, Shen et al. Quercetin is a method used in cancer treatment by heating, and it was found to reduce Doxorubicin hydrochloride resistance in leukemia cell line K562
eff↑, treatment with ellagic acid, luteolin, and curcumin alone showed excellent anticancer effects.
eff↑, co-treatment with quercetin and curcumin led to a reduction of mitochondrial membrane integrity, promotion of cytochrome C release, and apoptosis induction in CML cells
uPA↓, A-549 cells were shown to have reduced mRNA expressions of urokinase plasminogen activator (uPA), Upar, protein expression of CXCR-4, CXCL-12, SDF-1 when quercetin was applied at 20 and 40 mM/ml by real-time PCR.
CXCR4↓,
CXCL12↓,
CLDN2↓, A-549 cells, indicated that quercetin could reduce mRNA and protein expression of Claudin-2 in A-549 cell lines without involving Akt and ERK1/2,
CDK6↓, CDK6, which supports the growth and viability of various cancer cells, was hampered by the dose-dependent manner of quercetin (IC50 dose of QR for A-549 cells is 52.35 ± 2.44 μM).
MMP9↓, quercetin up-regulated the rates of G1 phase cell cycle and cellular apoptotic in both examined cell lines compared with the control group, while it declined the expressions of the PI3K, AKT, MMP-2, and MMP-9 proteins
TSP-1↑, quercetin increased TSP-1 mRNA and protein expression to inhibit angiogenesis,
Ki-67↓, significant reductions in Ki67 and PCNA proliferation markers and cell survival markers in response to quercetin and/or resveratrol.
PCNA↓,
ROS↑, Also, quercetin effectively causes intracellular ROS production and ER stress
ER Stress↑,

3374- QC,    Therapeutic effects of quercetin in oral cancer therapy: a systematic review of preclinical evidence focused on oxidative damage, apoptosis and anti-metastasis
- Review, Oral, NA - Review, AD, NA
α-SMA↓, In oral cancer cells, quercetin could inhibit EMT via up-regulation of claudin-1 and E-cadherin and down-regulation of α-SMA, vimentin, fibronectin, and Slug [29]
α-SMA↑, OSC20 Invasion: ↓Migration, ↑Expression of epithelial markers (E-cadherin & claudin-1), ↑Expression of mesenchymal markers (fibronectin, vimentin, & α-SMA),
TumCP↓, quercetin significantly reduced cancer cell proliferation, cell viability, tumor volume, invasion, metastasis and migration
tumCV↓,
TumVol↓,
TumCI↓,
TumMeta↓,
TumCMig↓,
ROS↑, This anti-cancer agent induced oxidative stress and apoptosis in the cancer cells.
Apoptosis↑,
BioAv↓, The efficacy of quercetin (as lipophilic) is much impacted by its poor absorption rates, which define its bioavailability. The research on quercetin's bioavailability in animal models shows it may be as low as 10%
*neuroP↑, quercetin has been observed to exhibit neuroprotective effects in Alzheimer's disease through its anti-oxidants, and anti-inflammatory properties and inhibition of amyloid-β (Aβ) fibril formation
*antiOx↑,
*Inflam↓,
*Aβ↓,
*cardioP↑, Additionally, quercetin protects the heart by stopping oxidative stress, inflammation, apoptosis, and protein kinases
MMP↓, ↓MMP, ↑Cytosolic Cyt. C,
Cyt‑c↑,
MMP2↓, ↓Activation MMP-2 & MMP-9, ↓Expression levels of EMT inducers & MMPs, Downregulated Twist & Slug
MMP9↓,
EMT↓,
MMPs↓,
Twist↓,
Slug↓,
Ca+2↑, ↑Apoptosis, ↑ROS, ↑Ca2+ production, ↑Activities of caspase‑3, caspase‑8 & caspase‑9
AIF↑, ↑Mitochondrial release of Cyt. C, AIF, & Endo G
Endon↑,
P-gp↓, ↓ Protein levels of P-gp, & P-gp Expression
LDH↑, ↑LDH release
HK2↓, CAL27 cells) 80µM/24h Molecular markers: ↓Activities of HK, PK, & LDH, ↓Glycolysis, ↓Glucose uptake, ↓Lactate production, ↓Viability, ↓G3BP1, & YWHA2 protein levels
PKA↓,
Glycolysis↓,
GlucoseCon↓,
lactateProd↓,
GRP78/BiP↑, Quercetin controls the activation of intracellular Ca2+ and calpain-1, which then activates GRP78, caspase-12, and C/EBP homologous protein (CHOP) in oral cancer cells
Casp12↑,
CHOP↑,

3369- QC,    Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects
- Review, Pca, NA
FAK↓, Quercetin can inhibit HGF-induced melanoma cell migration by inhibiting the activation of c-Met and its downstream Gabl, FAK and PAK [84]
TumCCA↑, stimulation of cell cycle arrest at the G1 stage
p‑pRB↓, mediated through regulation of p21 CDK inhibitor and suppression of pRb phosphorylation resulting in E2F1 sequestering.
CDK2↑, low dose of quercetin has brought minor DNA injury and Chk2 induction
CycB/CCNB1↓, quercetin has a role in the reduction of cyclin B1 and CDK1 levels,
CDK1↓,
EMT↓, quercetin suppresses epithelial to mesenchymal transition (EMT) and cell proliferation through modulation of Sonic Hedgehog signaling pathway
PI3K↓, quercetin on other pathways such as PI3K, MAPK and WNT pathways have also been validated in cervical cancer
MAPK↓,
Wnt↓,
ROS↑, colorectal cancer, quercetin has been shown to suppress carcinogenesis through various mechanisms including affecting cell proliferation, production of reactive oxygen species and expression of miR-21
miR-21↑,
Akt↓, Figure 1 anti-cancer mechanisms
NF-kB↓,
FasL↑,
Bak↑,
BAX↑,
Bcl-2↓,
Casp3↓,
Casp9↑,
P53↑,
p38↑,
MAPK↑,
Cyt‑c↑,
PARP↓,
CHOP↑,
ROS↓,
LDH↑,
GRP78/BiP↑,
ERK↑,
MDA↓,
SOD↑,
GSH↑,
NRF2↑,
VEGF↓,
PDGF↓,
EGF↓,
FGF↓,
TNF-α↓,
TGF-β↓,
VEGFR2↓,
EGFR↓,
FGFR1↓,
mTOR↓,
cMyc↓,
MMPs↓,
LC3B-II↑,
Beclin-1↑,
IL1β↓,
CRP↓,
IL10↓,
COX2↓,
IL6↓,
TLR4↓,
Shh↓,
HER2/EBBR2↓,
NOTCH↓,
DR5↑, quercetin has enhanced DR5 expression in prostate cancer cells
HSP70/HSPA5↓, Quercetin has also suppressed the upsurge of hsp70 expression in prostate cancer cells following heat treatment and enhanced the quantity of subG1 cells
CSCs↓, Quercetin could also suppress cancer stem cell attributes and metastatic aptitude of isolated prostate cancer cells through modulating JNK signaling pathway
angioG↓, Quercetin inhibits angiogenesis-mediated of human prostate cancer cells through negatively modulating angiogenic factors (TGF-β, VEGF, PDGF, EGF, bFGF, Ang-1, Ang-2, MMP-2, and MMP-9)
MMP2↓,
MMP9↓,
IGFBP3↑, Quercetin via increasing the level of IGFBP-3 could induce apoptosis in PC-3 cells
uPA↓, Quercetin through decreasing uPA and uPAR expression and suppressing cell survival protein and Ras/Raf signaling molecules could decrease prostate cancer progression
uPAR↓,
RAS↓,
Raf↓,
TSP-1↑, Quercetin through TSP-1 enhancement could effectively inhibit angiogenesis

3371- QC,    Quercetin induces MGMT+ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways
- in-vitro, GBM, T98G
TIMP2↑, MMP2, and MMP9 was significantly decreased by quercetin treatment, while TIMP1 and TIMP2 were upregulated (
TumCG↓, Quercetin significantly suppressed the growth and migration of human GBM T98G cells, induced apoptosis, and arrested cells in the S-phase cell cycle
TumCMig↓,
Apoptosis↑,
TumCCA↑,
MMP↓, collapse of mitochondrial membrane potential, ROS generation, enhanced Bax/Bcl-2 ratio, and strengthened cleaved-Caspase 9 and cleaved-Caspase 3 suggested the involvement of ROS-mediated mitochondria-dependent apoptosis in the process
ROS↑,
Bax:Bcl2↑,
cl‑Casp9↑,
cl‑Casp3↑,
DNAdam↑, quercetin-induced apoptosis was accompanied by intense DNA double-strand breaks (DSBs), γH2AX foci formation, methylation of MGMT promoter, increased cleaved-PARP, and reduced MGMT expression
γH2AX↑,
MGMT↓,
cl‑PARP↑,

3372- QC,  FIS,  KaempF,    Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers
- Review, HNSCC, NA
ROCK1↑, quercetin affects the level of RhoA and NF-κB proteins in SAS cells, and stimulates the expression of RhoA, ROCK1, and NF-κB in SAS cells [53].
TumCCA↓, inhibition of the cell cycle;
HSPs↓, inhibition of heat shock proteins;
RAS↓, inhibition of Ras protein expression.
ROS↑, fisetin induces production of reactive oxygen species (ROS), increases Ca2+ release, and decreases the mitochondrial membrane potential (Ψm) in head and neck neoplastic cells.
Ca+2↑,
MMP↓,
Cyt‑c↑, quercetin increases the expression level of cytochrome c, apoptosis inducing factor and endonuclease G
Endon↑,
MMP9↓, quercetin inhibits MMP-9 and MMP-2 expression and reduces levels of the following proteins: MMP-2, -7, -9 [49,53] and -10
MMP2↓,
MMP7↓,
MMP-10↓,
VEGF↓, as well as VEGF, NF-κB p65, iNOS, COX-2, and uPA, PI3K, IKB-α, IKB-α/β, p-IKKα/β, FAK, SOS1, GRB2, MEKK3 and MEKK7, ERK1/2, p-ERK1/2, JNK1/2, p38, p-p38, c-JUN, and pc-JUN
NF-kB↓,
p65↓,
iNOS↓,
COX2↓,
uPA↓,
PI3K↓,
FAK↓,
MEK↓,
ERK↓,
JNK↓,
p38↓,
cJun↓,
FOXO3↑, Quercetin causes an increase in the level of FOXO1 protein both in a dose- and time-dependent way; however, it does not affect changes in expression of FOXO3a

5031- QC,    Different roles of Nrf2 and NFKB in the antioxidant imbalance produced by esculetin or quercetin on NB4 leukemia cells
- in-vitro, AML, APL NB4
NRF2↓, Quercetin increased the levels of Nrf2 in the cytosol reducing them in the nucleus
ROS↑, AI summary: Suppresses NRF2 activity, Leads to: ↓ antioxidant gene expression, ↑ ROS accumulation, Oxidative stress–driven apoptosis
Apoptosis↑,

5026- QC,    Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes
- in-vitro, GC, NA
SLC1A5↓, We demonstrated that Quer inhibits SLC1A5 expression
ROS↑, we found that Quer altered the intracellular ROS levels, antioxidant system protein expression levels, and iron content.
Iron↓, Quer increased the intracellular iron content by inhibiting SLC1A5
NRF2↓, Mechanistically, Quer binds to SLC1A5, inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in decreased xCT/GPX4 expression.
GPx4↓,
Ferroptosis↑, These three changes collectively led to ferroptosis in GC cells

4827- QC,  CUR,    Synthetic Pathways and the Therapeutic Potential of Quercetin and Curcumin
- Review, Var, NA
*AntiCan↑, their anti-cancer effects, but also with regard to their anti-diabetic, anti-obesity, anti-inflammatory, and anti-bacterial actions.
*Inflam↓,
*Bacteria↓,
*AntiDiabetic↑,
*ROS↓, suppression of ROS formation via the inhibition of the enzyme activities involved in their production, or via scavenging ROS directly by acting as hydrogen donors; the chelation of the metal ions that induce ROS production;
*SOD↑, quercetin can eliminate free radicals and help maintain a stable redox state in cells by increasing anti-oxidant enzymes, such as superoxide dismutase (SOD), and catalase expressions, as well as the level of reduced glutathione (GSH)
*Catalase↑,
*GSH↑,
*NRF2↑, Quercetin can protect human granulosa cells from oxidative stress by inducing Nrf2 expression at both the gene and protein levels, which in turn induces the anti-oxidant thioredoxin (Trx) system.
*Trx↑,
*IronCh↑, pure curcumin, a metal chelator, directly removes ROS and regulates numerous enzymes.
*MDA↑, It has the potential to reduce the concentration of malondialdehyde (MDA) in serum and increase the total anti-oxidant potential
cycD1/CCND1↓, Cyclin D1 expression was significantly decreased in quercetin-treated ovarian SKOV-3 cells, but not in cisplatin (CDDP)-resistant SKOV3/CDDP cells.
PI3K↓, The levels of PI3K and phospho-Akt were decreased in curcumin-treated SKOV3 cells, which in turn increased caspase-3 and Bax levels.
Casp3↑,
BAX↑,
ChemoSen↑, Curcumin enhanced the efficacy of chemotherapy in colorectal cancer cells.
ROS↑, suggesting that quercetin-induced cytotoxicity and autophagy were initiated by the generation of ROS
eff↑, quercetin or curcumin with chemotherapeutic agents, as shown below, considerably enhances the antitumor potencies of doxorubicin (DOX) and cisplatin.
MMP↓, The synergistic treatment with curcumin and quercetin inhibited the cell proliferation associated with the loss of mitochondrial membrane potential (ΔΨm), the release of cytochrome c, a decrease in AKT and ERK phosphorylation in MGC803 human gastric
Cyt‑c↑,
Akt↓,
ERK↓,

66- QC,    Emerging impact of quercetin in the treatment of prostate cancer
- Review, Pca, NA
CycB/CCNB1↓, quercetin has a role in the reduction of cyclin B1 and CDK1 levels,
CDK1↓,
EMT↓, quercetin suppresses epithelial to mesenchymal transition (EMT) and cell proliferation through modulation of Sonic Hedgehog signaling pathway
PI3K↓, Inhibitory effects of quercetin on other pathways such as PI3K, MAPK and WNT pathways have also been validated in cervical cancer
MAPK↓,
Wnt/(β-catenin)↓, wnt
PSA↓,
VEGF↓,
PARP↑,
Casp3↑,
Casp9↑,
DR5↑,
ROS⇅,
Shh↓,
P53↑, figure 1
P21↑, quercetin regulates p21 expression
EGFR↓,
TumCCA↑, quercetin has cell-specific anti-proliferative impacts via stimulation of cell cycle arrest at the G1 stage.
ROS↑, quercetin has been shown to suppress carcinogenesis through various mechanisms including affecting cell proliferation, production of reactive oxygen species and expression of miR-21
miR-21↓,
TumCP↓,
selectivity↑, In breast cancer cells, quercetin inhibits cell proliferation without exerting any cytotoxic impact on normal breast epithelium
PDGF↓, figure 1
EGF↓,
TNF-α↓,
VEGFR2↓,
mTOR↓,
cMyc↓,
MMPs↓,
GRP78/BiP↑,
CHOP↑,

68- QC,  BaP,    Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines
- in-vitro, Pca, 22Rv1 - in-vitro, Pca, PrEC
PrxI∅, Prx-I, Prx-II PrEC cells
PrxII∅, PrEC cells
*toxicity↓, lack of quercetin-mediated changes in Prx expression suggests that quercetin does not interfere with H2O2 levels, and thus may have no deleterious effect in normal prostate cells
ROS↓, <10uM Quercetin
ROS↑, BaP-mediated toxicity in both 22Rv1 and PrEC cells was confirmed by a significant increase in reactive oxygen species
ROS∅, Quercetin also antagonized the increase in ROS by BaP which suggests that BaP-mediated oxidative stress could be blocked with quercetin in 22Rv1 and PrEC cells. S
chemoP↑, Studies have shown that quercetin can be a potential chemopreventative agent in prostate cancer.
PrxII↑, A physiologically achievable concentration (5uM) of quercetin increased the expression of Prx II without affecting the Prx I levels in 22Rv1 cells
i-H2O2↓, Upregulation of Prx II may reduce the intracellular levels of H 2 O2 which in turn can interfere with growth signaling pathways suppressing cell proliferation.

35- QC,    Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product
- Study, NA, NA
ROS↑, Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product
GSH↓, depletion of GSH

36- QC,    Quercetin induces G2 phase arrest and apoptosis with the activation of p53 in an E6 expression-independent manner in HPV-positive human cervical cancer-derived cells
- in-vitro, Cerv, HeLa - in-vitro, Cerv, SiHa
P53↑,
P21↑,
BAX↑,
Casp3↑,
Casp7↑,
TumCCA↑, G2 phase arrest
ROS↑, high concentrations (>40 µM) is able to act as a prooxidant
TumCCA↑, Quercetin induces G2 phase arrest and apoptosis
Apoptosis↑,

39- QC,    A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells
- Analysis, NA, NA
ROS↑, production of ROS in both cancer, and cancer stem cells,
GSH↓, By directly reducing the intracellular pool of glutathione (GSH), QC can influence ROS metabolism
IL6↓, QC is its ability to inhibit inflammatory mediators including IFN-γ, IL-6, COX-2, IL-8, iNOS, TNF-α, and many other cancer inflammatory mechanisms
COX2↓,
IL8↓,
iNOS↓,
TNF-α↓,
MAPK↑, quercetin-3-methyl ether stopped the growth of cancer in the esophagus by blocking the Akt/mTOR/P70S6k and MAPK pathways, which are important for the growth of cancer
ERK↑,
SOD↑,
ATP↓,
Casp↑,
PI3K/Akt↓,
mTOR↓,
NOTCH1↓,
Bcl-2↓,
BAX↑,
IFN-γ↓,
TumCP↓, QC directly involves inducing apoptosis and/or the cell cycle arrest process, and also inhibits the propagation of rapidly proliferating cells
TumCCA↑,
Akt↓, quercetin-3-methyl ether stopped the growth of cancer in the esophagus by blocking the Akt/mTOR/P70S6k and MAPK pathways, which are important for the growth of cancer
P70S6K↓,
*Keap1↓,
*GPx↑, inhibiting its negative regulator, Keap1, resulting in Nrf-2 nuclear translocation [86]. This results in the production and activation of enzymes namely GPX, CAT, heme oxygenase 1 (HO-1), peroxiredoxin (PRX)
*Catalase↑,
*HO-1↑,
*NRF2↑,
NRF2↑, The effect of QC on nuclear translocation of Nrf-2 in a time-dependent manner, and increased expression level in HepG2, MgM (malignant mesothelioma) MSTO-211H, and H2452 cells at mRNA and protein quantity has been reported recently
eff↑, quercetin coupled with gold nanoparticles promoted apoptosis by inhibiting the EGFR/P13K/Akt-mediated pathway
HIF-1↓, Quercetin has been shown to suppress the Akt-mTOR pathway and hypoxia-induced factor 1 signaling pathway in gastric cancer cells, resulting in preventative autophagy

41- QC,    Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft
- vitro+vivo, AML, HL-60
Casp8↑, quercetin significantly induced caspase-8, caspase-9, and caspase-3 activation
Casp9↑,
Casp3↑,
ROS↑, through induction of intracellular oxidative stress
ERK↑, quercetin induced sustained activation of extracellular signal-regulated kinase (ERK)
cl‑PARP↑, , poly ADP-ribose polymerase (PARP) cleavage, and mitochondrial membrane depolarization in HL-60 AML cells.
MMP↓,
eff↓, Moreover, both N-acetylcysteine(NAC) and the superoxide dismutase mimetic, MnTBAP, reversed quercetin-induced intracellular reactive oxygen species production, ERK activation, and subsequent cell death

89- QC,  doxoR,    Quercetin reverses the doxorubicin resistance of prostate cancer cells by downregulating the expression of c-met
- in-vitro, Pca, PC3
PI3K/Akt↓, quercetin targeted c-met to inhibit the PI3K/AKT pathway in doxorubicin-resistant prostate cancer cells.
cMET↓, quercetin treatment significantly inhibited c-met expression in PC3/R cells
Casp3↑, combination treatment with quercetin to induce expression of cleaved caspase-3 and −9
Casp9↑,
MMP↓, combination treatment with quercetin and doxorubicin induced a significant decrease of MMP in PC3/R cells compared with cells treated with doxorubicin alone.
ChemoSen↑, Quercetin increased the sensitivity of PC3/R cells to doxorubicin
ROS↑, ROS, which are considered to be key apoptotic inducers (17) were released from the mitochondria into the cytoplasm, due to MMP collapse induced by co-treatment with quercetin and doxorubicin

90- QC,  HP,    Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA‑21
- in-vitro, Pca, PC3
ROS↑, QH decreased the production of reactive oxygen species (ROS) and increased antioxidant capacity in PC3 cells at various concentrations (2.5‑60 µg/ml) with peak inhibition and augmentation changes of 3.22‑ and 3.00‑fold, respectively.
cl‑Casp3↑, activated/cleaved caspase-3 levels were found to be elevated at low concentration of QH (5 and 10 μg/ml) by ~1.5-fold and at higher concentrations (20 and 40 μg/ml) by ~2.7-fold (Fig. 2E). Poly(adenosine diphosphate ribose)
cl‑PARP↑, analysis revealed an increase in PARP cleavage in PC3 cells following QH treatment
miR-21↓, dose-dependent decrease in miR-21 expression, with inhibition rates of 42, 56 and 77% observed at 5, 10 and 20 μg/ml QH, respectively
PDCD4↑,
TAC↑,
tumCV↓, QH inhibits PC3 cell viability.
TumCI↓, QH inhibits the invasive activity of PC3 cells.

88- QC,  PacT,    Quercetin Enhanced Paclitaxel Therapeutic Effects Towards PC-3 Prostate Cancer Through ER Stress Induction and ROS Production
- vitro+vivo, Pca, PC3
ROS↑, quercetin and paclitaxel significantly inhibited cell proliferation, increased apoptosis, arrested the cell cycle at the G2/M phase, inhibited cell migration, dramatically induced ER stress to occur, and increased ROS generation.
ER Stress↑,
TumCP↓,
Apoptosis↑,
TumCCA↑,
TumCMig↓,
GRP78/BiP↑, The combined group effectively decreased hnRNPA1 gene expressions and increased the GRP78 and CHOP gene expressions, which are related to ER stress and ROS production
CHOP↑,
TumCG↓, In vivo Tumor Growth Inhibition

893- QC,    Quercetin: Prooxidant Effect and Apoptosis in Cancer
- Analysis, Var, NA
ROS↑, proposal that the capacity of quercetin as a phytochemical that is able to trigger apoptosis in several tumor cell lineages might be related to its prooxidant features.

892- QC,    Antioxidant vs. pro-oxidant activities of quercetin in aqueous phase: A Density Functional Theory study
- Analysis, Var, NA
ROS↑, influenced by concentration, pH of environment and the presence of redox metal.

891- QC,    Chapter 9 - Quercetin: Prooxidant Effect and Apoptosis in Cancer
- in-vitro, Var, NA
ROS↑, substantial evidence that its prooxidant features are also relevant regarding its tumoricidal effects
AntiTum↑, promote tumoricidal effects.

890- QC,    PROOXIDANT ACTIVITIES OF ANTIOXIDANTS AND THEIR IMPACT ON HEALTH
- Review, Var, NA
ROS↑, in the presence of the transition metal

889- QC,    The multifaceted role of quercetin derived from its mitochondrial mechanism
- vitro+vivo, Var, NA
MMP↓,
ATP↝,
OXPHOS↝,
ROS↑, a prooxidant effect

921- QC,    Essential requirement of reduced glutathione (GSH) for the anti-oxidant effect of the flavonoid quercetin
- in-vitro, lymphoma, U937
ROS↑, long periods it showed a pro-oxidant activity
GSH↓, long periods

904- QC,    Antioxidant and prooxidant effects of quercetin on glyceraldehyde-3-phosphate dehydrogenase
- Analysis, NA, NA
ROS↑, Quercetin significantly increased oxidation of GAPDH observed in the presence of ferrous ions
H2O2↑,

905- QC,    Anti- and pro-oxidant effects of quercetin in copper-induced low density lipoprotein oxidation. Quercetin as an effective antioxidant against pro-oxidant effects of urate
- Analysis, NA, NA
ROS↑, pro-oxidant behavior depends on the Cu(2+) concentration

906- QC,    The interplay between reactive oxygen species and antioxidants in cancer progression and therapy: a narrative review
- Review, NA, NA
ROS↑, quercetin at higher concentrations (>50 µM) can initiate ROS generation especially O2•−

908- QC,    Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update
- Review, NA, NA
AntiCan↑, quercetin exerts anticancer effect by binding to cellular receptors and proteins
ROS↑, The short-term effect causes scavenging of free radicals and it is mostly antioxidative and antiapoptotic in nature, while the long term effect is pro-oxidative

910- QC,    The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism
tumCV↓,
Apoptosis↑,
PI3k/Akt/mTOR↓, QUE induces cell death by inhibiting PI3K/Akt/mTOR and STAT3 pathways in PEL cells
Wnt/(β-catenin)↓, reducing β-catenin
MAPK↝,
ERK↝, ERK1/2
TumCCA↑, cell cycle arrest at the G1 phase
H2O2↑,
ROS↑,
TumAuto↑,
MMPs↓, Consistently, QUE was able to reduce the protein levels of MMP-2, MMP-9, VEGF and mTOR, and p-Akt in breast cancer cell lines
P53↑,
Casp3↑,
Hif1a↓, by inactivating the Akt-mTOR pathway [64,74] and HIF-1α
cFLIP↓,
IL6↓, QUE decreased the release of interleukin-6 (IL-6) and IL-10
IL10↓,
lactateProd↓,
Glycolysis↓, It is suggested that QUE alters glucose metabolism by inhibiting monocarboxylate transporter (MCT) activity
PKM2↓,
GLUT1↓,
COX2↓,
VEGF↓,
OCR↓,
ECAR↓,
STAT3↓,
MMP2↓, Consistently, QUE was able to reduce the protein levels of MMP-2, MMP-9, VEGF and mTOR, and p-Akt in breast cancer cell lines
MMP9:TIMP1↓,
mTOR↓,

923- QC,    Quercetin as an innovative therapeutic tool for cancer chemoprevention: Molecular mechanisms and implications in human health
- Review, Var, NA
ROS↑, decided by the availability of intracellular reduced glutathione (GSH),
GSH↓, extended exposure with high concentration of quercetin causes a substantial decline in GSH levels
Ca+2↝,
MMP↓,
Casp3↑, activation of caspase-3, -8, and -9
Casp8↑,
Casp9↑,
other↓, when p53 is inhibited, cancer cells become vulnerable to quercetin-induced apoptosis
*ROS↓, Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors.
*NRF2↑, Moreover, the therapeutic efficacy of QC has also been defined in rat models through the activation of Nrf-2/HO-1 against high glucose-induced damage
HO-1↑,
TumCCA↑, QC increases cell cycle arrest via regulating p21WAF1, cyclin B, and p27KIP1
Inflam↓, QC-mediated anti-inflammatory and anti-apoptotic properties play a key role in cancer prevention by modulating the TLR-2 (toll-like receptor-2) and JAK-2/STAT-3 pathways and significantly inhibit STAT-3 tyrosine phosphorylation within inflammatory ce
STAT3↓,
DR5↑, several studies showed that QC upregulated the death receptor (DR)
P450↓, it hinders the activity of cytochrome P450 (CYP) enzymes in hepatocytes
MMPs↓, QC has also been shown to suppress metastatic protein expression such as MMPs (matrix metalloproteases)
IFN-γ↓, QC is its ability to inhibit inflammatory mediators including IFN-γ, IL-6, COX-2, IL-8, iNOS, TNF-α,
IL6↓,
COX2↓,
IL8↓,
iNOS↓,
TNF-α↓,
cl‑PARP↑, Induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, mitochondrial membrane depolarization,
Apoptosis↑, increased apoptosis and p53 expression
P53↑,
Sp1/3/4↓, HT-29 colon cancer cells: decreased the expression of Sp1, Sp3, Sp4 mrna, and survivin,
survivin↓,
TRAILR↑, H460 Increased the expression of TRAILR, caspase-10, DFF45, TNFR 1, FAS, and decreased the expression of NF-κb, ikkα
Casp10↑,
DFF45↑,
TNFR 1↑,
Fas↑,
NF-kB↓,
IKKα↓,
cycD1/CCND1↓, SKOV3 Reduction in cyclin D1 level
Bcl-2↓, MCF-7, HCC1937, SK-Br3, 4T1, MDA-MB-231 Decreased Bcl-2 expression, increasedBax expression, inhibition of PI3K-Akt pathway
BAX↑,
PI3K↓,
Akt↓,
E-cadherin↓, MDA-MB-231 Induced the expression of E-cadherin and downregulated vimentin levels, modulation of β-catenin target genes such as cyclin D1 and c-Myc
Vim↓,
β-catenin/ZEB1↓,
cMyc↓,
EMT↓, MCF-7 Suppressed the epithelial–mesenchymal transition process, upregulated E-cadherin expression, downregulated vimentin and MMP-2 expression, decreased Notch1 expression
MMP2↓,
NOTCH1↓,
MMP7↓, PANC-1, PATU-8988 Decreased the secretion of MMP and MMP7, blocked the STAT3 signaling pathway
angioG↓, PC-3, HUVECs Reduced angiogenesis, increased TSP-1 protein and mrna expression
TSP-1↑,
CSCs↓, PC-3 and LNCaP cells Activated capase-3/7 and inhibit the expression of Bcl-2, surviving and XIAP in CSCs.
XIAP↓,
Snail↓, inhibiting the expression of vimentin, slug, snail and nuclear β-catenin, and the activity of LEF-1/TCF responsive reporter
Slug↓,
LEF1↓,
P-gp↓, MCF-7 and MCF-7/dox cell lines Downregulation of P-gp expression
EGFR↓, MCF-7 and MDA-MB-231 cells Suppressed EGFR signaling and inhibited PI3K/Akt/mTOR/GSK-3β
GSK‐3β↓,
mTOR↓,
RAGE↓, IA Paca-2, BxPC3, AsPC-1, HPAC and PANC1 Silencing RAGE expression
HSP27↓, Breast cancer In vivo NOD/SCID mice Inhibited the overexpression of Hsp27
VEGF↓, QC significantly reversed an elevation in profibrotic markers (VEGF, IL-6, TGF, COL-1, and COL-3)
TGF-β↓,
COL1↓,
COL3A1↓,

922- QC,    Quercetin and ovarian cancer: An evaluation based on a systematic review
- Review, NA, NA
ROS↑, presence of peroxidases, Q reacts with H2O2 to form a Q-quinone (QQ) that has a pro-oxidant effect

920- QC,    Interfering with ROS Metabolism in Cancer Cells: The Potential Role of Quercetin
- Review, NA, NA
GSH↓, Qu depletes GSH in a concentration-dependent manner;
ROS↑, Because normal, non-transformed cells have a lower basal intracellular ROS level, and have a full antioxidant capacity, they should be less vulnerable to the ROS stress that is induced by Qu. ****

919- QC,    Quercetin Regulates Sestrin 2-AMPK-mTOR Signaling Pathway and Induces Apoptosis via Increased Intracellular ROS in HCT116 Colon Cancer Cells
- in-vitro, CRC, HCT116
Apoptosis↑,
ROS↑,
SESN2↑,
P53↑,
AMPKα↑,
mTOR↓,

918- QC,  CUR,  VitC,    Anti- and pro-oxidant effects of oxidized quercetin, curcumin or curcumin-related compounds with thiols or ascorbate as measured by the induction period method
- Analysis, NA, NA
ROS↑, CUR enhances the prooxidant activity of ascorbate(vit C)
ROS↑, Under anaerobic conditions, QUE, with a catechol ring, may be more prooxidant than CUR, with a phenol ring.

915- QC,    Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management
- Review, NA, NA
ROS↑, Pro-oxidant effects are present at cellular concentrations of 40–100uM

914- QC,    Quercetin and Cancer Chemoprevention
- Review, NA, NA
GSH↓, high Qu concentration, causes a reduction in GSH content
ROS↑, in tumor cells
TumCCA↑, Depending on the cell type and tumor origin, Qu is able to block the cell cycle at G2/M or at the G1/S transition
Ca+2↑, Qu treatment increases cytosolic Ca2+ levels
MMP↓,
Casp3↑,
Casp8↑,
Casp9↑,
β-catenin/ZEB1↓,
AMPKα↑,
ASK1↑,
p38↑,
TRAIL↑, Qu is a potent enhancer of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, through the induction of the expression of death receptor (DR)-5, a phenomenon that specifically occurs in prostate cancer cells
DR5↑,
cFLIP↓,
Apoptosis↑, tumor cell lines are prone to cell-cycle arrest and apoptosis at Qu concentrations that have no or little effect on non-transformed cells ****

902- QC,    Prooxidant activities of quercetin, p-courmaric acid and their derivatives analysed by quantitative structure–activity relationship
- Analysis, NA, NA
ROS↑, metal ion and concentration of tested phenolics are widely suggested to affect the prooxidant activity of phenolics

896- QC,    Antioxidant and pro-oxidant actions of the plant phenolics quercetin, gossypol and myricetin: Effects on lipid peroxidation, hydroxyl radical generation and bleomycin-dependent damage to DNA
- in-vivo, Var, NA
ROS↑, Hence these naturally-occurring substances can have pro-oxidant effects under some reaction conditions and cannot be classified simplistically as “antioxidants”.

898- QC,    Anti- and pro-oxidant activity of rutin and quercetin derivatives
- Analysis, Var, NA
ROS↑, quercetin derivatives with free catechol moiety or free hydroxyl in position 3 (or both) were pro-oxidant

899- QC,    Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites
- in-vivo, Var, NA
ROS↑, effects of quercetin on cells seem to be dependent both on cell type and in particular on the concentration of quercetin
GSH↓,

900- QC,    Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice
- in-vivo, Nor, NA
*Weight↓, overall weight
*TAC∅, no significant decrease
*ROS↑, working hypothesis is that quercetin interferes with mitochondrial function exacerbating mitochondrial ROS generation and altering the physiology of tissues highly dependent on iron metabolism

901- QC,    Antioxidant/prooxidant effects of α-tocopherol, quercetin and isorhamnetin on linoleic acid peroxidation induced by Cu(II) and H2O2
- Analysis, Var, NA
ROS↑, presence/ absence of metal ions modulates the biological or pharmacological behavior of flavonoids to act as an antioxidant or prooxidant

1201- QC,    Quercetin: a silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1
- in-vivo, BC, NA
mitResp↓, significant reduction in the intracellular mitochondrial respiration
Glycolysis↓,
ATP↓,
ROS↑,
GSH↓,
TumMeta↓,
Apoptosis↑,
FAO↓,

2343- QC,    Pharmacological Activity of Quercetin: An Updated Review
- Review, Nor, NA
*ROS↓, Quercetin is a potent scavenger for ROS and hence protects the body against oxidative stress
*GSH↑, Studies of animals and cells have shown that the synthesis of GSH is induced by quercetin.
*Catalase↑, increased expression of superoxide dismutase (SOD), catalase (CAT), and GSH has been reported with the pretreatment of quercetin
*SOD↑,
*MDA↓, quercetin supplementation to layer chickens significantly reduced malondialdehyde (MDA) levels in the kidneys, liver, and heart and increased GSH, CAT, and glutathione peroxidase (GSH-Px) activities in the liver, kidney, and heart tissue
*GPx↑,
*Copper↓, In addition, quercetin can exert antioxidant effects by chelating Cu2+ and Fe2+ in its structure with catechol
*Iron↓,
Apoptosis↓, Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest [43].
TumCCA↑,
MMP2↓, In HSC-6, SCC-9 human oral cancer cell lines, quercetin inhibits cell viability, migration, and invasion, reduces MMP-2 and MMP-9 abundance, downgrades miR-16, and upgrades HOXA10
MMP9↓,
GlucoseCon↓, quercetin inhibits the mobility of cancer cells by inhibiting glucose uptake and lactic acid production and reducing levels of PKM2, GLUT1, and LDHA, which may have a significant role in controlling breast cancer [56].
lactateProd↓,
PKM2↓,
GLUT1↓,
LDHA↓,
ROS↑, Quercetin encapsulated in solid lipid nanoparticles ,MCF-7 and MCF-10A cells, Increase (ROS)

4668- RES,    Resveratrol Impedes the Stemness, Epithelial-Mesenchymal Transition, and Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma through p53 Activation
- in-vitro, NPC, NA
ROS↑, we found that resveratrol turned off the metabolic switch, increased the reactive oxygen species (ROS) level, and depolarized mitochondrial membranes.
MMP↓,
CSCs↓, We found that resveratrol impeded CSC properties through the activation of p53
P53↑,
EMT↓, Furthermore, resveratrol suppressed the stemness and EMT through reactivating p53 and inducing miR-145 and miR-200c, which were downregulated in NPC CSCs.

4666- RES,    Structural modification of resveratrol analogue exhibits anticancer activity against lung cancer stem cells via suppression of Akt signaling pathway
- in-vitro, Lung, H23 - in-vitro, Lung, H292 - in-vitro, Lung, A549
CSCs↓, we discovered the CSC-targeting activity of resveratrol (RES) analog moscatilin (MOS)
eff↑, Compared with RES, its analog MOS more effectively inhibited cell viability, colony formation, and induced apoptosis in all lung cancer cell lines (H23, H292, and A549).
Akt↓, MOS exerted its anti-CSC effects by inhibiting Akt and consequently restored the activation of glycogen synthase kinase 3β (GSK-3β) and decreased the pluripotent transcription factors (Sox2 and c-Myc).
GSK‐3β↑,
SOX2↓,
cMyc↓,
TumCCA↑, improved activation of various mechanism, such as cell cycle arrest at G2/M phase, production of ROS-mediated apoptosis, and inhibition of Akt activation.
ROS↑,
Apoptosis↑,

103- RES,  CUR,  QC,    The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice
- vitro+vivo, BC, 4T1
ROS↑, RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members
MMP↓,
Bcl-2↓,
BAX↑,
Casp9↑,
T-Cell↑, (CD4+CD8+)
TGF-β↓,

882- RES,    Resveratrol: A Double-Edged Sword in Health Benefits
- Review, NA, NA
AntiTum↑,
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
Bcl-xL↓,
P53↑,
NAF1↓,
NRF2↑,
ROS↑,
Apoptosis↑,
HDAC↓, Resveratrol is also an Histone deacetylase inhibitors
TumCCA↑,
TumAuto↑,
angioG↓,
iNOS↓, inhibit iNOS expression in colon cancer cells

924- RES,    Resveratrol sequentially induces replication and oxidative stresses to drive p53-CXCR2 mediated cellular senescence in cancer cells
- in-vitro, OS, U2OS - in-vitro, Lung, A549
TumCCA↑, S-phase arrest, which is commonly observed in cells treated with RSV
ROS↑,
γH2AX↑, remarkable increase in the amount of γ-H2AX, a marker for DNA double-strand breaks
ATM↑, a master regulator of DNA damage response, was activated by RSV
p‑CHK1↑,
cellSen↑,
CXCR2↑, peaks at day 5 then drops

871- RES,  CUR,  QC,    The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice
- in-vitro, BC, 4T1 - in-vivo, BC, 4T1
T-Cell↑, in tumor microenviroment
Neut↓,
Macrophages↓,
ROS↑, RCQ significantly increased reactive oxygen species
MMP↓, in cancer cells
other↓, alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect.
AntiTum↑, at least nearly 5 times higher than that of a single Res/Cur/Que  = 1:1:0.5
TumVol↓, 35-47% tumor inhibition rate

883- RES,    Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy
HDAC↓, Res is a naturally occurring HDACi
TumCCA↑, HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells.
Apoptosis↑,
angioG↓,
ROS↑,

2332- RES,    Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism
- Review, Var, NA
Glycolysis↓, Resveratrol reduces glucose uptake and glycolysis by affecting Glut1, PFK1, HIF-1α, ROS, PDH, and the CamKKB/AMPK pathway.
GLUT1↓, resveratrol reduces glycolytic flux and Glut1 expression by targeting ROS-mediated HIF-1α activation in Lewis lung carcinoma tumor-bearing mice
PFK1↓,
Hif1a↓, Resveratrol specifically suppresses the nuclear β-catenin protein by inhibiting HIF-1α
ROS↑, Resveratrol increases ROS production
PDH↑, leading to increased PDH activity, inhibiting HK and PFK, and downregulating PKM2 activity
AMPK↑, esveratrol elevated NAD+/NADH, subsequently activated Sirt1, and in turn activated the AMP-activated kinase (AMPK),
TumCG↓, inhibits cell growth, invasion, and proliferation by targeting NF-kB, Sirt1, Sirt3, LDH, PI-3K, mTOR, PKM2, R5P, G6PD, TKT, talin, and PGAM.
TumCI↓,
TumCP↓,
p‑NF-kB↓, suppressing NF-κB phosphorylation
SIRT1↑, Resveratrol activates the target subcellular histone deacetylase Sirt1 in various human tissues, including tumors
SIRT3↑,
LDH↓, decreases glycolytic enzymes (pyruvate kinase and LDH) in Caco2 and HCT-116 cells
PI3K↓, Resveratrol also targets “classical” tumor-promoting pathways, such as PI3K/Akt, STAT3/5, and MAPK, which support glycolysis
mTOR↓, AMPK activation further inhibits the mTOR pathway
PKM2↓, inhibiting HK and PFK, and downregulating PKM2 activity
R5P↝,
G6PD↓, G6PDH knockdown significantly reduced cell proliferation
TKT↝,
talin↓, induces apoptosis by targeting the pentose phosphate and talin-FAK signaling pathways
HK2↓, Resveratrol downregulates glucose metabolism, mainly by inhibiting HK2;
GRP78/BiP↑, resveratrol stimulates GRP-78, and decreases glucose uptake,
GlucoseCon↓,
ER Stress↑, resveratrol-induced ER-stress leads to apoptosis of CRC cells
Warburg↓, Resveratrol reverses the Warburg effect
PFK↓, leading to increased PDH activity, inhibiting HK and PFK, and downregulating PKM2 activity

2650- RES,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
ROS↑, Several molecular mechanisms have been proposed for the anticancer activity of resveratrol, including ROS induction
Dose↝, ROS, the effect of resveratrol appears to be concentration dependent; at low concentrations, it exerts antioxidant effects, whereas at high concentrations (50–100 µM), resveratrol induces ROS production
NRF2↑, Cheng et al. [27] reported that resveratrol-induced ROS activate the Nrf2 signaling pathway, which subsequently suppresses NAF1 and induces apoptosis in pancreatic cancer cells.
NAF1↓,
ChemoSen↑, This also increased their sensitivity to gemcitabine.
BioAv↓, Despite the promising potential of resveratrol, its unstable pharmacokinetics due to its high metabolism and poor bioavailability limit its clinical application.

2687- RES,    Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs
- Review, NA, NA - Review, AD, NA
NF-kB↓, RES affects NF-kappaB activity and inhibits cytochrome P450 isoenzyme (CYP A1) drug metabolism and cyclooxygenase activity.
P450↓,
COX2↓,
Hif1a↓, RES may inhibit also the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) and thus may have anti-cancer properties
VEGF↓,
*SIRT1↑, RES induces sirtuins, a class of proteins involved in regulation of gene expression. RES is also considered to be a SIRT1-activating compound (STACs).
SIRT1↓, In contrast, decreased levels of SIRT1 and SIRT2 were observed after treatment of BJ cells with concentrations of RES
SIRT2↓,
ChemoSen⇅, However, the effects of RES remain controversial as it has been reported to increase as well as decrease the effects of chemotherapy.
cardioP↑, RES has been shown to protect against doxorubicin-induced cardiotoxicity via restoration of SIRT1
*memory↑, RES has been shown to inhibit memory loss and mood dysfunction which can occur during aging.
*angioG↑, RES supplementation resulted in improved learning in the rats. This has been associated with increased angiogenesis and decreased astrocytic hypertrophy and decreased microglial activation in the hippocampus.
*neuroP↑, RES may have neuroprotective roles in AD and may improve memory function in dementia.
STAT3↓, RES was determined to inhibit STAT3, induce apoptosis, suppress the stemness gene signature and induced differentiation.
CSCs↓,
RadioS↑, synergistically increased radiosensitivity. RES treatment suppressed repair of radiation-induced DNA damage
Nestin↓, RES decreased NESTIN
Nanog↓, RES was determined to suppress the expression of NANOG
TP53↑, RES treatment activated TP53 and p21Cip1.
P21↑,
CXCR4↓, RES downregulated nuclear localization and activity of NF-kappa-B which resulted in decreased expression of MMP9 and C-X-C chemokine receptor type 4 (CXCR4), two proteins associated with metastasis.
*BioAv↓, The pharmacological properties of RES can be enhanced by nanoencapsulation. Normally the solubility and stability of RES is poor.
EMT↓, RES was determined to suppress many gene products associated with EMT such as decreased vimentin and SLUG expression but increased E-cadherin expression.
Vim↓,
Slug↓,
E-cadherin↑,
AMPK↑, RES can induce AMPK which results in inhibition of the drug transporter MDR1 in oxaliplatin-resistant (L-OHP) HCT116/L-OHP CRCs.
MDR1↓,
DNAdam↑, RES induced double strand DNA breaks by interfering with type II topoisomerase.
TOP2↓, The DNA damage was determined to be due to type II topoisomerase poisoning.
PTEN↑, RES was determined to upregulate phosphatase and tensin homolog (PTEN) expression and decrease the expression of activated Akt.
Akt↓,
Wnt↓, RES was shown to decrease WNT/beta-catenin pathway activity and the downstream targets c-Myc and MMP-7 in CRC cells.
β-catenin/ZEB1↓,
cMyc↓,
MMP7↓,
MALAT1↓, RES also decreased the expression of long non-coding metastasis associated lung adenocarcinoma transcript 1 (RNA-MALAT1) in the LoVo and HCT116 CRC cells.
TCF↓, Treatment of CRC cells with RES resulted in decreased expression of transcription factor 4 (TCF4), which is a critical effector molecule of the WNT/beta-catenin pathway.
ALDH↓, RES was determined to downregulate ALDH1 and CD44 in HNC-TICs in a dose-dependent fashion.
CD44↓,
Shh↓, RES has been determined to decrease IL-6-induced Sonic hedgehog homolog (SHH) signaling in AML.
IL6↓, RES has been shown to inhibit the secretion of IL-6 and VEGF from A549 lung cancer cells
VEGF↓,
eff↑, Combined RES and MET treatment resulted in a synergistic response in terms of decreased TP53, gammaH2AX and P-Chk2 expression. Thus, the combination of RES and MET might suppress some of the aging effects elicited by UVC-induced DNA damage
HK2↓, RES treatment resulted in a decrease in HK2 and increased mitochondrial-induced apoptosis.
ROS↑, RES was determined to shut off the metabolic shift and increase ROS levels and depolarized mitochondrial membranes.
MMP↓,

2441- RES,    Anti-Cancer Properties of Resveratrol: A Focus on Its Impact on Mitochondrial Functions
- Review, Var, NA
*toxicity↓, Although resveratrol at high doses up to 5 g has been reported to be non-toxic [34], in some clinical trials, resveratrol at daily doses of 2.5–5 g induced mild-to-moderate gastrointestinal symptoms [
*BioAv↝, After an oral dose of 25 mg in healthy human subjects, the concentrations of native resveratrol (40 nM) and total resveratrol (about 2 µM) in plasma suggested significantly greater bioavailability of resveratrol metabolites than native resveratrol
*Dose↝, The total plasma concentration of resveratrol did not exceed 10 µM following high oral doses of 2–5 g
*hepatoP↑, hepatoprotective effects
*neuroP↑, neuroprotective properties
*AntiAg↑, Resveratrol possesses the ability to impede platelet aggregation
*COX2↓, suppresses promotion by inhibiting cyclooxygenase-2 activity
*antiOx↑, It is widely recognized that resveratrol has antioxidant properties at concentrations ranging from 5 to 10 μM.
*ROS↓, antioxidant properties at concentrations ranging from 5 to 10 μM.
*ROS↑, pro-oxidant properties when present in doses ranging from 10 to 40 μM
PI3K↓, It is known that resveratrol suppresses PI3-kinase, AKT, and NF-κB signaling pathways [75] and may affect tumor growth via other mechanisms as well
Akt↓,
NF-kB↓,
Wnt↓, esveratrol inhibited breast cancer stem-like cells in vitro and in vivo by suppressing Wnt/β-catenin signaling pathway
β-catenin/ZEB1↓,
NRF2↑, Resveratrol activated the Nrf2 signaling pathway, causing separation of the Nrf2–Keap1 complex [84], leading to enhanced transcription of antioxidant enzymes, such as glutathione peroxidase-2 [85] and heme-oxygenase (HO-1)
GPx↑,
HO-1↑,
BioEnh?, Resveratrol was demonstrated to have an impact on drug bioavailability,
PTEN↑, Resveratrol could suppress leukemia cell proliferation and induce apoptosis due to increased expression of PTEN
ChemoSen↑, Resveratrol enhances the sensitivity of cancer cells to chemotherapeutic agents through various mechanisms, such as promoting drug absorption by tumor cells
eff↑, it can also be used in nanomedicines in combination with various compounds or drugs, such as curcumin [101], quercetin [102], paclitaxel [103], docetaxel [104], 5-fluorouracil [105], and small interfering ribonucleic acids (siRNAs)
mt-ROS↑, enhancing the oxidative stress within the mitochondria of these cells, leading to cell damage and death.
Warburg↓, Resveratrol Counteracts Warburg Effect
Glycolysis↓, demonstrated in several studies that resveratrol inhibits glycolysis through the PI3K/Akt/mTOR signaling pathway in human cancer cells
GlucoseCon↓, resveratrol reduced glucose uptake by cancer cells due to targeting carrier Glut1
GLUT1↓,
lactateProd↓, therefore, less lactate was produced
HK2↓, Resveratrol (100 µM for 48–72 h) had a negative impact on hexokinase II (HK2)-mediated glycolysis
EGFR↓, activation of EGFR and downstream kinases Akt and ERK1/2 was observed to diminish upon exposure to resveratrol
cMyc↓, resveratrol suppressed the expression of leptin and c-Myc while increasing the level of vascular endothelial growth factor.
ROS↝, it acts as an antioxidant in regular conditions but as a strong pro-oxidant in cancer cells,
MMPs↓, Main targets of resveratrol in tumor cells. COX-2—cyclooxygenase-2, SIRT-1—sirtuin 1, MMPs—matrix metalloproteinases,
MMP7↓, Resveratrol was shown to exert an inhibitory effect on the expression of β-catenins and also target genes c-Myc, MMP-7, and survivin in multiple myeloma cells, thus reducing the proliferation, migration, and invasion of cancer cells
survivin↓,
TumCP↓,
TumCMig↓,
TumCI↓,

3078- RES,    The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment
- Review, Pca, NA
*ROS↓, RSV appears to be both pro- and anti-oxidant, depending on the circumstances [76]. In non-cancer tissues, RSV serves as an antioxidant [77], and therefore RSV can exert a beneficial effect on a wide variety of issues, including neuronal [78], anti-in
ROS↑, However, to cancer cells with low pH environments due to the Warburg Effect, RSV shows more pro-oxidant characteristics.
DNAdam↑, RSV can induce cancer cell death by inducing ROS accumulation, which subsequently leads to oxidative DNA damage and apoptosis
Apoptosis↑,
Hif1a↑, Wang et al. demonstrated that RSV-enhanced cancer cell death is due to the upregulation of HIF1α, which enhances ROS concentration in the TME beyond the limit for survival
Casp3↑, superoxide can activate caspases 9 and 3, and subsequently promote the release of cytochrome C
Casp9↑,
Cyt‑c↑,
Dose↝, It is important to note that low concentration of RSV can serve as a pro-oxidant that favors cell survival, and pro-apoptotic effects occur only at relatively higher RSV concentrations to stimulate superoxide production.
MMPs↓, inhibitory effect of RSV on MMPs has been shown in many cancer types, and RSV is capable of inhibiting both MMP-2 and MMP-9
MMP2↓,
MMP9↓,
EMT↓, RSV can restore the epithelial phenotype of the mesenchymal cells and inhibit the expression of EMT-related markers
E-cadherin↑, RSV can inhibit EMT by up- and downregulating E-cadherin and N-cadherin, respectively, in prostate cancer cells.
N-cadherin↓,
AR↓, RSV can repress AR function by inhibiting AR transcriptional activity

3076- RES,    Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells
- Review, Var, NA
IL6↓, A dose-dependent reduction of IL-6 by resveratrol led to attenuation of matrix metalloproteinases (MMPs), including MMP2 and MMP9
MMPs↓,
MMP2↓,
MMP9↓,
BioAv↓, The most important weakness of the usual form of resveratrol is its low absorption in the intestine and its low bioavailability
Half-Life↑, some covers such as liposomes and micelles also can facilitate absorption and increase half-life
BioAv↑, another study showed that carboxymethyl chitosan can increase bioavailability by more than 3.5 times
Dose↝, low concentrations of resveratrol (lower than 50 uM) cause no remarkable toxicity for normal cells, while higher concentrations are associated with increased oxidative injury
angioG↓, It is suggested that inhibition of STAT3, IL-10, and a reduction of vascular endothelial growth factor (VEGF) by resveratrol is involved in the suppression of macrophages and reduction of invasion and angiogenesis
IL10↓,
VEGF↓,
NF-kB↓, Inhibition of NF-kB by resveratrol can attenuate the expression of COX-2.
COX2↓,
SIRT1↑, Activation of Sirt-1 by resveratrol has a role in the suppression of NF-kB
Wnt↓, Resveratrol has also been shown that inhibit the Wnt/C-Myc pathway too
cMyc↓,
STAT3↓, Resveratrol has been shown that attenuate the expression of STAT3 through reduction of IL-6 level
PTEN↑, Downregulation of miR-17, miR-20a and miR-106b by resveratrol can activate PTEN, which leads to suppression of PI3K and induction of apoptosis in cancer cells
ROS↑, Resveratrol can trigger NOX5-induced ROS, leading to the induction of DNA damage and cancer cells senescence
RadioS↑, The combination of radiation and resveratrol has shown that has a synergic effect for stimulation of ROS production and induction of senescence in non-small cell lung carci- noma
Hif1a↓, Resveratrol can inhibit HIF-1α and its downstream proteins, including E-cadherin and vimentin
E-cadherin↓,
Vim↓,
angioG↓, Furthermore, resveratrol inhibits angiogenesis markers and tumor growth through the inhibition of HIF-1a

3092- RES,    Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action
- Review, BC, MDA-MB-231 - Review, BC, MCF-7
TumCP↓, The anticancer mechanisms of RES in regard to breast cancer include the inhibition of cell proliferation, and reduction of cell viability, invasion, and metastasis.
tumCV↓,
TumCI↓,
TumMeta↓,
*antiOx↑, antioxidative, cardioprotective, estrogenic, antiestrogenic, anti-inflammatory, and antitumor properties it has been used against several diseases, including diabetes, neurodegenerative diseases, coronary diseases, pulmonary diseases, arthritis, and
*cardioP↑,
*Inflam↓,
*neuroP↑,
*Keap1↓, RES administration resulted in a downregulation of Keap1 expression, therefore, inducing Nrf2 signaling, and leading to a decrease in oxidative damage
*NRF2↑,
*ROS↓,
p62↓, decrease the severity of rheumatoid arthritis by inducing autophagy via p62 downregulation, decreasing the levels of interleukin-1β (IL-1β) and C-reactive protein as well as mitigating angiopoietin-1 and vascular endothelial growth factor (VEGF) path
IL1β↓,
CRP↓,
VEGF↓,
Bcl-2↓, RES downregulates the levels of Bcl-2, MMP-2, and MMP-9, and induces the phosphorylation of extracellular-signal-regulated kinase (ERK)/p-38 and FOXO4
MMP2↓,
MMP9↓,
FOXO4↓,
POLD1↓, The in vivo experiment involving a xenograft model confirmed the ability of RES to reduce tumor growth via POLD1 downregulation
CK2↓, RES reduces the expression of casein kinase 2 (CK2) and diminishes the viability of MCF-7 cells.
MMP↓, Furthermore, RES impairs mitochondrial membrane potential, enhances ROS generation, and induces apoptosis, impairing BC progression
ROS↑,
Apoptosis↑,
TumCCA↑, RES has the capability of triggering cell cycle arrest at S phase and reducing the number of 4T1 BC cells in G0/G1 phase
Beclin-1↓, RES administration promotes cytotoxicity of DOX against BC cells by downregulating Beclin-1 and subsequently inhibiting autophagy
Ki-67↓, Reducing the Ki-67
ATP↓, RES’s administration is responsible for decreasing ATP production and glucose metabolism in MCF-7 cells.
GlutMet↓,
PFK↓, RES decreased PFK activity, preventing glycolysis and glucose metabolism in BC cells and decreasing cellular growth rate
TGF-β↓, RES (12.5–100 µM) inhibited TGF-β signaling and reduced the expression levels of its downstream targets that include Smad2 and Smad3 and as a result impaired the progression of BC cells.
SMAD2↓,
SMAD3↓,
Vim?, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Snail↓,
Slug↓,
E-cadherin↑,
EMT↓,
Zeb1↓, a significant decrease in the levels of vimentin, Snail1 and Slug occurred, while E-cadherin levels increased to suppress EMT and metastasis of BC cells.
Fibronectin↓,
IGF-1↓, RES administration (10 and 20 µM) impaired the migration and invasion of BC cells via inhibiting PI3K/Akt and therefore decreasing IGF-1 expression and preventing the upregulation of MMP-2
PI3K↓,
Akt↓,
HO-1↑, The activation of heme oxygenase-1 (HO-1) signaling by RES reduced MMP-9 expression and prevented metastasis of BC cells
eff↑, RES-loaded gold nanoparticles were found to enhance RES’s ability to reduce MMP-9 expression as compared to RES alone
PD-1↓, RES inhibited PD-1 expression to promote CD8+ T cell activity and enhance Th1 immune responses.
CD8+↑,
Th1 response↑,
CSCs↓, RES has the ability to target CSCs in various tumors
RadioS↑, RES in reversing drug resistance and radio resistance.
SIRT1↑, RES administration (12.5–200 µmol/L) promotes sensitivity of BC cells to DOX by increasing Sirtuin 1 (SIRT1) expression
Hif1a↓, downregulating HIF-1α expression, an important factor in enhancing radiosensitivity
mTOR↓, mTOR suppression

3093- RES,    Pro-Oxidant Effect of Resveratrol on Human Breast Cancer MCF-7 Cells is Associated with CK2 Inhibition
- in-vitro, BC, MCF-7
ROS↑, pro-oxidant cytotoxic effects of resveratrol in association with the inhibition of CK2 activity on human breast carcinoma cells MCF-7
CK2↓,

3096- RES,    Identification of potential target genes of non-small cell lung cancer in response to resveratrol treatment by bioinformatics analysis
- in-vitro, Lung, A549 - in-vitro, Lung, H1299
TumCP↓, resveratrol might inhibit proliferation but induce apoptosis and autophagy via inhibiting Akt/mTOR pathway and activating p38-MAPK pathway in A549 and H1299 NSCLC cells [7]
Apoptosis↑,
Akt↓,
mTOR↓,
p38↑,
MAPK↑,
STAT3↓, inhibiting the messenger RNA (mRNA) and protein expression of signal transducer and activator of transcription 3 (STAT3) in A549 cells
ROS↑, by leading to mitochondrial dysfunction and increasing of reactive oxygen species (ROS)
SIRT1↑, suggested that resveratrol inhibited age-dependent spontaneous tumorigenesis by increasing the expression of SIRT1 and activating its downstream targets
SOX2↓, resveratrol treatment promoted EGFR and inhibited SOX2.

3071- RES,    Resveratrol and Its Anticancer Effects
- Review, Var, NA
chemoPv↑, In this review, the effects of resveratrol are emphasized on chemopreventive, therapeutic, and anticancer.
SIRT1↑, RSV can directly activate Sirt1 expression and induce autophagy independently or dependently on the mammalian target of rapamycin (mTOR)
Hif1a↓, RSV suppresses tumor angiogenesis by inhibiting HIF-1a and VEGF protein
VEGF↓,
STAT3↓, RSV effectively prevents cancer by inhibiting STAT3 expression
NF-kB↓, also has an inhibitory effect on antiapoptotic mediators such as NF-kB, COX-2, phosphatidylinositol 3-kinase (PI3K), and mTOR (52).
COX2↓,
PI3K↓,
mTOR↓,
NRF2↑, Activation of the Nrf2/antioxidant response element (ARE) pathway by endogenous or exogenous stimuli under normal physiological conditions has the potential to inhibit cancer and/or cancer cell survival, growth, and proliferation
NLRP3↓, RSV downregulates the NLRP3 gene by activating the Sirt1 protein, thereby inducing autophagy
H2O2↑, RSV mediates cytotoxicity in cancer cells by increasing intracellular hydrogen peroxide (H2O2) and oxidative stress levels that will cause cell death
ROS↑,
P53↑, RSV activates p53, increases the expression of PUMA and BAX
PUMA↑,
BAX↑,

3052- RES,    Resveratrol-Induced Downregulation of NAF-1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways
- in-vitro, PC, PANC1 - in-vitro, PC, MIA PaCa-2 - in-vitro, PC, Bxpc-3
NAF1↓, resveratrol suppresses the expression of NAF-1 in pancreatic cancer cells by inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling.
ROS↑,
NRF2↑,
eff↑, may enhance the efficacy of gemcitabine in pancreatic cancer therapy.
TumCG↓, Resveratrol decreased the growth of the cancer cells in a dose- and time-dependent manner.

3054- RES,    Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line
- in-vitro, Melanoma, A375
TumCG↓, Treating A375SM cells with resveratrol resulted in a decrease in cell growth.
P21↑, resveratrol was observed to increase the gene expression levels of p21 and p27, as well as decrease the gene expression of cyclin B.
p27↑,
CycB/CCNB1↓,
ROS↑, generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress were confirmed at the cellular and protein levels
ER Stress↑,
p‑p38↑, Resveratrol induced the ROS-p38-p53 pathway by increasing the gene expression of phosphorylated p38 mitogen-activated protein kinase
P53↑, while it induced the p53 and ER stress pathway by increasing the gene expression levels of phosphorylated eukaryotic initiation factor 2α and C/EBP homologous protein.
p‑eIF2α↑,
EP4↑,
CHOP↑,
Bcl-2↓, downregulating B-cell lymphoma-2 (Bcl-2) expression and upregulating Bcl-2-associated X protein expression
BAX↓,
TumCCA↑, Resveratrol induced cell cycle arrest of melanoma cell line
NRF2↓, the decrease in Nrf2 expression caused by resveratrol may prevent the development of such resistance and thereby increase the sensitivity of melanoma cells to chemotherapy.
ChemoSen↑,
GSH↓, (GSH/GSSG) ratio was not measured, it can easily be assumed that the increased ROS generation by resveratrol reduced the GSH/GSSG ratio compared with the control

3055- RES,    Resveratrol and Tumor Microenvironment: Mechanistic Basis and Therapeutic Targets
- Review, Var, NA
BioAv↓, Resveratrol is poorly bioavailable, and that considered the major hindrance to exert its therapeutic effect, especially for cancer management
BioAv↓, at lower doses (25 mg per healthy subject) demonstrate that the mean proportion of free resveratrol in plasma was 1.7–1.9% with a mean plasma concentration of free resveratrol around 20 nM
Dose↑, Boocock and his colleagues studied the pharmacokinetic of resveratrol; in vitro data showed that minimum of 5 µmol/L resveratrol is essential for the chemopreventive effects to be elicited
eff↑, Despite the low bioavailability of resveratrol, it shows efficacy in vivo. This may be due to the conversion of both glucuronides and sulfate back to resveratrol in target organs such as the liver
eff↑, repeated administration of high doses of resveratrol generates a higher plasma concentration of parent and a much higher concentration of sulfate and glucuronide conjugates in the plasma
Dose↑, The doses tested in this study were 0.5, 1.0, 2.5 or 5.0 g daily for 29 days. No toxicity was detected, but moderate gastrointestinal symptoms were reported for 2.5 and 5.0 g doses
BioAv↑, the co-administration of piperine with resveratrol was used to enhance resveratrol bioavailability
ROS↑, Recent studies have shown that resveratrol increases ROS generation and decreases mitochondrial membrane potential
MMP↓,
P21↑, treatment decreased the viability of melanoma cells by activating the expression of both p21 and p27, which promoted cell cycle arrest.
p27↑,
TumCCA↑,
ChemoSen↑, Additionally, the use of resveratrol with cisplatin in malignant human mesothelioma cells (MSTO-211H and H-2452 cells) synergistically induces cell death by increasing the intracellular ROS level [64].
COX2↓, covers the down-regulation of the products of the following genes, COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA [93].
5LO↓,
VEGF↓,
IL1↓,
IL6↓,
IL8↓,
AR↓,
PSA↓,
MAPK↓, by preventing also the activation of the MAPK and PI3K/Akt signaling pathways, it suppresses HIF-1a and VEGF release in ovarian cancer cells of humans
Hif1a↓,
Glycolysis↓, Resveratrol was found to effectively impede the activation, invasion, migration and glycolysis of PSCs induced by reactive oxygen species (ROS) by down-regulating the expression of microRNA 21 (miR-21)
miR-21↓,
PTEN↑, also by increasing the phosphatise and tensin homolog (PTEN) protein levels
Half-Life↝, 25 mg/70 kg resveratrol administered to healthy human participants, the compound predominantly appeared in the form of glucuronide and sulfate conjugates in serum and urine and reached its peak concentrations in serum about 30 min after ingestion
*IGF-1↓, Brown and colleagues noted how a major decline in circulating insulin-like growth factor (IGF)-I as well as IGF-binding proteins (IGFBP-3) among healthy individuals can be credited to the intake of resveratrol
*IGFBP3↑,
Half-Life↓, Microactive® and Resveratrol SR and manufactured by Bioactives. This compound is capable of sustained release for over 12 h to increase intestinal residence time.

1490- RES,    Anticancer Potential of Resveratrol, β-Lapachone and Their Analogues
- Review, Var, NA
TumCCA↑, lapachone and its iodine derivatives induce cell cycle arrest in G2/M in human oral squamous cell carcinoma cells
ROS↑, The primary mechanism of action of β-lapachone and its derivatives is the formation of ROS [92] through its processing by NAD(P)H quinone oxidoreductase 1 (NQO1).
Ca+2↑, abnormal production of ROS leads to an increase in Ca++
MMP↓, depolarization of the mitochondrial membrane
ATP↓, decrease in ATP synthesis
TOP1?, β-lapachone inhibits the catalytic activity of topoisomerase I
P53↑, including upregulation of the p53 tumor suppressor protein
p53 Wildtype∅,
Akt↓, inactivation of the Akt/mTOR pathway was again attributed to β-lapachone, promoting the inhibition of EMT transition in NQO1-positive cells.
mTOR↓,
EMT↓,
*BioAv↓, β-lapachone is a promising anticancer drug, its low bioavailability represents a limitation for clinical use due to low solubility in water and gastrointestinal fluids

1391- RES,  BBR,    Effects of Resveratrol, Berberine and Their Combinations on Reactive Oxygen Species, Survival and Apoptosis in Human Squamous Carcinoma (SCC-25) Cells
- in-vitro, Tong, SCC25
ROS↑,
eff↑, cytotoxicity of the compounds was significantly improved after their combined application Additive effects were observed for doses lower than the calculated IC50 of berberine [IC50=23µg/ml] and resveratrol [IC50=9µg/ml].

4570- RF,    Role of Mitochondria in the Oxidative Stress Induced by Electromagnetic Fields: Focus on Reproductive Systems
- Review, Nor, NA
*ETC↓, Numerous studies revealed the detrimental effects of EMFs from mobile phones, laptops, and other electric devices on sperm quality and provide evidence for extensive electron leakage from the mitochondrial electron transport chain
*ROS↑, a growing body of evidence suggests that EMF exposure during spermatogenesis induces increased ROS production associated with decreased ROS scavenging activity.
*ROS∅, Similarly, numerous authors did not find the increase in ROS levels described above

1748- RosA,    The Role of Rosmarinic Acid in Cancer Prevention and Therapy: Mechanisms of Antioxidant and Anticancer Activity
- Review, Var, NA
AntiCan↑, RA exhibits significant potential as a natural agent for cancer prevention and treatment
*BioAv↝, Various factors, including its lipophilic nature, stability in the gastrointestinal tract, and interactions with food, can significantly influence its absorption
*CardioT↓, RA attenuated these effects by reducing ROS levels, indicating its potential role as a cardioprotective agent during chemotherapy.
*Iron↓, Another significant mechanism antioxidant activity of RA is its capacity to chelate transition metal ions, particularly iron (Fe2+) and copper (Cu2+), which can catalyze the formation of highly reactive hydroxyl radicals through the Fenton reaction.
*ROS↓, forming stable complexes with Fe2+ and Cu2+, thus inhibiting their pro-oxidant activity.
*SOD↑, SOD, CAT, and GPx, play crucial roles in neutralizing ROS and maintaining cellular redox homeostasis. RA upregulates the expression and activity of these enzymes
*Catalase↑,
*GPx↑,
*NRF2↑, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a primary regulator of the antioxidant response
MARK4↓, Anwar’s study demonstrated that RA inhibited MARK4 activity in MDA-MB-231 breast cancer cells, resulting in dose-dependent apoptosis
MMP9↓, RA effectively inhibited cancer cell invasion and migration by reducing matrix metalloproteinase-9 (MMP-9) activity
TumCCA↑, caused cell cycle arrest
Bcl-2↓, RA downregulates Bcl-2 expression and upregulates Bax, thereby promoting apoptosis
BAX↑,
Apoptosis↑,
E-cadherin↑, promoting E-cadherin expression, while downregulating N-cadherin and vimentin
N-cadherin↓,
Vim↓,
Gli1↓, induced apoptosis by downregulating Gli1, a key component of the Hedgehog signaling pathway,
HDAC2↓, RA induced apoptosis by modulating histone deacetylase 2 (HDAC2) expression
Warburg↓, anti-Warburg effect of RA in colorectal carcinoma
Hif1a↓, RA inhibits hypoxia-inducible factor-1 alpha (HIF-1α) and downregulates miR-155
miR-155↓,
p‑PI3K↑, RA has been shown to upregulate p-PI3K, protecting cells through the PI3K/Akt pathway,
ROS↑, RA, induces significant ROS generation in A549 cells, which triggers both apoptosis and autophagy.
*IronCh↑, RA’s dual nature as both a phenolic acid and a flavonoid-related compound enables it to chelate metal ions and prevent the formation of free radicals,

1744- RosA,    Therapeutic Applications of Rosmarinic Acid in Cancer-Chemotherapy-Associated Resistance and Toxicity
- Review, Var, NA
chemoR↓, Recently, several studies have shown that RA is able to reverse cancer resistance to first-line chemotherapeutics
ChemoSideEff↓, as well as play a protective role against toxicity induced by chemotherapy and radiotherapy
RadioS↑, RA decreased radiation-induced ROS with RA by 21% compared to control
ROS↓, mainly due to its scavenger capacity
ChemoSen↑, recent years, evidence has emerged demonstrating the ability of RA to act as a chemosensitizer
BioAv↑, bioavailability of RA have been studied in animal models, revealing rapid absorption in the stomach and intestine
Half-Life↝, Urine was the primary route of RA excretion, with 83% of the total metabolites excreted during the period from 8 to 18 h after RA administration
antiOx↑, RA, well known for its antioxidant properties,
ROS↑, has recently been identified as a potential pro-oxidant in the presence of superoxide anions.
Fenton↑, Studies indicate that RA can facilitate the reduction of Cu (II) to Cu (I) and Fe (III) to Fe (II) leading to Fenton-type reactions that generate reactive hydroxyl radicals (HO˙)
DNAdam↑, These radicals are implicated in DNA damage and induction of apoptosis in cancer cells
Apoptosis↑,
CSCs↓, RA has demonstrated potential in controlling breast cancer stem cells (CSCs)
HH↓, RA inhibits stem-like breast cancer cells by targeting the hedgehog signaling pathway and modulating the Bcl-2/Bax ratio at concentrations of 270 and 810 μM
Bax:Bcl2↑,
MDR1↓, It has been observed to downregulate P-glycoprotein (P-gp) expression and decrease MDR1 gene transcription, thereby reversing MDR.
P-gp↓,
eff↑, RA has been reported to modulate the ADAM17/EGFR/AKT/GSK3β signaling axis in A375 melanoma cells, potentially enhancing synergy with cisplatin
eff↑, RA has demonstrated effectiveness in enhancing chemosensitivity to 5-FU, a commonly used chemotherapy agent for gastrointestinal cancers.
FOXO4↑, By upregulating FOXO4 expression, RA restored the sensitivity of cells to 5-FU
*eff↑, RA has been shown to reduce DOX-induced apoptosis in H9c2 cardiac muscle cells, and reduce intracellular ROS generation through downregulation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), as well as to restore the
*ROS↓,
*JNK↓,
*ERK↓,
*GSH↑, RA has also shown an antioxidant role, which is evidenced by the ability and recovery of levels of glutathione (GSH), hydrogen peroxide (H2O2), and superoxide radicals (O2·), reducing the expression of malondialdehyde
*H2O2↑,
*MDA↓,
*SOD↑, regulating the expression of antioxidant enzymes such as superoxide dismutase (SOD), as well as upregulating catalase heme oxygenase-1, resulting in significantly improved viability
*HO-1↑,
*CardioT↓, The cardioprotective effect of RA
selectivity↑, RA blocked caspases 3 and 9 activation, cytochrome c release, and ROS generation induced by cisplatin in HEI-OC1(normal)cells

1743- RosA,    New insights into the competition between antioxidant activities and pro-oxidant risks of rosmarinic acid
- Analysis, Var, NA
ROS↑, Finally, the pro-oxidant risk of RA− was also considered via the Fe(iii)-to-Fe(ii) complex reduction process, which may initiate Fenton-like reactions forming reactive HO˙ radicals.
Fenton↑,
eff↑, RA− does not enhance the reduction process when ascorbate anions are present as reducing agents, whereas the pro-oxidant risk becomes remarkable when superoxide anions are found
antiOx↑, The antioxidant activity of RA in this studied system is remarkably higher than that of trolox, ascorbic acid and taxifolin
Iron↓, it is noteworthy that RA− represents strong chelating ability towards both Fe(ii) and Fe(iii) ions compared to its neutral form RA
ROS↑, it is noteworthy that RA− represents strong chelating ability towards both Fe(ii) and Fe(iii) ions compared to its neutral form RA

1742- RosA,    Rosmarinic acid, a natural polyphenol, has a potential pro-oxidant risk via NADH-mediated oxidative DNA damage
- Analysis, Var, NA
ROS↑, RA plus Cu(II), but not Fe(III), significantly increased 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) formation, an indicator of oxidative DNA damage, in calf thymus DNA
eff↑, RA plus Cu(II) caused DNA cleavage, which was enhanced by piperidine treatment, suggesting that RA causes not only DNA strand breakage but also base modification.
eff↑, metals such as copper and iron could be associated with the pro-oxidant risk of RA;
eff↑, Interestingly, the addition of NADH markedly enhanced 8-oxodG formation by RA plus Cu(II) (approximately 30-fold increase at 0.1–0.5 µM) (Fig. 1B). On the other hand, RA plus Fe(III) did not increase 8-oxodG formation even in the presence of NADH
eff↑, RA caused DNA cleavage in a concentration-dependent manner, and piperidine treatment enhanced DNA cleavage.
eff↓, Catalase, an H2O2 scavenger, and bathocuproine, a Cu(I)-specific chelator [26], inhibited DNA damage induced by RA plus Cu(II)
Dose↝, The maximum serum concentration of RA was reported to reach approximately 0.16 µM after the administration of plant extracts containing 500 mg of RA in humans
Dose↝, In this study, 0.1 µM RA induced oxidative DNA damage in the presence of physiologically relevant concentrations of Cu(II) (20 µM) [35] and NADH (100 µM)

3010- RosA,    Exploring the mechanism of rosmarinic acid in the treatment of lung adenocarcinoma based on bioinformatics methods and experimental validation
- in-vitro, Lung, A549 - in-vivo, NA, NA
TumCG↓, RosA could inhibit the growth of transplanted tumors in nude mice bearing tumors of lung cancer cells, reduce the positive expression of Ki67 in lung tumor tissue, and hinder the proliferation of lung tumor cells.
Ki-67↓,
FABP4↑, Upregulated expression of PPARG and FABP4 by activating the PPAR signaling pathway increases the level of ROS in lung tumor tissues and promotes apoptosis of lung tumor cells.
PPARα↑,
ROS↑, RosA increases ROS levels in lung tumor tissues and induces apoptosis
Apoptosis↑,
MMP9↓, In addition, RosA can also reduce the expression of MMP-9 and IGFBP3, inhibit the migration and invasion of lung tumor tissue cells.
IGFBP3↓,
MMP2↓, In addition, RosA down-regulated the expression of MMP-9 and MMP2, regulated epithelial-mesenchymal transition to inhibit cell invasion, and slow down tumor development.
EMT↓,
TumCI↓,
PI3K↓, his study also confirmed that RosA down-regulated the expression of the PI3K/AKT/mTOR pathway-related proteins
Akt↓,
mTOR↓,
Gli1↓, Xiang Zhou et al. [28] reported that RosA inhibited the growth of PDAC tumors by inhibiting Gli1.
PPARγ↑, Upregulated expression of PPARG
Cyt‑c↑, figure 7

3005- RosA,    Nanoformulated rosemary extract impact on oral cancer: in vitro study
- in-vitro, Laryn, HEp2
TumCCA↑, They induced apoptotic changes as well as cell cycle arrest at G2/M phase. They enhanced ROS expression in cancer cells
ROS↑, The treatment of cancer cells with RE leads to a strong increase in intracellular ROS that results in cell death.
Bcl-2↓,
BAX↑,
Casp3↑,
P53↑,
necrosis↑, RE in a dose of 20–40 µg/ml resulted in an obvious increase in ROS intracellularly which guided cells toward necrosis and death.
eff↑, Chitosan was chosen as a nanodrug delivery in our research as per our aim, and we intended to offer a locally acting formula that may be applicable in managing oral cancerous lesions. Chitosan has a penetration capability as it is able to open tight
BioAv↑, chitosan nanoparticles, an increase in the surface-to-volume ratio occurs as well as the specific surface area. This enhances the dissolution of poorly water-soluble drugs so increases their bioavailability.

3002- RosA,    Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols
- Review, Var, NA
TumCG↓, SW480 colon cancer cells and found RE to significantly decrease cell growth at a concentration of 31.25 µg/mL (48 h),
TumCP↓, Cell proliferation was dramatically decreased and cell cycle arrest was induced in HT-29 and SW480 c
TumCCA↑,
ChemoSen↑, RE enhanced the inhibitory effects of the chemotherapeutic drug 5-fluorouracil (5-FU) on proliferation and sensitized 5-FU resistant cells
NRF2↑, HCT116 ↑ Nrf2, ↑ PERK, ↑ sestrin-2, ↑ HO-1, ↑ cleaved-casp 3
PERK↑,
SESN2↑,
HO-1↑,
cl‑Casp3↑,
ROS↑, HT-29 ↑ ROS accumulation, ↑ UPR, ↑ ER-stress
UPR↑,
ER Stress↑,
CHOP↑, HT-29: ↑ ROS levels, ↑ HO-1 and CHOP
HER2/EBBR2↓, SK-BR-3: ↑ FOS levels, ↑ PARP cleavage, ↓ HER2, ↓ ERBB2, ↓ ERα receptor.
ER-α36↓,
PSA↓, LNCaP : ↑ CHOP, ↓ PSA production, ↑ Bax, ↑ cleaved-casp 3, ↓ androgen receptor expression
BAX↑,
AR↓,
P-gp↓, A2780: ↓ P-glyco protein, ↑ cytochrome c gene, ↑ hsp70 gene
Cyt‑c↑,
HSP70/HSPA5↑,
eff↑, This study noted that the rosemary essential oil was more potent than its individual components (α-pinene, β-pinene, 1,8-cineole) when tested alone at the same concentrations.
p‑Akt↓, A549: ↓ p-Akt, ↓ p-mTOR, ↓ p-P70S6K, ↑ PARP cleavage
p‑mTOR↓,
p‑P70S6K↓,
cl‑PARP↑,
eff↑, RE containing 10 µM equivalent of CA, or 10 µM CA alone (96 h) potentiated the ability of vitamin D derivatives to inhibit cell viability and proliferation, induce apoptosis and cell cycle arrest and increase differentiation of WEHI-3BD murine leukem

3038- RosA,    Prooxidant action of rosmarinic acid: transition metal-dependent generation of reactive oxygen species
- in-vitro, Nor, NA
IronCh↑, rosmarinic acid may be related to the prooxidant action resulting from metal-reducing activity
ROS↑, Rosmarinic acid and caVeic acid could act as prooxidants by generating reactive oxygen species, which was demonstrated by the inactivation of aconitase, the most sensitive to reactive oxygen species

3037- RosA,    Unraveling rosmarinic acid anticancer mechanisms in oral cancer malignant transformation
- in-vitro, Oral, SCC9 - in-vitro, Oral, HSC3
survivin↓, Rosmarinic acid significantly downregulates BIRC5, the encoded gene for Survivin, in highly invasive oral cancer cells.
AntiCan↑, Rosmarinic acid (RA) has been recognized for its anticancer properties
Vim↓, downregulation of VIM, CADM2, SNAIL1, and SOX9 highlighted the modulation of epithelial-mesenchymal transition
Snail↓,
SOX9↓,
EMT↓,
MMP2↓, remodeling of the extracellular matrix by the downregulation of MMP-2 and MMP-9
MMP9↓,
P-gp↓, RA interacts with P-glycoprotein with the highest docking score of −6.4 kcal/mol.
TumCG↓, RA also shrank the growth and the metabolic activity of multicellular tumor spheroids
ROS↑, RA evokes cell death through the increase of intracellular reactive oxygen species production and the modulation of mitochondrial membrane potential in OSCC cells
MMP↓, significant decrease in the MMP was observed in both cell lines
GSH↓, significant decrease in the glutathione levels in treated HSC-3 cells.
P-gp↓, RA can bind to nine sites of the P-gp ATP model, with a strong binding affinity of −6.3 kcal/mol to −5.4 kcal/mol.
ATP↓,

323- Sal,  AgNPs,    Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy
- in-vitro, BC, MDA-MB-231 - in-vitro, Ovarian, A2780S
TumCD↑, Sal and AgNPs enhanced the cell death (81%)
LDH↓, Sal increased LDH release and MDA levels
MDA↑,
SOD↓,
ROS↑,
GSH↓,
Catalase↓,
MMP↓, loss of Mitochondrial membrane potential
P53↑, 1.5x combined treatment
P21↑, 25x combined treatment
BAX↑,
Bcl-2↓,
Casp3↑,
Casp9↑,
Apoptosis↑,
TumAuto↑, upregulates autophagy genes that are involved in autophagosome formation

4898- Sal,    Salinomycin as a potent anticancer stem cell agent: State of the art and future directions
- Review, Var, NA
CSCs↓, Salinomycin, a widely used antibiotic in poultry farming, was identified by the Weinberg group as a potent anti‐CSC agent in 2009.
AntiCan↑, figure 1
ChemoSen↑, potent partner in cotherapies of cancer, as it has been shown to sensitize radiation and many clinically used chemodrugs such as doxorubicin, trastuzumab, gemcitabine, temozolomide, and tamoxifen.
RadioS↑,
Wnt↓, inhibition of Wnt and mitogen‐activated protein kinase (MAPK) pathways,
MAPK↓,
TumAuto↑, the initiation of autophagy, 41 , 42 the decrease of adenosine triphosphate (ATP) levels along with the elevation of reactive oxygen species (ROS) production,
ATP↓,
ROS↑,
DNAdam↑, he triggering of DNA damage and prevention of DNA repair, 32 , 38 , 45 , 46 the induction of endoplasmic reticulum (ER) stress,
ER Stress↑,
CSCsMark↓, suppression of CSC marker expression via the interaction with its cellular binding target nucleolin (NCL).
Iron↑, salinomycin (0.5 μM) treatment led to the accumulation of iron in lysosome,
*toxicity↝, salinomycin‐induced cytotoxic and proinflammatory effects were seen at concentrations ~fivefold higher and ~twofold higher than that relevant to anticancer treatment, whereas the suppression of cell differentiation was observed at a low dose.

4899- Sal,    Anticancer activity of salinomycin quaternary phosphonium salts
- in-vitro, Var, NA
eff↑, The effects of TPP + conjugates on mitochondria were stronger than that of salinomycin
selectivity↑, Significant selectivity of action of salinomcyin – TPP+ conjugates is proved. Compound 3b showed low toxic effects on both tested non-tumour cell lines as compared to that shown towards cancer cells (SI values ranged from 1.2 to 8.6).
CSCs↓, specific toxicity towards epithelial cancer stem cells (CSCs) in breast cancer.
TumCCA↑, compound 3a an increase in the percentage of cells in G0/G1 phase was noted
MMP↓, treatment with SAL and its derivatives resulted in the loss of MMP
ROS↑, results obtained in the present study showed that the ROS level was around 2-fold elevated after treatment with compounds 3a and 3f of both cancer cell lines as compared to the control.
mitResp↑, 2.5 times increase in the mitochondria respiration rate when applied in a concentration of 1 μM.

4900- Sal,    Anticancer Mechanisms of Salinomycin in Breast Cancer and Its Clinical Applications
- Review, BC, NA
CSCs↓, Salinomycin, a monocarboxylic polyether antibiotic isolated from Streptomyces albus, can precisely kill cancer stem cells (CSCs), particularly BCSCs, by various mechanisms, including apoptosis, autophagy, and necrosis.
Apoptosis↑,
TumAuto↑,
necrosis↑,
TumCP↓, salinomycin can inhibit cell proliferation, invasion, and migration in BC and reverse the immune-inhibitory microenvironment to prevent tumor growth and metastasis.
TumCI↓,
TumCMig↓,
TumCG↓,
TumMeta↓,
eff↑, Salinomycin is over 100 times more effective against BCSCs than paclitaxel, the traditional chemotherapy drug for the treatment of BC
Bcl-2↓, downregulation of Bcl-2 expression, and decreases their migration capacity, which is accompanied by downregulation of c-Myc and Snail expression
cMyc↓,
Snail↓,
ALDH↓, salinomycin reduces aldehyde dehydrogenase activity and the expression of MYC, AR, and ERG; it induces oxidative stress and inhibits nuclear factor (NF)-κB activity
Myc↓,
AR↓,
ROS↑, Salinomycin also induces autophagy by increasing intracellular ROS level, which is accompanied by MAPK signaling pathway activation
NF-kB↓,
PTCH1↓, significantly reduces tumor growth, which is accompanied by decreased PTCH, SMO, Gli1, and Gli2 expression
Smo↓,
Gli1↓,
GLI2↓,
Wnt↓, Figure 2
mTOR↓,
GSK‐3β↓,
cycD1/CCND1↓,
survivin↓,
P21↑,
p27↑,
CHOP↑,
Ca+2↑, cytosolic
DNAdam↑,
Hif1a↓,
VEGF↓,
angioG↓,
MMP↓, salinomycin can affect the cell membrane potential and reduce the level of ATP to induce mitophagy and mitoptosis.
ATP↓,
p‑P53↑, Salinomycin increases DNA breaks in BC cells as well as the expression of phosphorylated p53 and γH2AX in Hs578T cells.
γH2AX↑,
ChemoSen↑, Table 3 Synergistic anticancer co-action of salinomycin with other agents in BC.

4902- Sal,  OXA,    Salinomycin and oxaliplatin synergistically enhances cytotoxic effect on human colorectal cancer cells in vitro and in vivo
- vitro+vivo, CRC, NA
RadioS↑, Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs.
ChemoSen↑,
TumCP↓, The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells.
Apoptosis↑,
ROS↑, SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway
MMP↓,
MAPK↑,
eff↓, pretreatment with N-acetylcysteine (NAC) reversed this effect.
TumCG↓, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone
TumCCA↑, SAL combined with OXA induced apoptosis and cell phase arrest in CRC cells

4903- Sal,    Salinomycin: A new paradigm in cancer therapy
- Review, Var, NA
TumCG↓, multiple pathways by which salinomycin inhibits tumor growth
ATP↓, Salinomycin decreases the expression of adenosine triphosphate–binding cassette transporter in multidrug resistance cells
CSCs↓, Salinomycin selectively targets cancer stem cells.
ROS↑, inhibited growth and migration of prostate cancer cells,37 and led to reactive oxygen species (ROS) accumulation in androgen-dependent and independent prostate cancer cells.
Casp↑, via caspase activation and destabilization of mitochondrial membrane potential
MMP↓,
selectivity↑, Salinomycin also acted on OVCAR-3 human ovarian cancer cells through caspase-mediated apoptosis without harming normal cells
OXPHOS↓, Salinomycin inhibited mitochondrial oxidative phosphorylation without affecting the substrate-level phosphorylation.
STAT3↓, CSC population was inhibited by STAT3 down-regulation
P53↑, Salinomycin increased tumor-suppressor protein p53 and DNA damaging protein pH2AX and decreased cyclin D1 level, which led to cell-cycle arrest and high DNA damage.
γH2AX↑,
cycD1/CCND1↓,
TumCCA↑,
DNAdam↑,
ChemoSen↑, Salinomycin works synergistically with conventional chemotherapeutic drugs to inhibit invasion and migration of cancer cells.

5004- Sal,    Targeting Telomerase Enhances Cytotoxicity of Salinomycin in Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
eff↑, Herein, we improve the toxicity of salinomycin against cancer cells by telomerase inhibition BIBR1532 (BIBR), which binds to the active site of telomerase reverse transcriptase.
AntiCan↑, targeting telomerase improves anti-cancer effects of salinomycin.
CSCs↑, Until 2009, Weinberg group reported that salinomycin possessed anti-cancer effects, especially anti-cancer stem-like cell activities
Wnt↓, inhibition of the Wnt/β-catenin signaling pathway, induction differentiation, and overproduction of reactive oxygen species (ROS).
β-catenin/ZEB1↓,
Diff↑,
ROS↑,
toxicity↝, has been reported that salinomycin in high dose exhibits severe systemic adverse reactions in mammals, which hinders its application as a drug for human diseases.
selectivity↝, Therefore, it is urgent to find more effective methods for increasing salinomycin’s toxicity to cancer cells with little effects on normal cells.
eff↑, BIBR improves salinomycin’s toxicity partially through enhancing ROS generation.

5003- Sal,    Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review
- Review, Var, NA
CSCs↓, Since Salinomycin (Sal) emerged its ability to target breast cancer stem cells in 2009, numerous experiments have been carried out to test Sal’s anticancer effects
TumAuto↑, dual role of Sal involving in autophagy may account for its unique anticancer effects
selectivity↑, the mechanism by which Sal brings about cancer cell death while non-malignant cells are exempted from the lethal effects remaining poorly understood.
DNAdam↑, Death receptor - mediated cell death [14], increased DNA damage and cell cycle arrest [22, 23], p-glycoprotein inhibition [24, 25] have been reported to involve the predominant anticancer effects of Sal.
TumCCA↑,
P-gp↓,
Wnt↓, Further studies have demonstrated that Sal suppresses Wnt/β-catenin signaling pathway conferring CSCs resistance to radiation [26, 27] and to chemotherapeutical agents
β-catenin/ZEB1↓,
RadioS↑,
ChemoSen↑,
Shh↓, other studies have showed that Sal blocks the Hedgehog (Hh) pathway, which plays a crucial role in the stemness maintenance of CSCs
eff↓, In addition, pretreatment with NAC, a general ROS scavenger, inhibits Sal-induced autophagy by suppressing ROS production
ROS↑, Sal can lead to the formation of ROS eliciting JNK activation a
AMPK↑, Sal induces a profound AMPK activation.
JNK↑,
ER Stress↑, Sal upregulates ER stress-related proteins such as phospho-EIF2A, ATF4, DDIT3 in a time- and dose- dependent manner in human NSCLC cells.

5000- Sal,    Salinomycin kills cancer stem cells by sequestering iron in lysosomes
- vitro+vivo, BC, NA
CSCsMark↓, Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive.
eff↑, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo
Ferroptosis↑, Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis.
ROS↑,

4994- Sal,  Rad,    Salinomycin overcomes radioresistance in nasopharyngeal carcinoma cells by inhibiting Nrf2 level and promoting ROS generation
AntiCan↑, . Salinomycin (SAL) has been identified as a promising anticancer drug during chemical screening
RadioS↓, SAL promoted radiation-induced apoptosis in radioresistant NPC cells.
Apoptosis↑,
NRF2↓, SAL inhibited increased Nrf2 in SUNE1IR cells.
ROS↑, combination treatment of Nrf2-deficient CNE2 cells with SAL and IR markedly increased the level of reactive oxygen species (ROS) and DNA damage.
DNAdam↑,

4904- Sal,  CUR,    Co-delivery of Salinomycin and Curcumin for Cancer Stem Cell Treatment by Inhibition of Cell Proliferation, Cell Cycle Arrest, and Epithelial–Mesenchymal Transition
CSCs↓, We determined CD44-targeting co-delivery nanoparticles are highly efficacious against BCSCs by inducing G1 cell cycle arrest and limiting epithelial–mesenchymal transition.
TumCCA↑,
EMT↓,
other↝, anti-cancer mechanism of salinomycin is associated with dysregulation of metal ions
TumAuto↑, activation of autophagy-mediated cell death, and inhibition of stem cell maintenance
Iron↑, recent study found that salinomycin and its derivative, ironomycin, exhibited a potent and selective activity against breast cancer stem cells (BCSCs) by accumulating and sequestering iron to induce ferroptosis,
Ferroptosis↑,
BioAv↓, challenging to efficiently deliver salinomycin (Sal) to tumor sites due to its hydrophobicity, unfavorable pharmacokinetic profile, and cytotoxicity during systemic drug administration
ROS↑, Our previous studies showed that conjugation of salinomycin with gold nanoparticles can efficiently induce ferroptotic cell death of BCSCs by increasing the generation of ROS, mitochondrial dysfunction, and lipid oxidation with higher iron accumulati
lipid-P↑,
GPx4↓, and GPX-4 inactivation
eff↑, Salinomycin and curcumin were loaded onto poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles via double emulsion method to form nanoparticles . salinomycin and curcumin showed improved therapeutic efficiency against BCSCs

4905- Sal,    Salinomycin as a drug for targeting human cancer stem cells
- Review, Var, NA
CSCs↓, Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers,
selectivity↑, Salinomycin has been shown to induce massive apoptosis in acute T-cell leukemia cells [125] and chronic lymphocytic leukemia cells [126] isolated from leukemia patients but failed to induce apoptosis in normal human T cells
Apoptosis↑, salinomycin induces apoptosis in CSCs of different origin
Casp3↑, salinomycin has been shown to activate the mitochondrial pathway of apoptosis and the caspase-3-mediated cleavage of PARP in human PC-3 prostate cancer cells
ROS↑, Salinomycin is able to generate reactive oxygen species (ROS) in prostate cancer cells
Wnt↓, downregulating the expression of the Wnt target genes LEF1, cyclin D1, and fibronectin, finally leading to apoptosis
cycD1/CCND1↓,
Fibronectin↓,
OXPHOS↓, salinomycin is known to inhibit oxidative phosphorylation in mitochondria [144] that may contribute to the elimination of CSCs by salinomycin.
Diff↑, salinomycin is able to promote differentiation of CSCs
Dose↝, the patient received 12 intravenous administrations of 200 μg·kg−1 salinomycin every second day.

4906- Sal,    A Concise Review of Prodigious Salinomycin and Its Derivatives Effective in Treatment of Breast Cancer: (2012–2022)
- Review, BC, NA
CSCs↓, Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs.
Casp3↑, SAL has been shown to affect the mitochondria, leading to caspase-3 cleaving poly-ADP ribose polymerase (PARP), resulting in apoptosis.
cl‑PARP↝,
Apoptosis↑,
ROS↑, SAL has shown the ability to affect prostate cancer (PC-3) cell lines through the production of reactive oxygen species (ROS), leading to programmed cell death.
ABC↓, potential use of SAL as an ABC transporter inhibitor
OXPHOS↓, Inhibition of Oxidative Phosphorylation and Glycolysis
Glycolysis↓,
eff↑, SAL in combination with glucose analogs (2-DG, 2-FDG) increased the toxicity of SAL towards cancer cells and showed that cancer cells are dependent on glycolysis for ATP production
TumAuto↑, Induction of Autophagy, ROS, and DNA Damage
DNAdam↑,
Wnt↓, Inhibition of the Wnt Signaling Cascade
Ferritin↓, SAL was tested, and at 0.5 μM iron accumulation in the lysosome, a reduction in iron keeper ferritin expression and elevated iron regulatory protein-2 (IRP2) were observed
Iron↑, a novel mechanism of action of SAL affecting breast CSCs is iron accumulation in the lysosome. and an increased amount of iron in the lysosome produces ROS, which leads to apoptosis

4908- Sal,    Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
tumCV↓, salinomycin inhibited the viability and induced the apoptosis of PC-3 and DU145 cells in a dose-dependent manner
ROS↑, salinomycin increased the production of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and the lipid peroxidation.
lipid-P↑,
UPR↑, salinomycin induced the activation of unfolded protein response and endoplasmic reticulum stress in DU145 and PC-3 cells
ER Stress↑,
NRF2↓, salinomycin significantly downregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone dehydrogenase 1
NADPH↓,
HO-1↓,
SOD↓, and decreased the activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in PC-3 and DU145 cells.
Catalase↓,
GPx↓,
eff↓, Nrf2 activator, tert-butylhydroquinone, significantly reversed the therapeutic effects of salinomycin by stimulating the Nrf2 pathway and increasing the activity of antioxidant enzymes.
TumCP↓, proliferation of PC-3 and DU145 cells was significantly decreased following treatment with salinomycin (2-50 µM

4909- Sal,    Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model
- vitro+vivo, CRC, NA
AntiTum↑, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer
Apoptosis↑, Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species
mtDam↑,
ROS↑, Accumulation of dysfunctional mitochondria and increased production of reactive oxygen species upon salinomycin treatment
SOD1↓, These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment.
ChemoSen↑, salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.
CSCs↑, Anti-stem cell activity of salinomycin in TIC cultures
ALDH↓, Strikingly, exposure to 5-FU and oxaliplatin resulted in a more pronounced reduction of the ALDH1+ population compared to salinomycin treatment
TumCG↓, Salinomycin inhibits tumor growth in a patient-derived xenograft model
TumCP↓, Salinomycin inhibits proliferation, induces cell death and abolishes ATP production of human colorectal cancer cells
TumCD↑,
ATP↓,

5125- Sal,    Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma
- in-vitro, GBM, NA
ER Stress↑, SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations.
UPR↑,
autoF↓, SLM treatment does not trigger apoptosis and blocks the autophagy flux in glioma cell line
lysosome↝,
ROS↑, aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS)
lipid-P↑, our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation.
CSCs↓, SLM induces a potent antitumor effect in brain tumor stem cells (BTSCs) and established adult and pediatric glioma cell lines in vitro
necrosis↑, SLM induces necrosis cell death
ATP↓, with increasing doses of SLM displayed a decrease in intracellular ATP levels
MMP↓, SLM treated cells displayed significantly lower ΔΨm than untreated cells
MOMP↑, SLM induces mitochondrial MOMP.
DNAdam↑, We observed double strand breaks in SLM-treated cells (Figure 4C) and it is possible that this DNA damage is induced as a consequence of AIF internalization.
AIF↑,
lysoMP↑, hypothesis that SLM treatment triggers an autophagic process that cannot proceed adequately because of LMP resulting from oxidative stress.
MitoP↑, In addition, impairment of mitochondrial activity would trigger mitophagy, with engulfment of the organelle and initiation of autophagy.
Ca+2↑, The elevated levels of calcium and ROS inside mitochondria results in MOMP

1208- SANG,    Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single-stranded DNA-binding protein 1 (SSBP1) promoter region
- in-vitro, OS, NA
SSBP1↑,
mtDam↑,
Apoptosis↑,
JAK↓,
STAT3↓,
PI3k/Akt/mTOR↓,
ROS↑,
MMP↓,

5139- SAS,    Sulfasalazine induces ferroptosis in osteosarcomas by regulating Nrf2/SLC7A11/GPX4 signaling axis
- in-vitro, OS, MG63 - in-vitro, OS, U2OS
*Inflam↓, Sulfasalazine (SAS), a commonly used anti-inflammatory drug prescribed for nonspecific gastrointestinal diseases, autoimmune rheumatic diseases, ankylosing spondylitis, and various skin conditions
TumCP↓, Our results demonstrate that SAS significantly inhibited the proliferation and migration of OS cells, inducing apoptosis and effectively attenuating their malignant progression.
TumCMig↓,
Apoptosis↑,
Ferroptosis↑, Notably, SAS-treated OS cells displayed hallmarks of ferroptosis, including iron accumulation, elevated levels of malondialdehyde and reactive oxygen species, and reduced levels of glutathione and superoxide dismutase
Iron↑,
MDA↑,
ROS↑,
GSH↓,
SOD↓,
MMP↓, SAS decreased mitochondrial membrane potential in OS cells, potentially indicating mitochondrial damage during ferroptosis.
NRF2↓, Mechanistically, we found that SAS induced ferroptosis by downregulating the expression of NRF2,
xCT↓, subsequently decreasing the expression of the light chain subunit of the cysteine/glutamate transporter system Xc- (SLC7A11) and glutathione peroxidase 4.
GPx4↓,
FTH1↓, SAS treatment decreased FTH1 protein expression

5044- SAS,    xCT inhibitor sulfasalazine depletes paclitaxel-resistant tumor cells through ferroptosis in uterine serous carcinoma
- in-vitro, Var, NA
xCT↓, Thus, the present study investigated the effect of the xCT inhibitor, sulfasalazine (SAS) on cytotoxicity in paclitaxel-sensitive and -resistant USC cell lines.
Ferroptosis↑, SAS-mediated cell death was induced through ferroptosis
ROS↑, ROS production was increased in paclitaxel-resistant but not in -sensitive cells, even at low SAS concentration
IL1↓, inhibit leukocyte motility and interleukin (IL)-1 and IL-2 production (18), and inhibit nuclear factor κ B (NFκB)
IL2↓,
NF-kB↓,
GSH↓, SAS has also been reported to effectively induce GSH depletion (90%) and arrest growth
TumCG↓,
ChemoSen↑, and to enhance sensitivity to chemotherapeutic agents in pancreatic, prostate and mammary cancer

5042- SAS,    xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling
- Review, Var, NA
xCT↓, It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies.
GSH↓, xCT inhibition by sulfasalazine was shown to decrease tumor growth through GSH depletion.
TumCG↓, Similarly, inhibition of xCT also disrupted glioma, melanoma, and prostate cancer cell growth, and it decreased cell proliferation and tumor progression in non-small-cell lung cancer, suggesting a critical role of xCT in solid tumor growth as well
TumCI↓, The xCT inhibitor sulfasalazine suppressed cell invasion of KYSE150, a cell line of esophageal squamous cell carcinoma (ESCC), likely through ROS-induced p38 mitogen-activated protein kinase (MAPK) activation.
ROS↑,
RadioS↑, However, the xCT inhibitor sulfasalazine and radiation synergistically increased glioma cell death,
eff↓, which could be reversed by the antioxidant N-acetyl-l-cysteine (NAC).7

5041- SAS,  Cisplatin,    Xc− inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism
- in-vitro, CRC, NA
xCT↓, Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc−
Inflam↓,
Apoptosis↓,
GSH↓, Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis
ROS↑, SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells.
TumCG↓,
selectivity↑, In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation.
eff↑, Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells.
eff↓, synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC).

5138- SAS,  Rad,    Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion
- vitro+vivo, GBM, NA
cystine↓, SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro.
GSH↓,
ROS↑,
RadioS↑, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death
eff↓, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death
DNAdam↑, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death.
OS↑, Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit.

5039- SAS,    Regulatory network of ferroptosis and autophagy by targeting oxidative stress defense using sulfasalazine in triple-negative breast cancer
- vitro+vivo, BC, NA
xCT↓, using sulfasalazine (SASP), which is a widely employed xCT inhibitor.
ROS↑, SASP significantly attenuated oxidative stress resistance in MDA-MB-231
GSH↓, through decreased glutathione levels, causing a marked iron-dependent ferroptotic cell death induction.
Ferroptosis↑,
TumCG↓, SASP suppressed tumor growth and metastasis progression through total glutathione reduction in the primary tumor, indicating high anticancer activity against TNBC without liver injury in vivo.
toxicity↓,
lipid-P↑, graphical abstract

5038- SAS,  Rad,    Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma
- in-vivo, Melanoma, B16-F10
xCT↓, Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential.
ROS↑,
RadioS↓, radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model.
GSH↓, Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts.
selectivity↑,
DNArepair↓, It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation.
TumCCA↑,
H2O2↑, SAS decreases cellular GSH and increases H2O2 cytotoxicity in B16F10 cells
Dose↝, At lower SAS concentrations (10–100 μM), we did not observe any increase in intracellular ROS. At higher concentrations of SAS (800–1,000 μM), intracellular ROS increased approximately 2.3-fold in B16F10 cells

1388- Sco,    Scoulerine promotes cell viability reduction and apoptosis by activating ROS-dependent endoplasmic reticulum stress in colorectal cancer cells
- in-vitro, CRC, NA
tumCV↓,
Apoptosis↑,
Casp3↑,
Casp7↑,
BAX↑,
Bcl-2↓,
ROS↑,
GSH↓,
SOD↓,
ER Stress↑,
GRP78/BiP↑,
CHOP↑,
eff↓, blocking ROS production by ROS scavenger N-acetyl-cysteine (NAC) attenuated scoulerine-induced ER stress.

1403- SDT,  BBR,    From 2D to 3D In Vitro World: Sonodynamically-Induced Prooxidant Proapoptotic Effects of C60-Berberine Nanocomplex on Cancer Cells
- in-vitro, Cerv, HeLa - in-vitro, Lung, LLC1
eff↑, revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability
tumCV↓,
ATP↓,
ROS↑,
Casp3↑,
Casp7↑,
mtDam↑,

2549- SDT,    Landscape of Cellular Bioeffects Triggered by Ultrasound-Induced Sonoporation
- Review, Var, NA
sonoP↑, Numerous studies have provided us with firm evidence that sonoporation may assist cancer treatment through effective drug and gene delivery. provide greater drug distribution within tissues.
tumCV↓, Until now, numerous studies have reported various cellular alterations caused by US, e.g., a decreased viability [23], disrupted cell membrane potential [24,25], altered calcium signalling [26,27], production of reactive oxygen species
MMP↓,
ROS↑, When the gas pressure increases significantly or the temperature rapidly rises during the collapse of MBs, such extreme conditions can generate reactive oxygen species (ROS) as well as electromagnetic waves
Ca+2↑, an increased intracellular concentration of Ca2+ ions is known to induce the production of free radicals by mitochondria.
eff↝, US, microbubble responds in a wide range of behaviours that cause acoustic cavitation
eff↑, Several studies have shown that the higher the concentration of MBs, the more intensified the sonoporation and the bigger the pores in the cell membrane
selectivity↑, Interestingly, they found that MCF-7/ADR cells displayed a higher sensitivity to sonoporation
Half-Life↝, discovered that the size of the generated pore determined the reversibility of the sonoporation: membrane perforations smaller than 30 μm2 disappeared within 1 min after US treatment, whereas pores >100 μm2 were still open within half an hour.
Dose↝, Whereas US exposure at 0.75 W/cm2 provided the highest level of methane dicarboxylic aldehyde (MDA) in doxorubicin resisted cells
P-gp↓, Microbubble-based sonoporation has been shown to reduce the expression of Pgp in the blood-brain barrier in rats. Aryal et al. [136] observed a suppression of Pgp that lasted more than 72 h.
ER Stress↑, Zhong et al. revealed that sonoporation is not only capable of ER stress induction but also that these signals can be transduced to mitochondria and guide US-treated cells toward apoptosis.
other↑, This review has clearly highlighted that ultrasound (US)-triggered bioeffects are not limited to the cell membrane, but they also alter cell functioning at diverse levels.

2536- SDT,    Sonodynamic Therapy: Rapid Progress and New Opportunities for Non-Invasive Tumor Cell Killing with Sound
- Review, Var, NA
ROS↑, [i.e. focused ultrasound (FUS)] to drive highly localized formation of tumor cell-killing reactive oxygen species (ROS).
eff↑, FUS activates “sonosensitizers”, which like photosensitizers, selectively accumulate in tumor cells and generate ROS.
Dose?, typically 1W/cm2 and up

4714- Se,  SSE,  SeNPs,    Selenium in cancer management: exploring the therapeutic potential
- Review, Var, NA
Risk↓, Prolonged selenium deficiency has been conclusively linked to an elevated risk of various diseases, including but not limited to cancer, cardiovascular disease, inflammatory bowel disease, Keshan disease, and acquired immunodeficiency syndrome.
*BioAv↑, compounds such as selenite, selenate, and selenium-enriched amino acid analogs are more amenable to absorption, particularly when synergized by vitamins A, D and E
eff↝, Based on current research, selenium supplementation alone has not shown favorable results in prostate cancer treatment.
*ROS↓, It is a well-established fact that selenium demonstrates its anticancer capabilities primarily through its antioxidant attributes. These attributes help maintain the cellular redox balance and shield healthy cells from ROS
MMP↓, Sodium selenite, the most abundant inorganic selenium compound in nature, reduces mitochondrial membrane potential and enhances the antiproliferative and apoptosis-inducing effects of polyene paclitaxel on prostate cancer cell PC3
ROS↑, The above studies also suggest that ROS generation, upregulation of p53, and reduction of mitochondrial membrane potential play important roles in selenium-assisted anti-tumor processes.
P53↑,
*toxicity↓, selenium-containing nanoparticles an attractive avenue for research, with the potential to revolutionize cancer treatment by offering targeted, effective therapies with reduced toxicity.
TumCP↓, SeNPs effectively curbed the proliferation of these cancer cells by triggering a cascade of caspase-mediated apoptosis
Casp↑,
Apoptosis↑,

4483- Se,  Chit,    Anti-cancer potential of chitosan-starch selenium Nanocomposite: Targeting osteoblastoma and insights of molecular docking
- in-vitro, OS, NA
AntiCan↑, CS/S/SeNC acts as a potential anti-cancer agent, specifically targeting osteoblastoma cells was evaluated for anti-cancer activity using in-vitro studies MTT assay
TumCP↓, strong ability to inhibit cancer cell proliferation in a dose-dependent manner, and induce apoptosis via ROS- mediated mechanism
Apoptosis↑,
ROS↑,
eff↑, biocompatibility of CS/S/SeNC was confirmed through its interaction with the endogenous protein Decorin, thereby augmenting its potential as a therapeutic agent for the treatment of bone cancer.
other↝, The utilization of chitosan composite materials and their applications in bone tissue engineering have gained a lot of interest lately due to evidence that chitosan accelerates the development of extracellular matrix and formation
eff↑, major advantage of selenium nanoparticles is that they have improved efficacy against cancer cells and their unique function is that they are highly effective at targeted drug delivery
TumCCA↑, function as a pro – oxidants and raise ROS levels in cancer cells, which causes apoptosis and cell cycle arrest

4484- Se,  Chit,  PEG,    Anti-cancer potential of selenium-chitosan-polyethylene glycol-carvacrol nanocomposites in multiple myeloma U266 cells
- in-vitro, Melanoma, U266
tumCV↓, SCP-Car-NCs decreased the viability of U266 cells while having no impact on the proliferation of Vero cells.
selectivity↑,
ROS↑, SCP-Car-NCs significantly boosted ROS production, decreased the MMP level, and promoted apoptosis
MMP↓,
Apoptosis↑,
BAX↑, Bax, caspase-3, and −9 activities had increased while the Bcl-2 level had decreased.
Casp3↑,
Casp9↑,
Bcl-2↓,

4485- Se,    Selenium stimulates the antitumour immunity: Insights to future research
- Review, NA, NA
*antiOx↑, At nutritional low doses, selenium, depending on its form, may act as an antioxidant, protecting against oxidative stress, supporting cell survival and growth, thus, plays a chemo-preventive role
chemoPv↑,
ROS↑, at supra-nutritional higher pharmacological doses, selenium acts as pro-oxidant inducing redox signalling and cell death
Imm↑, selenium stimulates the immune system against cancer
selenoP↑, anti-oxidant through selenoproteins
*IL2↑, consumption of Se-enriched foods (200 μg per serving for 3 days) increases the levels of interleukin IL-2, IL-4, IL-5, IL-13 and IL-22, indicating an activated Th2-type response
*IL4↑,
*TNF-α↓, taking selenised yeast (300 μg.day−1) downregulates the gene expression of tumour necrosis factor (TNF)α and transforming growth factor (TGF)β; thus, consequently inhibit the epithelial-to-mesenchymal transition (EMT) in non-malignant prostate tissue
*TGF-β↓,
*EMT↓,
Risk↓, immune-enhancing effects of Se may reduce the risk of cancer
*GPx↑, chemo-preventive effects of Se are mainly mediated by the anti-oxidant function of selenoenzymes such as GPxs and TXNRDs [68] because Se supplementation increases both GPx1 and GPx4 activity in humans
*TrxR↑,

4486- Se,  Chit,    Selenium-Modified Chitosan Induces HepG2 Cell Apoptosis and Differential Protein Analysis
- in-vitro, Liver, HepG2
Apoptosis↑, selenium-modified chitosan (SMC)can induce HepG2 cell apoptosis with the cell cycle arrested in the S and G2/M phases
TumCCA↑,
MMP↓, gradual disruption of mitochondrial membrane potential
Bcl-2↓, reduce the expression of Bcl2, and improve the expression of Bax, cytochrome C, cleaved caspase 9, and cleaved caspase 3
BAX↑,
cl‑Casp9↑,
cl‑Casp3↑,
Risk↓, Relevant research suggests that an inverse relationship exists between selenium intake and cancer incidence, and selenium levels are usually lower in cancer patients.
*BioAv↑, favorable biocompatibility, good bioadhesivness, and low toxicity.
*toxicity↑,
TumCG↓, Studies have found that water-soluble chitosan can significantly inhibit the growth of liver cancer cells in a dose-dependent manner
AntiTum↑, SMC has been proved to possess stronger antitumor functions and lower toxicity in cancer patients
ROS↑, SMC induced A549 cell apoptosis via a reactive oxygen species–mediated mitochondrial apoptosis pathway, which upregulated Bax and downregulated Bcl2, promoted cytochrome C release from mitochondria to cytoplasm, and activated cleaved caspase 3
Cyt‑c↑,
Fas↑, upregulating the expression levels of Fas, FasL, and Fadd,
FasL↑,
FADD↑,

4752- SeNPs,  CUR,  Chemo,    Curcumin-Modified Selenium Nanoparticles Improve S180 Tumour Therapy in Mice by Regulating the Gut Microbiota and Chemotherapy
- in-vitro, Cerv, HeLa - in-vitro, sarcoma, S180
tumCV↓, Cur/Se nanoparticles showed higher cytotoxicity against HeLa and S180 tumour cells.
ROS↑, Cur/Se nanoparticles significantly delivered more curcumin into the HeLa tumour cells and induced greater ROS production.
*GutMicro↑, Cur and Cur/Se nanoparticles significantly reduced the relative abundances of Rikenellaceae_RC9_gut_group, Enterorhabdus and Bilophila and increased the relative abundance of Lachnospiraceae_UCG-006.
BioAv↑, Cur/Se nanoparticles could increase the bioactivity of curcumin and improve cancer therapy by regulating the gut microbiota.
other↝, The Cur/Se nanoparticles were prepared by reducing sodium selenite with curcumin in one step
Dose↝, The IC50 values of Cur and Cur/Se nanoparticles were 33.0 μg/mL and 8.4 μg/mL, respectively, against S180

4719- SeNPs,    Selenium nanoparticles are more efficient than sodium selenite in producing reactive oxygen species and hyper-accumulation of selenium nanoparticles in cancer cells generates potent therapeutic effects
- in-vivo, Var, NA
ROS↑, ROS production by SeNPs in above systems is more efficient than by selenite.
selenoP↑, (SeNPs) administered via oral route possess similar capacities of increasing selenoenzyme activities as the extensively examined sodium selenite, selenomethionine and methylselenocysteine, and yet display the lowest toxicity among these selenium comp
*toxicity↓,

4469- SeNPs,    Selenium Nanoparticles in Cancer Therapy: Unveiling Cytotoxic Mechanisms and Therapeutic Potential
- Review, Var, NA
antiOx↑, SeNPs demonstrate intrinsic antioxidant properties that counteract oxidative stress commonly observed in cancer cells.
selectivity↑, They modulate critical cellular pathways and exhibit selective toxicity, damaging cancer cells while sparing healthy tissues.
eff↑, Additionally, their biocompatibility and capacity to deliver therapeutic agents contribute to improved safety and efficacy compared to other nanoparticle platforms.
AntiCan↑, Additionally, SeNPs modified with ferulic acid showed promising anticancer effects against HepG2 cells, triggering apoptosis via mitochondrial pathways through the generation of intracellular reactive oxygen species and disruption of mitochondrial m
Apoptosis↑,
ROS↑,
MMP↓,
Casp3↑,
Casp9↑,
AntiTum↑, Furthermore, in vivo experiments using zebrafish models confirmed the inhibitory effects of SeNPs on tumor growth, migration, and angiogenesis.
TumCG↓,
TumMeta↓,
angioG↓,
Cyt‑c↑, leading to the release of cytochrome C from mitochondria into the cytoplasm, culminating in cell death and the induction of permanent DNA damage.
DNAdam↑,
RadioS↑, Interestingly, the caspase expression was enhanced under X-ray exposure compared to absence, suggesting a synergistic effect between SeNPs and radiation therapy
BBB↑, SeNPs have shown promise in glioblastoma treatment by significantly reducing cell viability in a dose-dependent manner, indicating their potential to cross the BBB and serve as an alternative therapeutic approach for gliomas
*toxicity↓, However, at proper concentrations, SeNPs are nontoxic to healthy cells, unlike other chemotherapeutic drugs
ChemoSen↑, Anticancer Activity of SeNPs via Autophagy, ROS, and Chemosensitization

4471- SeNPs,    Green synthesis of selenium nanoparticles with extract of hawthorn fruit induced HepG2 cells apoptosis
- in-vitro, Liver, HepG2
eff↑, hawthorn fruit extract (HE) was chosen as a reductant to prepare SeNPs.
ROS↑, treatment of HE-SeNPs up-regulated intracellular ROS levels and reduced the MMP
MMP↓,
Casp9↑, HE-SeNPs induced the up-regulation of caspase-9 and down-regulation of Bcl-2.
Bcl-2↓,
selectivity↑, Furthermore, the results in Figure 3(B) suggested that He-SeNPs were almost non-cytotoxic to HL02 cells (healthy hepatic cells).
Apoptosis↑, HE-SeNPs induced apoptosis of HepG2 cells

4473- SeNPs,    Anti-cancerous effect and biological evaluation of green synthesized Selenium nanoparticles on MCF-7 breast cancer and HUVEC cell lines
- in-vitro, BC, MCF-7 - in-vitro, Nor, HUVECs
AntiCan↑, Se NPs demonstrated a non-toxic effect on the Human Umbilical Vein Endothelial Cells (HUVEC) normal cell line and anticancer activity on the MCF-7 breast cancer cell line.
selectivity↓,
*Bacteria↓, As a result, Se NPsexhibit outstanding antibacterial, antioxidant, ROSscavenging (i.e., anticancer), and enzyme inhibitionactivities
*antiOx↑,
*toxicity↓, lower toxicity comparedto other conventional organic and inorganicselenium compounds
ROS↑, Selenium nanoparticles have the unique abilityto generate Reactive Oxygen Species (ROS), thus exhibiting pro-oxidant effects.
tumCV↓, In the MCF-7 breast cancer cell line, cell viability decreased to approximately 70% after treatment with 200 μg/mL of Se nanoparticle

4449- SeNPs,    PEG-nanolized ultrasmall selenium nanoparticles overcome drug resistance in hepatocellular carcinoma HepG2 cells through induction of mitochondria dysfunction
- in-vitro, Liver, HepG2
MMP↓, depletion of mitochondrial membrane potential and generation of superoxide anions contributed to PEG-SeNPs-induced apoptotic cell death in R-HepG2 cells.
selectivity↑, Despite this potency, PEG-SeNPs showed much lower cytotoxicity toward normal cells (human kidney HK-2 cells)
Apoptosis↑, PEG-SeNPs inhibit R-HepG2 cell growth though induction of apoptosis
ROS↑, The results showed that treatments of PEG-SeNPs led to dose- and time-dependent increases in intracellular superoxide anion level

4453- SeNPs,    Selenium Nanoparticles: Green Synthesis and Biomedical Application
- Review, NA, NA
*toxicity↓, “Green” synthesis has special advantages due to the growing necessity for environmentally friendly, non-toxic, and low-cost methods.
*Bacteria↓, SeNPs are active against both Gram-positive and Gram-negative microorganisms
ROS↑, The cancer cells exhibit an acidic pH and an imbalanced redox state. These conditions in cancer cells initiate the pro-oxidant conversion of SeNPs and trigger the development of free radicals in malignant cells
MMP↓, mitochondrial membrane destruction
ER Stress↑, on the other hand, to stress in the endoplasmic reticulum (ER)
P53↑, Selenium nanoparticles can stimulate p53 expression in cancer cells, leading to caspase-9 activation, mitochondrial membrane potential depletion, and the induction of apoptosis.
Apoptosis↑,
Casp9↑,
DNAdam↑, In addition, in cellular processes, DNA structure is damaged, causing the cell cycle to stop and, ultimately, cell death.
TumCCA↑,
eff↑, positively charged SeNPs may have a strong affinity for breast cancer cells, causing the enhanced anticancer efficacy of SeNPs
Catalase↓, was accompanied by a decrease in antioxidant marker levels (CAT, SOD, GPx activity and GSH levels) in MCF-7 cells exposed to green SeNPs
SOD↓,
GSH↓,
selectivity↓, in contrast to control cells
selectivity↑, SeNPs selectively affect LDH leakage and membrane disruption in cancer cells because the SeNP concentration required to influence LDH leakage in normal cells is much higher compared to that in cancer cells
PCNA↓, SeNPs reduced the PCNA expression level in MCF-7 cells, showing their role in suppressing oncogenesis and proliferation in breast cancer by inhibiting PCNA gene expression
eff↑, Nanoparticle capping can enhance their absorption via accumulation by endocytosis in cancer cells, which can therefore lead to ROS generation induction
*ALAT↓, SeNPs could significantly decrease hepatic (serum ALT, AST, and ALP) and renal (serum uric acid, urea, and creatinine) function markers, total lipid, total cholesterol, triglyceride and low-density lipoprotein cholesterol levels, and glucose-6-phosph
*AST↓,
*ALP↓,
*creat↓,
*Inflam↓, selenium nanoparticles appear to be a possible anti-inflammatory agent.
*toxicity↓, Most studies confirm that SeNPs are less toxic than sodium selenite
selectivity↑, despite affecting cancer cells and causing their death, SeNPs do not harm normal cells,

4605- SeNPs,    Selenium nanoparticles: An insight on its Pro-oxidant andantioxidant properties
- Review, NA, NA
*antiOx↑, unique antioxidant properties
*selenoP↑, antioxidant effect is chiefly due to the selenoenzymes such as thioredoxin reductase (TR) and glutathione peroxidasefamily (GPxs) which is having ROS scavenging activity.
*Dose↝, In humans, Se has the narrowest margin levels ranges between dietary deficiency (<40mg/day) and toxic levels (>400mg/day).
*toxicity↓, selenium having a narrow therapeutic window and the toxicity margins while, the selenium nanoparticle (SeNPs) having unusually reduced toxicity.
ROS↑, Because of the acidic pH state with redox imbalance these malignant cells will enables the selenium nanoparticles to exhibits pro-oxidant effect
ER Stress↑, cause mitochondrial membrane disruption which can cause leakageof mitochondrial (Mt) proteins and also causes endoplasmic reticulum(ER) stress.

4609- SeNPs,    Physiological Benefits of Novel Selenium Delivery via Nanoparticles
- Review, Var, NA - Review, IBD, NA - Review, Diabetic, NA
*selenoP↑, Biologically, Se is incorporated primarily into selenoproteins as the selenomethionine and selenocysteine amino acids at active sites
Risk↓, Se deficiency and high Se status is coincident with a range of pathologies, including obesity [10,11], cancer [12,13], arthropathy [14] as well as several immune- and neurological-related disorders
AntiCan↑, There is a growing body of research with a focus on the role of Se in cancer prevention which indicates a link between high Se exposure and decreased risk of breast, oesophagus, and prostate cancers
ROS↑, selenite treatment stimulated cancer cell apoptosis via a mechanism involving enhanced ROS generation and the accumulation of hydrogen peroxide which, ultimately, decreased cell viability
*Dose↝, IBD patients had lower Se levels than that of healthy individuals, potentially illustrating the importance of dietary Se as an antioxidant/micronutrient in the pathogenesis of IBD in humans
*toxicity↓, A major benefit of SeNPs is the significantly lower toxicity while retaining similar physiological impacts and efficacy in enhancing selenoprotein activities in comparison to that of other chemical seleno-forms
*BioAv↑, Selenium nanoparticles show an enhanced uptake post-ingestion as these SeNPs are smaller in size with larger surface areas and are more permeable through capillary walls, leading to superior epithelial cell uptake and enhanced bioactivity.
*GutMicro↑, research has also show that dietary Se improved the gut microbiome favourably by enhancing the abundance of beneficial bacteria and limiting the growth of undesirable pathogens
*other↓, In diabetic rats, SeNPs have shown to reduce proinflammatory markers, including IL-1β and TNF levels and renal MDA levels leading to lower oxidative stress, indicated by improved renal functions due to lower serum urea and creatinine along with reduc

4608- SeNPs,    Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics
- Review, Var, NA - NA, AD, NA
*toxicity↝, Although Se shows several beneficial properties in human health, it has also a narrow therapeutic window, and therefore the excessive intake of inorganic and organic Se-based compounds often leads to toxicity
*toxicity↓, Nanoparticles based on Se (SeNPs) are less toxic than inorganic and organic Se.
*other↝, The twenty-first amino acid, selenocysteine (Sec),[4] is used to produce selenoproteins, whose function often depends on the presence of Se in their active site,[5] such as reactive oxygen species (ROS) protection.
ROS↑, SeNPs led to the production of higher levels of ROS than those obtained following the treatment of cancer cells with selenite, therefore presenting better antitumor properties than the Se salts
*Dose↝, recommended daily allowance (RDA) is 60 µg/day for women, 70 µg d−1 for men,[3] 75 µg d−1 for lactating women, and 65 µg d−1 for pregnant women according to the European Food Safety Authority
*selenoP↑, Se is mostly used for the production of selenoproteins, which are essential to human health due to their antioxidant effect, and role in controlling thyroid hormone metabolism, protein folding, redox signaling, among other functions.
AntiCan↑, Se has demonstrated antitumor, antiviral, antibacterial, and antifungal properties,[3] decreasing the risk of tuberculosis in HIV infected patients,[7, 47] and is well correlated to cancer prevention.
AntiTum↑,
*Bacteria↓,
*radioP↑, Se has shown to protect against heavy metals and radiation toxicity
*BioAv↑, food processing can also influence Se bioavailability, since increased temperatures improve protein digestibility, and enhance Se release and bioavailability
*Inflam↓, Se has anti-inflammatory and immunomodulatory actions
*Imm↑,
ChemoSen↑, Se has also been studied for cancer treatment as a radiotherapy and chemotherapeutic adjuvant since malignant cells are more susceptible to Se pro-oxidant effects than healthy cells.
*AntiAg↑, potential role of Se and selenoproteins in protecting the cardiovascular system against oxidative damage and excessive platelet aggregation
selectivity↑, SeNPs have shown potential to target specific cancer cells, by passive targeting based on the fact that the tumor environment is more acidic than the environment existing in healthy tissues
eff↑, chitosan(h)–SeNPs presented higher cellular uptake by cancer cells lines than normal cell lines, probably due to the higher amount of -NH3+ groups, which permits an enhanced electrostatic attraction between the positively charged chitosan(h)–SeNPs
other↝, In general, the charge of SeNPs is negative,[37, 138, 121] however surface modification with positive charged compounds such as chitosan can also flip the charge of SeNPs to positive
*eff↑, SeNPs have also shown to have a synergistic effect when combined with metformin
*Aβ↓, SeNPs have been shown to reduce Aβ aggregation and induce their disaggregation, in addition to acting as an antioxidant in the brain, either directly or by being part of GPx
*eff↑, SeNPs have also been studied together with other compounds that also shown properties against Alzheimer's disease, such as resveratrol (Res),[188] curcumin (Cur),[184] chiral D-penicillamine (DPen),[167] and chlorogenic acid (CGA)

4607- SeNPs,  AgNPs,    A Review on synthesis and their antibacterial activity of Silver and Selenium nanoparticles against biofilm forming Staphylococcus aureus
- Review, NA, NA
*Bacteria↓, antibacterial activity of Silver and Selenium nanoparticles against biofilm forming Staphylococcus aureus
*eff↑, Ag-based antiseptics that may be linked to broad-spectrum activity and far lower propensity to induce microbial resistance than antibiotics
ROS↑, In general, certain selenium compounds are catalytic and produce ROS by their interactionwith thiols, such as reduced glutathione, forming the glutathione selenide anion, GSSe. ̄ ... produced ROS which kills tumor cells
*Dose↝, According to the World Health Organization (WHO), a recommendeddaily dietary selenium intake is 40 μg Se/day
*eff↑, Silver coating of medical devices is believed to preserve infection resistance
toxicity↝, Exact mechanism of selenium toxicity remains unclear but there are many data about its prooxidant effect particularly in the form of selenite,while selenomethionine and selenocysteine are less toxic.
*Sepsis↓, We postulated that high-conc. supplementation of sodium-selenite would recover the outcome of patients with severe sepsis.(14 daily constant infusions of 1000 μg intravenously)
*other↝, Selenium is an essential dietary nutrient for most animals and humans, which is incorporated into twelve or more known proteins or enzymes as an amino acid, selenocysteine.
eff↑, Selenodiglutathione is the most potent selenium compound against cancer cells and readily arrests their growth as compared to selenite and any other selenium compound.

4603- SeNPs,    Therapeutic applications of selenium nanoparticles
- Review, Var, NA
AntiCan↑, SeNPs have attractive anticancer and immunomodulatory properties.
Imm↑,
*AntiDiabetic↑, Figure 1
*antiOx↑,
*Inflam↓,
ROS↑, The anticancer activity is largely due to its prooxidant properties in these cells triggering reactive oxygen species (ROS) synthesis leading to mitochondrial and endoplasmic reticulum damage which in turn leads to DNA damage.
ER Stress↑,
DNAdam↑,
*toxicity↓, use of Se in the form of nanoparticles has substantially answered the toxicological concerns associated with Se
*eff↑, Bo Huang et al. showed that small sized (5–15 nm) SeNPs have better free radical scavenging capacity and prevented the oxidation of DNA.
*BioAv↑, SeNPs show better bioavailability, biological activity compared with inorganic and organic Se compounds.
selectivity↑, Interestingly, the NPs were found to preferentially localize inside the cancer cells and caused production of reactive oxygen species (ROS) thereby causing cytotoxicity
TumCCA↑, SeNPs effectively arrested the S phase in MDA-MB-231 cells at 10 μmol/L
Risk↓, In the case of lung cancer, pretreatment of SeNPs inhibited the incidence of lung cancer induced by ferric nitrilotriacetate.
*lipid-P↓, SeNPs decreased the lipid peroxidation, inflammation (TNF-α) and C reactive protein levels
*TNF-α↓,
*CRP↓,
TumMeta↓, SeNPs inhibit the matrix metalloprotein-2 expression which is mainly involved in tumor invasion, metastasis and angiogenesis in fibro-sarcoma cell lines (HT-1080)
angioG↓,
selectivity↑, SeNPs showed remarkable antiproliferative activity and no toxicity to normal HaCat cell lines
eff↑, SeNPs decorated with chitosan were found to induce comparatively higher apoptosis in A375 melanoma cells in a dose dependent manner, compared to liver (HepG2) and osteosarcoma (MG-63) cells and no toxicity to normal human kidney
*eff↑, Melatonin-SeNPs treatment (5, 10 and 20 mg/Kg) increased the activity of antioxidant enzymes like SOD, GPX activity, decreased serum ALT, AST, NO, MDA levels

4480- SeNPs,  Chit,    Biogenic synthesized selenium nanoparticles combined chitosan nanoparticles controlled lung cancer growth via ROS generation and mitochondrial damage pathway
- in-vitro, Lung, A549 - in-vitro, Nor, HK-2
selectivity↑, (MCF-10) were not significantly cytotoxically affected by SeNPs and Se-chitosan NPs.
*toxicity↓,
ROS↑, SeNP and Se-chitosan NP treatment resulted in increased ROS generation and caused mitochondrial dysfunction
mtDam↑,
Apoptosis↑, Chito-NPs, SeNPs, and Se-chitosan NPs cause apoptosis and death in A549 cells.
LDH↑, Chito-NPs, SeNPs, and Se-chitosan NPs increase the LDH release

3183- SFN,    Sulforaphane potentiates the efficacy of chemoradiotherapy in glioblastoma by selectively targeting thioredoxin reductase 1
- in-vitro, GBM, NA
RadioS↑, SFN synergistically improves chemoradiotherapy efficacy in GBM cells
TrxR1↓, Herein, we demonstrate that sulforaphane (SFN), an isothiocyanate phytochemical with anti-cancer effects, inhibits the activity of thioredoxin reductase 1 (TrxR1)
ROS↑, This inhibition of TrxR1 leads to the accumulation of reactive oxygen species (ROS), thereby enhancing chemoradiotherapy-induced apoptosis in GBM cells.
ChemoSen↑,
Prx↓, Impaired/reduced function(ai)

2552- SFN,  Chemo,    Chemopreventive activity of sulforaphane
- Review, Var, NA
chemoPv↑, chemopreventive activity of SFN
TumCG↓, SFN can inhibit the initiation of tumor development or halt the progression of cancer
*ROS↓, SFN can also exhibit chemopreventive behavior by interfering with various signaling pathways that regulate oxidative stress, inflammation, cell proliferation, differentiation, and apoptosis
*Inflam↓,
*Dose↝, In rats, the pharmacokinetics of SFN was assessed following an oral dose of 50 μmol of SFN. The plasma concentration of SFN can be detected at 1 hour and it peaks at 20 μM at 4 hours.
*NRF2↑, epigenetic reactivation of Nrf2 and subsequent induction of downstream target genes HO-1, NQO1, and UGT1A1
*HO-1↑,
*NQO1↑,
NF-kB↓, inactivation of NF-κB is an important chemopreventive mechanism of SFN
ROS↑, It was demonstrated that SFN-induced apoptosis is mediated by reactive oxygen species (ROS)-mediated activation of AMPK in human gastric cancer cells.

2448- SFN,    Sulforaphane and bladder cancer: a potential novel antitumor compound
- Review, Bladder, NA
Apoptosis↑, Recent studies have demonstrated that Sulforaphane not only induces apoptosis and cell cycle arrest in BC cells, but also inhibits the growth, invasion, and metastasis of BC cells
TumCG↓,
TumCI↓,
TumMeta↓,
glucoNG↓, Additionally, it can inhibit BC gluconeogenesis
ChemoSen↑, demonstrate definite effects when combined with chemotherapeutic drugs/carcinogens.
TumCCA↑, SFN can block the cell cycle in G2/M phase, upregulate the expression of Caspase3/7 and PARP cleavage, and downregulate the expression of Survivin, EGFR and HER2/neu
Casp3↑,
Casp7↑,
cl‑PARP↑,
survivin↓,
EGFR↓,
HER2/EBBR2↓,
ATP↓, SFN inhibits the production of ATP by inhibiting glycolysis and mitochondrial oxidative phosphorylation in BC cells in a dose-dependent manner
Glycolysis↓,
mt-OXPHOS↓,
AKT1↓, dysregulation of glucose metabolism by inhibiting the AKT1-HK2 axis
HK2↓,
Hif1a↓, Sulforaphane inhibits glycolysis by down-regulating hypoxia-induced HIF-1α
ROS↑, SFN can upregulate ROS production and Nrf2 activity
NRF2↑,
EMT↓, inhibiting EMT process through Cox-2/MMP-2, 9/ ZEB1 and Snail and miR-200c/ZEB1 pathways
COX2↓,
MMP2↓,
MMP9↓,
Zeb1↓,
Snail↓,
HDAC↓, FN modulates the histone status in BC cells by regulating specific HDAC and HATs,
HATs↓,
MMP↓, SFN upregulates ROS production, induces mitochondrial oxidative damage, mitochondrial membrane potential depolarization, cytochrome c release
Cyt‑c↓,
Shh↓, SFN significantly lowers the expression of key components of the SHH pathway (Shh, Smo, and Gli1) and inhibits tumor sphere formation, thereby suppressing the stemness of cancer cells
Smo↓,
Gli1↓,
BioAv↝, SFN is unstable in aqueous solutions and at high temperatures, sensitive to oxygen, heat and alkaline conditions, with a decrease in quantity of 20% after cooking, 36% after frying, and 88% after boiling
BioAv↝, It has been reported that the ability of individuals to use gut myrosinase to convert glucoraphanin into SFN varies widely
Dose↝, Excitingly, it has been reported that daily oral administration of 200 μM SFN in melanoma patients can achieve plasma levels of 655 ng/mL with good tolerance

1459- SFN,  AF,    Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway
- in-vitro, Liver, Hep3B - in-vitro, Liver, HepG2
eff↑, sulforaphane significantly enhanced auranofin-induced apoptosis by inhibiting TrxR activity and cell proliferation compared to either single treatment
TumCCA↑, Sub-G1 cells
Apoptosis↑,
MMP↓,
BAX↑,
cl‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
ROS↑, combined treatment induced excessive generation of reactive oxygen species (ROS)
eff↓, treatment with N-acetyl-L-cysteine, a ROS scavenger, reduced combined treatment-induced ROS production and apoptosis.
PI3K↓,
Akt↓,
TrxR↓, treatment with either sulforaphane or auranofin alone at low concentrations weakly inhibit TrxR activity Combined treatment significantly reduced TrxR activity and cell viability
BAX↑,
Bcl-2∅,

1471- SFN,    ROS-mediated activation of AMPK plays a critical role in sulforaphane-induced apoptosis and mitotic arrest in AGS human gastric cancer cells
- in-vitro, GC, AGS
TumCP↓,
Apoptosis↑,
TumCCA↑, G2/M phase
CycB/CCNB1↑,
P21↑,
p‑H3↑,
p‑AMPK↑,
eff↓, compound C, an AMPK inhibitor, significantly blocked sulforaphane-induced apoptosis
MMP↓,
Cyt‑c↑,
ROS↑, sulforaphane provoked the generation of intracellular ROS
eff↓, sulforaphane provoked the generation of intracellular ROS; especially when ROS production was blocked by antioxidant N-acetylcysteine, both AMPK activation and growth inhibition by sulforaphane were completely abolished

1470- SFN,  Rad,    Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vitro, Lung, A549 - in-vitro, lymphoma, U937
eff↓, NK cell mediated killing was abrogated by N-acetyl cysteine in A549 and MDA-MB-231 cells suggesting a ROS mediated mechanism.
ROS↑,
NKG2D↑, ability to up-regulate natural killer group 2, member D (NKG2D) ligands and modulate the susceptibility of tumor cells to natural killer (NK) cell-mediated killing.

1469- SFN,    Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vivo, Pca, NA
eff↑, Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells.
ROS↑,
MMP↓,
Casp3↑,
Casp9↑,
DR4↑,
DR5↑,
BAX↑,
Bak↑,
BIM↑,
NOXA↑,
Bcl-2↓,
Bcl-xL↓,
Mcl-1↓,
eff↓, quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis.
TumCG↓,
TumCP↓,
eff↑, enhanced the antitumor activity of TRAIL.
NF-kB↓,
PI3K↓,
Akt↓,
MEK↓,
ERK↓,
angioG↓, combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone.
FOXO3↑,

1468- SFN,    Cellular responses to dietary cancer chemopreventive agent D,L-sulforaphane in human prostate cancer cells are initiated by mitochondrial reactive oxygen species
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3
ROS↑,
DNAdam↑,
MMP↓,
Cyt‑c↑,
TumCCA↑, G2/M phase cell cycle arrest

1467- SFN,    Sulforaphane generates reactive oxygen species leading to mitochondrial perturbation for apoptosis in human leukemia U937 cells
- in-vitro, AML, U937
Apoptosis↑,
ROS↑,
MMP↓, collapse of MMP
Casp3↑,
Bcl-2↓,
eff↓, quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-elicited ROS generation, disruption of the MMP, caspase-3 activation and apoptosis.

1466- SFN,    Sulforaphane inhibits thyroid cancer cell growth and invasiveness through the reactive oxygen species-dependent pathway
- vitro+vivo, Thyroid, FTC-133
TumCP↓,
TumCCA↑, G2/M phase
Apoptosis↑,
TumCMig↓,
TumCI↓,
EMT↓,
Slug↓,
Twist↓,
MMP2↓,
MMP9↓,
TumCG↓,
p‑Akt↓,
P21↑,
ERK↑,
p38↑,
ROS↑, ROS was significantly induced in both FTC133 and K1 cells when cells were treated with 40 μM SFN for 4 h Several previous studies have shown that SFN induces ROS
*toxicity∅, we did not find significant effect of SFN on body weight and liver function of mice.
MMP↓,
eff↓, Like NAC, ASC treatment significantly attenuated anti-proliferative effect of SFN in these two cell lines

1465- SFN,    TRAIL attenuates sulforaphane-mediated Nrf2 and sustains ROS generation, leading to apoptosis of TRAIL-resistant human bladder cancer cells
- NA, Bladder, NA
eff↑, Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis
Apoptosis↑,
Casp↑,
MMP↓,
BID↑,
DR5↑,
ROS↑, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme.
NRF2↑,
eff↑, Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone.
eff↓, blockade of ROS generation inhibited apoptotic activity

1464- SFN,    d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway
- in-vitro, GBM, NA
Apoptosis↑,
Casp3↑,
BAX↑,
Bcl-2↓,
ROS↑, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells
p‑STAT3↓,
JAK2↓,
eff↓, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis

1463- SFN,    Sulforaphane induces reactive oxygen species-mediated mitotic arrest and subsequent apoptosis in human bladder cancer 5637 cells
- in-vitro, Bladder, 5637
tumCV↓,
CycB/CCNB1↑, concomitant increased complex between cyclin B1 and Cdk1
p‑CDK1↑, of cyclin B1 and phosphorylation of Cdk1
Apoptosis↑,
Casp8↑,
Casp9↑,
Casp3↑,
cl‑PARP↑,
ROS↑, maximum level of ROS accumulation was observed 3h after sulforaphane treatment.
eff↓, ROS scavenger, N-acetyl-L-cysteine, notably attenuated sulforaphane-mediated apoptosis as well as mitotic arrest

1460- SFN,    High levels of EGFR prevent sulforaphane-induced reactive oxygen species-mediated apoptosis in non-small-cell lung cancer cells
- in-vitro, Lung, NA
ROS↑, Sulforaphane (SFN) has been shown to induce the production of reactive oxygen species (ROS) and inhibit epidermal growth factor receptor (EGFR)
EGFR↓,
eff↓, We present evidence that cells with high-level EGFR expression (CL1-5) are more resistant to SFN treatment than those with low-level expression (CL1-0)
TumCCA↑, S-phase
γH2AX↑,
DNAdam↑,
eff↓, Pretreatment with the antioxidant N-acetyl-L-cysteine prevented SFN-induced apoptosis in CL1-0 cells and production of γH2AX in both CL1-0 and CL1-5 cells.

1472- SFN,    Sulforaphane Inhibits Autophagy and Induces Exosome-Mediated Paracrine Senescence via Regulating mTOR/TFE3
- in-vitro, ESCC, NA
TumCP↓,
ROS↑, SFN induces reactive oxygen species (ROS) via disrupting the balance between glutathione and oxidized glutathione, leading to DNA damage.
DNAdam↑,

1458- SFN,    Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma
- Review, Bladder, NA
HDAC↓, SFN’s role as a natural HDAC-inhibitor is highly relevant
eff↓, SFN exerts stronger anti-proliferative effects on bladder cancer cell lines under hypoxia, compared to normoxic conditions
TumW↓, mice, SFN (52 mg/kg body weight) for 2 weeks reduced tumor weight by 42%
TumW↓, In another study a 63% inhibition was noted when tumor bearing mice were treated with SFN (12 mg/kg body weight) for 5 weeks
angioG↓,
*toxicity↓, In both investigations, the administration of SFN did not evoke apparent toxicity
GutMicro↝, SFN may protect against chemical-induced bladder cancer by normalizing the composition of gut microbiota and repairing pathophysiological destruction of the gut barrier,
AntiCan↑, A prospective study involving nearly 50,000 men indicated that high cruciferous vegetable consumption may reduce bladder cancer risk
ROS↑, Evidence shows that SFN upregulates the ROS level in T24 bladder cancer cells to induce apoptosis
MMP↓,
Cyt‑c↑,
Bax:Bcl2↑,
Casp3↑,
Casp9↑,
Casp8∅,
cl‑PARP↑,
TRAIL↑, ROS generation promotes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity
DR5↑,
eff↓, Blockade of ROS generation inhibited apoptotic activity and prevented Nrf2 activation in cells treated with SFN, pointing to a direct effect of ROS on apoptosis
NRF2↑, SFN potently inhibits carcinogenesis via activation of the Nrf2 pathway
ER Stress↑, endoplasmic reticulum stress evoked by SFN
COX2↓, downregulates COX-2 in T24 cells
EGFR↓, downregulation of both the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2/neu
HER2/EBBR2↓,
ChemoSen↑, gemcitabine/cisplatin and SFN triggered pathway alterations in bladder cancer may open new therapeutic strategies, including a combined treatment regimen to cause additive effects.
NF-kB↓,
TumCCA?, cell cycle at the G2/M phase
p‑Akt↓,
p‑mTOR↓,
p70S6↓,
p19↑, p19 and p21, are elevated under SFN
P21↑,
CD44↓, CD44s expression correlates with induced intracellular levels of ROS in bladder cancer cells variants v3–v7 on bladder cancer cells following SFN exposure
CSCs↓, CD44 is not only involved in cytoskeletal changes and cellular motility but also serves as a cancer stem cell (CSC) marker

1456- SFN,    Sulforaphane regulates cell proliferation and induces apoptotic cell death mediated by ROS-cell cycle arrest in pancreatic cancer cells
- in-vitro, PC, MIA PaCa-2 - in-vitro, PC, PANC1
tumCV↓,
TumCP↓,
cl‑PARP↑,
cl‑Casp3↑,
TumCCA↑, accumulation in the sub G1 phase
ROS↑, SFN caused a considerable increase in ROS in MIA PaCa-2 and PANC-1 cells as compared to the control group
MMP↓, SFN increased ROS level and γH2A.X expression while decreasing mitochondrial membrane potential (ΔΨm).
γH2AX↑,
eff↓, (NAC) was shown to reverse SFN-induced cytotoxicity and ROS level.
*toxicity↓, HUVECs, used as normal control cells, did not show significant inhibitory effects at SFN concentrations below 20 μM

1455- SFN,    Sulforaphane Activates a lysosome-dependent transcriptional program to mitigate oxidative stress
- in-vitro, Cerv, HeLa - in-vitro, Nor, 1321N1
*ROS↓, SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases. SFN treatment prevented CCCP-induced ROS increases in WT 1321N1 cells(normal)
*BioAv↑, Tissue concentrations of SFN can reach 3–30 μM upon broccoli consumption
LC3II↑, SFN (15 μM, 3–9 h) treatment markedly increased endogenous LC3-II levels in HeLa cells
LAMP1?, gradual (within hours) increases in the expression of LAMP1 proteins upon SFN (15 μM, 3–9 h) treatment in HeLa cells
TumAuto↑, SFN led to enhanced lysosomal and autophagic function.
TFEB↑, SFN (10–15 μM) treatment for 4 h induced nuclear translocation of endogenous TFEB in HeLa cells
ROS↑, SFN treatment for 2 h resulted in a mild increase of intracellular ROS. ROS mediate some effects of SFN
eff↓, NAC (5 mM), a commonly used membrane-permeable antioxidant compound [7], prevented SFN-induced increases in ROS

1474- SFN,    Sulforaphane induces p53‑deficient SW480 cell apoptosis via the ROS‑MAPK signaling pathway
- in-vitro, Colon, SW480
TumCG↓,
Apoptosis↑,
MMP↓,
Bax:Bcl2↑,
Casp3↑,
Casp7↑,
Casp9↑,
ROS↑, increase in the generation of reactive oxygen species (ROS)
e-ERK↑, activation of extracellular signal‑regulated kinases (Erk)
p38↑,
P53∅,
eff↓, specific inhibitors for ROS, phosphorylated (p)‑Erk and p‑p38, completely or partially attenuated the SFN‑induced reduction in SW480 cell viability
ChemoSen↑, even at the lowest concentrations (5 µM), SFN increased the sensitivity of p53‑proficient HCT‑116 cells to cisplatin

1494- SFN,  doxoR,    Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model
- in-vivo, BC, NA - in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
CardioT↓, SFN (4 mg/kg, 5 days/week) protected against mortality and cardiac dysfunction induced by DOX
*GSH↑, Rats Hearts: SFN and DOX co-treatment reduced MDA and 4-HNE adduct formation and also prevented DOX-induced depletion of GSH levels
*ROS↓, SFN reduces DOX-induced oxidative stress in the heart of non-tumor bearing rats.
*NRF2↑, activates Nrf2 in rat hearts during DOX treatment
NRF2∅, SFN does not interfere with DOX toxicity or Nrf2 activity in breast cancer cell lines
HDAC↓, SFN acts synergistically with DOX to inhibit HDAC and DNMT activity, decrease ERα detection and increase caspase-3 activity
DNMTs↓,
Casp3↑,
ER-α36↓, ERα levels in MCF-7, MDA-MB-231
Remission↑, SFN+DOX treatment (with a total DOX dose of 20 mg/kg) was able to eradicate the tumors in all rats by day 35 after tumor implantation
eff↑, SFN (4 mg/kg oral; 5 days/week for 5 weeks) with DOX (total of 10 or 20 mg/kg i.p. administered over 4 weeks) and showed that in combination with SFN, the dosage of DOX could be < by 50% while still eliciting the same anti-cancer effects as DOX alone
ROS↑, Increased generation of reactive oxygen species (ROS), an altered redox status, and aerobic glycolysis for energy production distinguish highly proliferative cancer cells from normal healthy cells
selectivity?, ROS production... distinguish highly proliferative cancer cells from normal healthy cells

1483- SFN,    Targeting p62 by sulforaphane promotes autolysosomal degradation of SLC7A11, inducing ferroptosis for osteosarcoma treatment
- in-vitro, OS, 143B - in-vitro, Nor, HEK293 - in-vivo, OS, NA
AntiCan↑, has shown potential anti-cancer effects with negligible toxicity
*toxicity∅, (liver, kidney, heart, spleen, and lung) showed no evidence of toxicity associated with SFN treatment
Ferroptosis↑, results demonstrate the dependency of downregulation of SLC7A11 in SFN-induced ferroptosis in OS cells
ROS↑, elevated ROS levels, lipid peroxidation, and GSH depletion
lipid-P↑,
GSH↓, which was dependent on decreased levels of SLC7A11
p62↑, enhanced p62/SLC7A11 protein-protein interaction, thereby promoting the lysosomal degradation of SLC7A11 and triggering ferroptosis
SLC12A5↓, SFN induces ferroptosis of OS cells through downregulation of SLC7A11
eff↓, ferroptosis inhibitors Fer-1 (ferrostatin-1), DFO (deferoxamine), and Lip-1 (liproxstatin-1) substantially rescued the cells from SFN-induced cell death
GPx4↓, SFN treatment markedly reduced the expression levels of ferroptosis markers GPX4 and SLC7A11 in OS cells
i-Iron↑, validated the intracellular Fe2+ accumulation by SFN
eff↓, SLC7A11 overexpression notably reversed SFN-induced changes in the ROS level, GSH level, and lipid peroxidation
MDA↑, SFN treatment reduced GSH levels and increased MDA production, indicating the induction of ferroptosis
TumVol↓,
TumW↓,
Ki-67↓, subcutaneous tumors revealed significantly lower expression levels of Ki67, SLC7A11, and GPX4, along with upregulated LC3B in the SFN-treated group
LC3B↑,
*Weight∅, no significant difference in body weight was observed between the control and SFN-treated groups

1482- SFN,    Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway
- in-vitro, Bladder, T24/HTB-9
tumCV↓,
Apoptosis↑,
Cyt‑c↑,
Bax:Bcl2↑, Bcl-2/Bax dysregulation
Casp9↑,
Casp3↑,
Casp8∅,
cl‑PARP↑,
ROS↑, sulforaphane triggered reactive oxygen species (ROS) generation
MMP↓,
eff↓, blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine.
ER Stress↑,
p‑NRF2↑, accumulation of phosphorylated Nrf2 proteins in the nucleus
HO-1↑, induction of heme oxygenase-1 expression

1481- SFN,  docx,    Combination of Low-Dose Sulforaphane and Docetaxel on Mitochondrial Function and Metabolic Reprogramming in Prostate Cancer Cell Lines
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3
ChemoSen↑, SFN:DCT combination reduced cell viability to 50%
Casp3↑,
ROS↑, see figure 4
Casp8↑,
Cyt‑c↑, see figure 4
Glycolysis↓, see figure 4
GSH↓, see figure 4
GSH/GSSG↓, GSH/GSSG
*toxicity↓, SFN:DCT combination, administered at reduced doses, not only preserves efficacy but also minimizes toxicity

1480- SFN,    Sulforaphane Induces Cell Death Through G2/M Phase Arrest and Triggers Apoptosis in HCT 116 Human Colon Cancer Cells
- in-vitro, CRC, HCT116
tumCV↓,
TumCCA↑, G2/M phase arrest
Apoptosis↑,
cycA1/CCNA1↑,
CycB/CCNB1↑,
CDC25↓, Cdc 25C
CDK1↓,
ROS↑, SFN induced the generation of reactive oxygen species (ROS)
eff↓, Ca[Formula: see text] and decreased mitochondria membrane potential and increased caspase-8, -9 and -3 activities in HCT 116 cell
Cyt‑c↑,
AIF↑,
ER Stress↑,

1479- SFN,    Sulforaphane triggers Sirtuin 3-mediated ferroptosis in colorectal cancer cells via activating the adenosine 5'-monophosphate (AMP)-activated protein kinase/ mechanistic target of rapamycin signaling pathway
- in-vitro, CRC, HCT116
Ferroptosis↑, sulforaphane triggered the ferroptosis of HCT-116 cells by activating the SIRT3/AMPK/mTOR axis
SIRT3↑,
AMPK↑,
mTOR↑,
tumCV↓, SIRT3 overexpression reduced cell viability and increased intracellular levels of ROS, MDA, and iron
ROS↑,
MDA↑,
Iron↑,

1477- SFN,    Sulforaphane Induces Oxidative Stress and Death by p53-Independent Mechanism: Implication of Impaired Glutathione Recycling
- in-vitro, OS, MG63
tumCV↓,
Apoptosis↑,
Casp3↑,
ROS↑, >=10 μM, At these higher doses, SFN increased ROS levels
GSR↓, inhibition of glutathione reductase
GPx↓,

1476- SFN,  PDT,    Enhancement of cytotoxic effect on human head and neck cancer cells by combination of photodynamic therapy and sulforaphane
- in-vitro, HNSCC, NA
eff↑, Cell viability was decreased significantly by combination treatment
tumCV↓,
ROS↑, ROS generation was also higher in combination treatment
eff↓, In combination treatment group, apoptosis and necrosis were decreased by administration of sodium azide (SA) which is scavenger of ROS.
Casp↑,

1475- SFN,  Form,    Combination of Formononetin and Sulforaphane Natural Drug Repress the Proliferation of Cervical Cancer Cells via Impeding PI3K/AKT/mTOR Pathway
- in-vitro, Cerv, HeLa
TumCP↓,
PI3K↓,
Akt↓,
mTOR↓,
eff↑, cytotoxicity of FN and SFN was determined to be around 23.7 µM and 26.92 µM, respectively. Combining FN and SFN causes considerable cytotoxicity in HeLa cells, with an IC50 of 21.6 µM
ROS↑, considerable ROS generation

1730- SFN,    Sulforaphane: An emergent anti-cancer stem cell agent
- Review, Var, NA
BioAv↓, When exposed to high temperatures during meal preparation, myrosinase can be degraded, lose its function, and subsequently compromise the synthesis of SFN.
BioAv↑, eating raw cruciferous vegetables, instead of heating them can significantly improve the biodisponibility of SFN and its subsequent beneficial effects.
GSTA1↑, induction of Phase II enzymes [glutathione S-transferase (GST)
P450↓, (cytochrome P450, CYP) inhibition
TumCCA↑, herb-derived agent can also promote cell cycle arrest and apoptosis by regulating different signaling pathways including Nuclear Factor erythroid Related Factor 2 (Nrf2)-Keap1 and NF-κB.
HDAC↓, modulate the activity of some epigenetic factors, such as histone deacetylases (HDAC),
P21↑, upregulation of p21 and p27,
p27↑,
DNMT1↓, SFN was able to decrease the expression of DNMT1 and DNMT3 in LnCap prostate cancer cells
DNMT3A↓,
cycD1/CCND1↑, reduce methylation in Cyclin D2 promoter, thus inducing Cyclin D2 gene expression in those cells
DNAdam↑, SFN induced DNA damage, enhanced Bax expression and the release of cytochrome C followed by apoptosis
BAX↑,
Cyt‑c↑,
Apoptosis↑,
ROS↑, SFN increased reactive oxygen species (ROS), apoptosis-inducing factor (AIF)
AIF↑,
CDK1↑,
Casp3↑, activation of caspase-3, -8, and -9
Casp8↑,
Casp9↑,
NRF2↑, SFN significantly activated the major antioxidant marker Nrf2 and decreased NFκB, TNF-α, IL-1β
NF-kB↓,
TNF-α↓,
IL1β↓,
CSCs↓, SFN, have attracted attention due to their anti-CSC effect
CD133↓,
CD44↓,
ALDH↓,
Nanog↓,
OCT4↓,
hTERT/TERT↓,
MMP2↓,
EMT↓, SFN was reported to inhibit EMT and metastasis in the NSCLC, the cell lines H1299
ALDH1A1↓, ALDH1A1), Wnt3, and Notch4, other CSC-related genes inhibited by SFN treatment
Wnt↓,
NOTCH↓, SFN can inhibit aberrantly activated embryonic pathways in CSCs, including Sonic Hedgehog (SHH), Wnt/β-catenin, Cripto-1 (CR-1), and Notch.
ChemoSen↑, These results suggest that the antioxidant properties of SFN do not impact the cytotoxicity of antineoplastic drugs, but on the contrary, seems to improve it.
*Ki-67↓, Ki-67 and HDAC3 levels significantly decreased in benign breast tissues, and there was also a reduction in HDAC activity in blood cells
*HDAC3↓,
*HDAC↓,

1723- SFN,    Sulforaphane as a potential remedy against cancer: Comprehensive mechanistic review
- Review, Var, NA
*NRF2↑, activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In this way, the oxidative stress and other toxicants are diminished
ROS↑, Cytotoxic effects of SFN are delivered via complex mechanisms where ROS generation results in improving apoptosis
MMP↓, ROS generation is also followed by mitochondrial membrane potential disruption that results in cytochrome c cytosolic release cleaving the poly-ADP-ribose polymerase and apoptosi
Cyt‑c↑,
cl‑PARP↑,
Apoptosis↑,
AMPK↑, AMPK signaling activated by SFN, high concentrations of ROS are produced
GSH↓, SFN-induced ROS generation also results in depletion of GSH levels

1722- SFN,    Sulforaphane as an anticancer molecule: mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems
- Review, Var, NA
TumCCA↑, arresting cell cycle in the G2/M and G1 phase
CYP1A1↓, Sulforaphane inhibits CYP1A1 and CYP3A4 and decease the activity of CYP3A4
CYP3A4↓,
Cyt‑c↑, release of cytochrome C from the mitochondria
Casp9↑,
Apoptosis↑,
ROS↑, generation of reactive oxygen species (ROS), and mitogen-activated protein kinases (MAPK)
MAPK↑,
P53↑, sulforaphane treatment increased p53 protein expression with associated increase in the protein levels of Bax
BAX↑,
ChemoSen↑, Combination therapies target multiple cell survival pathways, which results in synergism
HDAC↓, HDACi Histone deacetylase inhibition
GSH↓, fig 3
HO-1↑, They found that the protective effect of sulforaphane is mediated by the activation of the Keap1/Nrf2/ARE pathway, which consequently induce HO-1

3301- SIL,    Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid
- Review, Var, NA
Inflam↓, graphical abstract
TumCCA↑,
Apoptosis↓,
TumMeta↓,
TumCG↓,
angioG↓,
chemoP↑, The chemo-protective effects of silymarin and silibinin propose that they could be applied to decrease the side effects and increase the anti-tumor effects of chemotherapy and radiotherapy in different types of cancers.
radioP↑,
p‑ERK↓, fig 2
p‑p38↓,
p‑JNK↓,
P53↑,
Bcl-2↓,
Bcl-xL↓,
TGF-β↓,
MMP2↓,
MMP9↓,
E-cadherin↑,
Wnt↓,
Vim↓,
VEGF↓,
IL6↓,
STAT3↓,
*ROS↓,
IL1β↓,
PGE2↓,
CDK1↓, Causes cell cycle arrest by down-regulating CDK1, cyclinB1, survivin, Bcl-xl, Mcl-1 and activating caspase 3 and caspase 9,
CycB/CCNB1↓,
survivin↓,
Mcl-1↓,
Casp3↑,
Casp9↑,
cMyc↓, Silibinin treatment diminishes c-MYC
COX2↓, Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, Ang-4, MMP-2, MMP-9, CCR-2 and CXCR-4
Hif1a↓,
CXCR4↓,
CSCs↓, HCT-116 cells, Induction of apoptosis, suppression of migration, elimination of CSCs. Attenuation of EMT via decreased expression of N- cadherin and vimentin and increased expression of (E-cadherin).
EMT↓,
N-cadherin↓,
PCNA↓, Decrease in PCNA and cyclin D1 level.
cycD1/CCND1↓,
ROS↑, Hepatocellular carcinoma: Silymarin nanoemulsion reduced the cell viability and increased ROS intensity and chromatin condensation.
eff↑, Silymarin + Curcumin
eff↑, Silibinin + Metformin
eff↑, Silibinin + 1, 25-vitamin D3
HER2/EBBR2↓, Significant down regulation of HER2 by 150 and 250 µM of silybin after 24, 48 and 72 h.

3306- SIL,  Rad,    Radioprotective and radiosensitizing properties of silymarin/silibinin in response to ionizing radiation
- Review, Var, NA
radioP↑, Radioprotective and radiosensitizing properties of silymarin/silibinin in response to ionizing radiation
RadioS↑, graphical abstract
TumCMig↓, mechanisms for radiosensitization of silymarin/silibinin have been reported including suppression of migration and invasion of cancer cells, inhibition of angiogenesis, induction of apoptosis and cell cycle arrest, damage to DNA
TumCI↓,
angioG↓,
Apoptosis↑,
DNAdam↓,
ROS↑, increasing the formation of free radicals, and targeting some crucial pathways.
*ROS↓, The combination of silymarin/silibinin and irradiation decreases the toxicities caused by ionizing radiation because of their antioxidant, anti-apoptotic, anti-inflammatory and other properties.
*Inflam↓,

3309- SIL,    Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives
- Review, NA, NA
*ROS↓, (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut.
*IronCh↑,
*MMP↑, (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance.
*NRF2↑, (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation
*Inflam↓, (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases.
*hepatoP↑,
*HSPs↑, (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins
*Trx↑,
*SIRT2↑, increased expression of protective molecules (GSH, Thioredoxins, heat shock proteins (HSPs), sirtuins, etc.)
*GSH↑,
*ROS↑, Similarly, production of O2− and NO in isolated rat Kupffer cells were inhibited by silibinin in a dose-dependent manner, with IC50 80 μM
*NADPH↓, It also decreased the NADPH oxidase, iNOS and NF-κB over expression by As and upregulated the Nrf2 expression in the renal tissue.
*iNOS↓,
*NF-kB↓,
*BioAv↓, active free silibinin concentration in plasma after oral consumption of SM, depending on dose of supplementation, could be in the range 0.2–2.0 μM.
*Dose↝, healthy volunteers, after an oral administration of SM (equivalent to 120 mg silibinin), total (unconjugated + conjugated) silibinin concentration in plasma was 1.1–1.3 μg/mL
*BioAv↑, For example, silibinin concentration in the gut could reach 800 μM

3299- SIL,    Silymarin Effect on Mitophagy Pathway in the Human Colon Cancer HT-29 Cells
- in-vitro, Colon, HT29
tumCV↓, Silymarin significantly reduced the viability percentage of the HT-29 cells depending on the concentration
MMP↓, It also significantly decreased MMP in a concentration-dependent manner while significantly increased ROS formation in the HT-29 cells
ROS↑,
selectivity↑, Silymarin did not cause significant changes in the viability percentage, ROS level, and MMP of the NIH-3T3 non-cancerous cells at different concentrations.

3298- SIL,    Silibinin, a natural flavonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells
- in-vitro, BC, MCF-7
LC3II↑, silibinin triggered the conversion of light chain 3 (LC3)-I to LC3-II, promoted the upregulation of Atg12-Atg5 formation, increased Beclin-1 expression, and decreased the Bcl-2 level.
Beclin-1↑,
Bcl-2↓,
ROS↑, Moreover, we noted elevated reactive oxygen species (ROS) generation, concomitant with the dissipation of mitochondrial transmembrane potential (ΔΨm) and a drastic decline in ATP levels following silibinin treatment,
MMP↓,
ATP↓,
eff↓, which were effectively prevented by the antioxidants, N-acetylcysteine and ascorbic acid
BNIP3?, silibinin upregulated BNIP3 protein and transcript levels
TumAuto↑, uggesting that the MCF7 cells were more sensitive to silibinin-induced autophagic cell death under the starvation condition.
eff↑, more sensitive to silibinin-induced autophagic cell death under the starvation condition.

3296- SIL,    Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway
- in-vitro, Oral, Ca9-22 - in-vivo, Oral, YD10B
TumCP↓, Silibinin effectively suppressed YD10B and Ca9-22 cell proliferation and colony formation in a dose-dependent manner.
TumCCA↑, Moreover, it induced cell cycle arrest in the G0/G1 phase, apoptosis, and ROS generation in these cells.
ROS↑,
SOD1↓, silibinin downregulated SOD1 and SOD2 and triggered the JNK/c-Jun pathway in oral cancer cells.
SOD2↓,
*JNK↑, inducing apoptosis, G0/G1 arrest, ROS generation, and activation of the JNK/c-Jun pathway.
toxicity?, Silibinin significantly inhibited xenograft tumor growth in nude mice, with no obvious toxicity.
TumCMig↓, Silibinin inhibits oral cancer cell migration and invasion
TumCI↓,
N-cadherin↓, silibinin downregulated N-cadherin and vimentin expression and upregulated E-cadherin expression in YD10B and Ca9-22 cells
Vim↓,
E-cadherin↑,
EMT↓, Together, these results indicate that silibinin inhibits the migration and invasion of oral cancer cells by suppressing the EMT.
P53↑, silibinin significantly induced the expression of p53, cleaved caspase-3, cleaved PARP, and Bax, and downregulated the expression of the anti-apoptotic marker protein Bcl-2
cl‑Casp3↑,
cl‑PARP↑,
BAX↑,
Bcl-2↓,
SOD↓, silibinin inhibits SOD expression, induces ROS production, and activates the JNK/c-Jun pathway in oral cancer cells.

3292- SIL,  Fe,    Anti-tumor activity of silymarin nanoliposomes in combination with iron: In vitro and in vivo study
- in-vitro, BC, 4T1 - in-vivo, BC, 4T1
*antiOx↑, Silymarin (SLM) has been extensively investigated due to its potent antioxidant properties and demonstrated efficacy against cancer cells.
ROS↑, we hypothesized that the simultaneous administration of iron (Fe) could alter the antioxidant characteristic of SLM nanoliposomes (SLM Lip) to a prooxidant state
OS↑,
Weight↑,
TumVol↓,
eff↑, In the current study, silymarin nanoliposomes showed higher toxicity on 4 T1 cells when combined with iron sucrose.
Fenton↑, By exchanging iron species during the Fenton reaction (Fe3+ ↔ Fe2+), the ROS levels could increase

3290- SIL,    A review of therapeutic potentials of milk thistle (Silybum marianum L.) and its main constituent, silymarin, on cancer, and their related patents
- Analysis, Var, NA
hepatoP↑, well as hepatoprotective agents.
chemoP↑, silymarin could be beneficial to oncology patients, especially for the treatment of the side effects of anticancer chemotherapeutics.
*lipid-P↓, Silymarin has been shown to significantly reduce lipid peroxidation and exhibit anti-oxidant, antihypertensive, antidiabetic, and hepatoprotective effects
*antiOx↑,
tumCV↓, reduces the viability, adhesion, and migration of tumor cells by induction of apoptosis and formation of reactive oxygen species (ROS), reducing glutathione levels, B-cell lymphoma 2 (Bcl-2), survivin, cyclin D1, Notch 1 intracellular domain (NICD),
TumCMig↓,
Apoptosis↑,
ROS↑,
GSH↓,
Bcl-2↓,
survivin↓,
cycD1/CCND1↓,
NOTCH1↓,
BAX↑, as well as enhancing the amount of Bcl-2-associated X protein (Bax) level (
NF-kB↓, The suppression of NK-κB-regulated gene products (e.g., cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), and interleukin-1 (IL-1)) mediates the anti-inflammatory effect of silymarin
COX2↓,
LOX1↓,
iNOS↓,
TNF-α↓,
IL1↓,
Inflam↓,
*toxicity↓, Silymarin is also safe for humans, hence at therapeutic doses patients demonstrated no negative effects at the high dose of 700 mg, three times a day, for 24 weeks
CXCR4↓, fig 2
EGFR↓,
ERK↓,
MMP↓, reduction in mitochondrial transmembrane potential due to an increase in cytosolic cytochrome complex (Cyt c) levels.
Cyt‑c↑,
TumCCA↑, Moreover, silymarin increased the percentage of cells in the gap 0/gap 1 (G0/G1) phase and decreased the percentage of cells in the synthesis (S)-phase,
RB1↑, concomitant up-regulation of retinoblastoma protein (Rb), p53, cyclin-dependent kinase inhibitor 1 (p21Cip1), and cyclin-dependent kinase inhibitor 1B (p27Kip1)
P53↑,
P21↑,
p27↑,
cycE/CCNE↓, and down-regulation of cyclin D1, cyclin E, cyclin-dependent kinase 4 (CDK4), and phospho-Rb
CDK4↓,
p‑pRB↓,
Hif1a↓, silibinin inhibited proliferation of Hep3B cells due to simultaneous induction of apoptosis and prevented the accumulation
cMyc↓, Silibinin also reduces cellular myelocytomatosis oncogene (c-MYC) expression, a key regulator of cancer metabolism in pancreatic cancer cells
IL1β↓, Silymarin can also inhibit the production of inflammatory cytokines, such as interleukin-1beta (IL-1β), interferon-gamma (IFNγ),
IFN-γ↓,
PCNA↓, ilymarin suppresses the high proliferative activity of cells started with a carcinogen so that it significantly inhibits proliferating cell nuclear antigen (PCNA) and cyclin D1 labeling indices
PSA↓, In another patent, S. marianum has been used as an estrogen receptor β-agonist and an inhibitor of PSA for treating prostate cancer
CYP1A1↓, Silymarin prevents the expression of CYP1A1 and COX-2

2410- SIL,    Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vivo, NA, NA
TumAuto↑, Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis.
ATP↓,
Glycolysis↓, Silibinin suppressed glycolysis in glioma cells
H2O2↑, Then, autophagy improves intracellular H2O2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT
P53↑,
GSH↓,
xCT↓,
BNIP3↝, The increased H2O2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria
MMP↑, silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide
mt-ROS↑,
mtDam↑, Autophagy contributed to silibinin-induced mitochondria damage
HK2↓, protein levels of HK II, PFKP, and PKM2 were all downregulated time-dependently by silibinin in U87, U251, SHG-44, and C6 glioma cells
PFKP↓,
PKM2↓, silibinin suppressed glycolysis via downregulation of HK II, PFKP, and PKM2.
TumCG↓, Silibinin inhibited glioma cell growth in vivo

978- SIL,    A comprehensive evaluation of the therapeutic potential of silibinin: a ray of hope in cancer treatment
- Review, NA, NA
PI3K↓,
Akt↓,
NF-kB↓,
Wnt/(β-catenin)↓,
MAPK↓,
TumCP↓,
TumCCA↑, G0/G1 cell cycle arrest
Apoptosis↑, In T24 and UM-UC-3 human bladder cancer cells, silibinin treatment at a concentration of 10 μM significantly inhibited proliferation, migration, invasion, and induced apoptosis.
p‑EGFR↓,
JAK2↓,
STAT5↓,
cycD1/CCND1↓,
hTERT/TERT↓,
AP-1↓,
MMP9↓,
miR-21↓,
miR-155↓,
Casp9↑,
BID↑,
ERK↓, ERK1/2
Akt2↓,
DNMT1↓,
P53↑,
survivin↓,
Casp3↑,
ROS↑, cytotoxicity of silibinin in Hep-2 cells was associated with the accumulation of intracellular reactive oxygen species (ROS), which could be mitigated by the ROS scavenger NAC.

5102- SK,  GEM,    Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway
TumCG↓, shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine.
ChemoSen↑,
NF-kB↓, down-regulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67)
PCNA↓,
Ki-67↓,
p‑EGFR↓, suppress EGFR phosphorylation [26], generate reactive oxygen species (ROS) [27], [28], arrest the cell cycle through p53 upregulation
ROS↑,
TumCCA↑,
P53↑,
JNK↑, activate the stress-related c-Jun-N-terminal kinase (JNK) pathway [30], and inactivate Akt and NF-κB pathways
Akt↓,

5101- SK,    Shikonin induces colorectal carcinoma cells apoptosis and autophagy by targeting galectin-1/JNK signaling axis
- vitro+vivo, CRC, SW-620 - vitro+vivo, CRC, HCT116
Apoptosis↑, shikonin induced CRC cells apoptosis and autophagy by targeting galectin-1 and JNK signaling pathway both in vitro and in vivo,
TumAuto↑,
Gal1↑, Our results also indicated that shikonin could up-regulate the expression and promote the dimerization of galectin-1
TumCP↓, Shikonin inhibits cell proliferation and induces apoptosis of colorectal cancer cells
ROS↑, Shikonin activates apoptosis and autophagy by upregulating levels of ROS in colorectal cancer cells
eff↑, we overexpressed galectin-1 in SW620 and HCT116 cells and found the two cell lines became more sensitive to shikonin

5100- SK,    Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression
- vitro+vivo, NPC, NA
TumCP↓, Shikonin exhibited a strong inhibitory effect on 5-8F cells in vitro and in vivo
RIP1↑, Moreover, RIPK1, RIPK3, and MLKL were upregulated by shikonin in a dose-dependent manner.
ROS↑, Shikonin induced 5-8F cell death via increased ROS production and the upregulation of RIPK1/RIPK3/MLKL expression, resulting in necroptosis.
Necroptosis↑,
Casp3↑, 7.5 μΜ shikonin significantly increased the activity of caspase-8 (Figure 2A) and caspase-3 (Figure 2B) compared with those of the control
Casp8↑,
eff↓, pretreatment with NAC protected the cells from shikonin mediated cell death.
TumCG↓, nude mice. Shikonin significantly inhibited the growth of the NPC tumors

2416- SK,    Shikonin induces cell death by inhibiting glycolysis in human testicular cancer I-10 and seminoma TCAM-2 cells
- in-vitro, Testi, TCAM-2
MMP↓, Shikonin treatment significantly reduced mitochondrial membrane potential, increased ROS levels and lower the level of lactic acid in both I-10 and TCAM-2 cells
ROS↑,
lactateProd↓,
Bcl-2↓, shikonin treatment significantly down- regulated the expressions of Bax, Bcl-2, cleaved caspase-3, PKM2, GLUT1 and HK2, and up-regulated the expression of autophagy-related protein LC3B
cl‑Casp3↓,
PKM2↓,
GLUT1↓,
HK2↓,
LC3B↑,

2415- SK,    Shikonin induces programmed death of fibroblast synovial cells in rheumatoid arthritis by inhibiting energy pathways
- in-vivo, Arthritis, NA
Apoptosis?, shikonin induced apoptosis and autophagy in RA-FLSs by activating the production of reactive oxygen species (ROS) and inhibiting intracellular ATP levels, glycolysis-related proteins, and the PI3K-AKT-mTOR signaling pathway.
TumAuto↑,
ROS↑,
ATP↓,
Glycolysis↓, shikonin can inhibit RA-glycolysis in FLSs
PI3K↓,
Akt↓,
mTOR↓,
*Apoptosis↓, Shikonin can significantly reduce the expression of apoptosis-related proteins, paw swelling in rat arthritic tissues, and the levels of inflammatory factors in peripheral blood, such as TNF-α, IL-6, IL-8, IL-10, IL-17A, and IL-1β while showing less
*Inflam↓,
*TNF-α↓,
*IL6↓,
*IL8↓,
*IL10↓,
*IL17↓,
*hepatoP↑, while showing less toxicity to the liver and kidney.
*RenoP↑,
PKM2↓, The expression of glycogen proteins PKM2, GLUT1, and HK2 decreased with increasing concentrations of shikonin
GLUT1↓,
HK2↓,

2355- SK,    Pharmacological properties and derivatives of shikonin-A review in recent years
- Review, Var, NA
AntiCan↑, anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis.
TumCP↓,
TumCMig↓,
Apoptosis↑,
TumAuto↑,
Necroptosis↑,
ROS↑, Shikonin also triggers Reactive Oxygen Species (ROS) generation
TrxR1↓, inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK
PKM2↓,
RIP1↓,
RIP3↓,
Src↓,
FAK↓,
PI3K↓, modulating the PI3K/AKT/mTOR and MAPKs signaling;
Akt↓, shikonin induced a dose-dependent reduction of miR-19a to inhibit the activity of PI3K/AKT/mTOR pathway
mTOR↓,
GRP58↓, shikonin induced apoptosis in human myeloid cell line HL-60 cells through downregulating the expression of ERS protein ERP57 (42).
MMPs↓, hikonin suppressed cell migration through inhibiting the NF-κB pathway and reducing the expression of MMP-2 and MMP-9
ATF2↓, shikonin inhibited cell proliferation and tumor growth through suppressing the ATF2 pathway
cl‑PARP↑, shikonin significantly upregulated the expression of apoptosis-related proteins cleaved PARP and caspase-3 and increased cell apoptosis through increasing the phosphorylation of p38 MAPK and JNK, and inhibiting the phosphorylation of ERK
Casp3↑,
p‑p38↑,
p‑JNK↑,
p‑ERK↓,

2362- SK,    RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide
- in-vitro, GBM, U87MG - in-vivo, GBM, NA - in-vitro, GBM, U251
RIP1↑, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression
RIP3↑,
Glycolysis↓,
G6PD↓, shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2
HK2↓,
PKM2↓,
H2O2↑, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine
GSH↓,
ROS↑, It was documented that inhibition of HK II with its inhibitor 3-bromopyruvate or knockdown of its level resulted in accumulation of ROS

2230- SK,    Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
TumCG↓, shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo
Bcl-2↓, Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins.
ROS↑, found that shikonin dose-dependently increased the generation of intracellular ROS in colon cancer cells
Bcl-xL↓, generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade
MMP↓,
Casp↑,
selectivity↑, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models
cycD1/CCND1↓, Cyclin D expression was decreased with shikonin treatment
TumCCA↑, induced cell growth inhibition by the induction G1 cell cycle arrest.
eff↓, NAC or GSH could block the shikonin-dependent burst of intracellular ROS

2200- SK,    Shikonin inhibits the growth of anaplastic thyroid carcinoma cells by promoting ferroptosis and inhibiting glycolysis
- in-vitro, Thyroid, CAL-62 - in-vitro, Thyroid, 8505C
NF-kB↓, SKN inhibits the expression of NF-κB,GPX4,TXNRD1,PKM2,GLUT1.
GPx4↓,
TrxR1↓, TXNRD1
PKM2↓,
GLUT1↓,
Glycolysis↓, inhibiting glycolysis in ATC cells.
Ferroptosis↑, SKN in inducing intracellular ferroptosis
GlucoseCon↓, Measurements of glucose uptake after 1, 3, and 5 μM concentrations of SKN treatment for 24 h showed a decrease in both cells
lactateProd↓, Lactate production in the cells decreased with the rise of SKN treatment concentration
ROS↑, cellular ROS increased significantly with the rise in SKN concentration

2199- SK,    Induction of Ferroptosis by Shikonin in Gastric Cancer via the DLEU1/mTOR/GPX4 Axis
- in-vitro, GC, NA
ROS↑, Shikonin could induce reactive oxygen species (ROS), lipid ROS, intracellular ferrous iron (Fe2+), and malondialdehyde (MDA) in GC.
lipid-P↑,
Iron↑,
MDA↑,
GPx4↓, shikonin decreased the expression of GPX4 by suppressing GPX4 synthesis and decreasing ferritin.
Ferritin↓,
DLEU1↓, shikonin decreased DLEU1 expression in GC cells
mTOR↓, shikonin might decrease GPX4 levels by inhibiting the DLEU1/mTOR pathway.
Ferroptosis↑, shikonin-induced ferroptosis

2198- SK,    Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis
- in-vitro, OS, MG63 - in-vitro, OS, 143B
TumCP↓, shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro.
TumCCA↑,
Ferroptosis↑, ferroptosis in OS cells by promoting the Fe2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
mtDam↑,
NRF2↓, influenced Nrf2 stability via inducing ubiquitin degradation, which suppressed the expression of Nrf2 downstream targets xCT and GPX4, and led to stimulating ferroptosis. Promoted Nrf2 degradation
xCT↓,
GPx4↓,
GSH/GSSG↓, GSH/GSSG ratio declined after shikonin (1.5 uM) treatment
Keap1↑, shikonin (1.5 uM) significantly downregulated the expression of Nrf2 and upregulated the expression of Keap1

2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
Ca+2↑,
BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
Bcl-2↓,
MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
NF-kB↓,
PKM2↓, Figure 4
Hif1a↓,
NRF2↓,
P53↑,
DNMT1↓,
MDR1↓,
COX2↓,
VEGF↓,
EMT↓,
MMP7↓,
MMP13↓,
uPA↓,
RIP1↑,
RIP3↑,
Casp3↑,
Casp7↑,
Casp9↑,
P21↓,
DFF45↓,
TRAIL↑,
PTEN↑,
mTOR↓,
AR↓,
FAK↓,
Src↓,
Myc↓,
RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

2195- SK,    Shikonin induces ferroptosis in osteosarcomas through the mitochondrial ROS-regulated HIF-1α/HO-1 axis
- in-vitro, OS, NA
TumCP↓, At a low dose, Shikonin inhibits OS progression and has a excellent biosafety.
Ferroptosis↓, Shikonin induces ferroptosis in OS cel
Hif1a↑, Shikonin upregualtes HIF-1α/HO-1 axis to produce excess Fe2+ which leads to ROS accumulation on OS cell, followed by ferroptosis.
HO-1↑,
Iron↑,
ROS↑,
GSH/GSSG↓, while simultaneously reducing the GSH/GSSG ratio and GPX4 and SLC7A11 expression
GPx4↓,

2228- SK,    Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells
- in-vitro, CRC, HCT116 - in-vitro, CRC, HCT15 - in-vivo, NA, NA
Apoptosis↑, shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP.
Bcl-2↓,
Casp3↑,
Casp9↑,
cl‑PARP↑,
GRP78/BiP↑, The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment.
PERK↑,
eIF2α↑,
ATF4↑,
CHOP↑,
JNK↑,
eff↓, pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin
ER Stress↑, Shikonin induced endoplasmic reticulum stress
ROS↑, Shikonin induced reactive oxygen species-mediated ER stress
TumCG↓, Shikonin suppressed the growth of colorectal cancer cells in vivo

2190- SK,    Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
- in-vitro, HCC, HCCLM3
TumCP↓, shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner
TumCMig↓,
TumCI↓,
Apoptosis↑,
MMP↓, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status.
ROS↑,
OCR↓, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle)
ATP↓,
PKM2↓, Shikonin decreased the expression of PKM2 in the mitochondria

2189- SK,    PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells
- in-vitro, Melanoma, NA
PKM2↓, shikonin suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) induced neoplastic cell transformation and PKM2 activation in the early stage of carcinogenesis.
chemoPv↑, results suggest that shikonin bears chemopreventive potential for human skin cancers in which PKM2 is upregulated,
eff↝, PKM2 activity was increased by 2.5-fold in tumor samples than normal tissues
lactateProd↓, Shikonin Suppressed TPA-Induced Lactate Production
ROS↑, shikonin induces apoptosis in hepatocellular carcinoma cells by the reactive oxygen species (ROS)/Akt and RIP1/NF-κB pathways
*ROS?, in our study, shikonin could preserve mitochondrial function and decrease the levels of ROS, leading to blocking PKM2 activation.
*PKM2↓,

2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
ROS↑, their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis
EGFR↓,
PI3K↓,
Akt↓,
angioG↓,
Apoptosis↑,
Necroptosis↑,
GSH↓, leading to the increased consumption of reduced glutathione (GSH) and increased Ca2+ concentration in the cells and destroying the mitochondrial membrane potential.
Ca+2↓,
MMP↓,
ERK↓, 24 h of treatment with shikonin, ERK 1/2 and AKT activities were significantly inhibited, and p38 activity was upregulated, which ultimately led to pro-caspase-3 cleavage and triggered the apoptosis of GC cells.
p38↑,
proCasp3↑,
eff↓, pretreated with the ROS scavengers NAC and GSH before treatment with shikonin, the production of ROS was significantly inhibited, the cytotoxicity of shikonin was attenuated
VEGF↓, shikonin can inhibit the expression of VEGF
FOXO3↑, Activated FOXO3a/EGR1/SIRT1 signaling
EGR1↑,
SIRT1↑,
RIP1↑, Upregulation of RIP1 and RIP3
RIP3↑,
BioAv↓, limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution
NF-kB↓, Shikonin can also prevent the activation of NF-κB by AKT and then downregulate the expression of Bcl-xl,
Half-Life↓, due to the limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution.

2186- SK,    Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a refractory HCC cell line
- in-vitro, HCC, HepG2 - in-vitro, HCC, HCCLM3
Glycolysis↓, shikonin treatment has been reported to inhibit glycolysis by suppressing the activity of pyruvate kinase M2 (PKM2) and to induce apoptosis by increasing reactive oxygen species (ROS) production.
PKM2↓,
Apoptosis↑,
ROS↑,
OXPHOS⇅, Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation in HepG2 cells, but displayed the opposite trend in HCCLM3 cells.
eff↓, insensitivity of HCCLM3 cells to shikonin treatment.

2203- SK,    Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation
- in-vitro, Lung, NA
TumCP↓, shikonin effectively suppressed cell proliferation, apoptosis, migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells
Apoptosis↓,
TumCMig↓,
TumCI↓,
Ferroptosis↑, shikonin could also induced ferroptosis in SCLC cells
ERK↓, Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4, and elevated the level of 4-HNE, a biomarker of ferroptosis
GPx4↓,
4-HNE↑, elevated the level of 4-HNE, a biomarker of ferroptosis
ROS↑, ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment.
GSH↓,
ATF3↑, shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter, and subsequently elevating of histone acetylation
HDAC1↓,
ac‑Histones↑,

2229- SK,    Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways
- in-vitro, Melanoma, A375
Apoptosis↑, Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation
TumAuto↑,
TumCP↓,
TumCCA↑, Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1
P21↑,
cycD1/CCND1↓,
ER Stress↑, Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3.
p‑eIF2α↑,
CHOP↑,
cl‑Casp3↑,
p38↑, induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1
LC3B-II↑,
Beclin-1↑,
ROS↑, Shikonin increased the production of reactive oxygen species
eff↓, NAC treatment significantly decreased the expression of p-p38, LC3B-II, and Beclin 1.

2227- SK,    Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901 - in-vitro, Nor, GES-1
selectivity↑, In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells.
TumCP↓,
TumCD↑,
ROS↑, SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis.
MMP↓,
Casp↑, SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade
Cyt‑c↑,
Endon↑, nuclear translocation of AIF and Endonuclease G
AIF↑,
eff↓, NAC and GSH significantly inhibited SHK-induced death
ChemoSen↑, SHK enhances chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin
TumCCA↑, SHK caused S-phase cell cycle arrest in SGC-7901 and BGC-823 gastric cancer cells
GSH/GSSG↓, We found that the GSH/GSSG ratio was significantly decreased when treated with SHK.
lipid-P↑, SHK increases lipid peroxidation and induces apoptosis in vivo

2226- SK,    Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
- in-vitro, HCC, HUH7 - in-vitro, HCC, Bel-7402
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

2221- SK,    Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression
- in-vitro, Lung, A549
Apoptosis↑, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner.
TumCP↓,
tumCV↓, shikonin (1–2.5 μg/mL) cause viability reduction
Necroptosis↑, while higher concentrations (5–10 μg/mL) precipitate both apoptosis and necrosis.
P53↑, via p53-mediated cell fate pathways
ROS↑, Its cytotoxic actions are largely through enhancing ROS generation to trigger caspase-dependent apoptosis and to downregulate nuclear factor-kappa B- (NF-kB-) mediated matrix metalloproteinase (MMP) expressions to reduce tumor survival and invasion
NF-kB↓,

2219- SK,    Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways
- in-vitro, Nor, HaCaT
*MMP↓, Shikonin decreases the Δψm and induces ROS generation
*ROS↑,
*Casp3↑, shikonin significantly increased caspase 3 cleavage, as compared with the untreated cells
*TumCG↓, Shikonin inhibits the growth of HaCaT cells

2210- SK,    Shikonin inhibits the cell viability, adhesion, invasion and migration of the human gastric cancer cell line MGC-803 via the Toll-like receptor 2/nuclear factor-kappa B pathway
- in-vitro, BC, MGC803
TumCA↓, Shikonin (1 μm) inhibited significantly the adhesion, invasion and migratory ability of MGC-803 cells.
TumCI↓,
TumCMig↓,
MMP2↓, matrix metalloproteinases (MMP)-2, MMP-7, TLR2 and p65 NF-κB
MMP7↓,
TLR2↓,
p65↓,
NF-kB↓,
eff↑, In addition, the co-incubation of Shikonin and anti-TLR2/MG-132 has a significant stronger activity than anti-TLR2 or MG-132 alone.
ROS↑, Shikonin-induced ROS generation

2202- SK,    Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification
- in-vitro, Var, NA
Iron↑, After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe2+ to induce cell death via ferroptosis.
Ferroptosis↑,
pH↝, GOx executes its catalytic activity to produce an acid environment and plenty of H2O2 for stimulating •OH generation via the Fenton reaction
H2O2↑,
ROS↑,
Fenton↑,
GSH↓, SRF will suppress the biosynthesis of GSH by inhibiting system Xc-, further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4).
GPx4↓,
lipid-P↑, Up-regulation of the oxidative stress level and down-regulation of GPX4 expression can dramatically accelerate the accumulation of lethal lipid peroxides, leading to ferroptosis amplification of tumor cells

3045- SK,    Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)
- in-vitro, PC, MIA PaCa-2
ECAR↓, Shikonin caused a concentration- and time-dependent inhibition of ECAR, which was more effective in highly glycolytic cells cultured in high-glucose (25 mM, Fig. 3ci) vs glucose-restricted cells (5 mM, Fig. 3cii).
Glycolysis↓, Collectively, these data suggest that shikonin exerts its cytotoxicity by inhibiting glycolysis and inducing ATP depletion, most likely due to inhibition of PKM2.
ATP↓, Only the highest concentration of shikonin (5 µM) induced a significant ATP depletion between 15 min and 6 h
PKM2↓,
TumCMig↓, Shikonin reduces PDAC cell migration
Ca+2↑, Shikonin induces cytotoxic Ca2+ overload
GlucoseCon↓, shikonin inhibited glucose consumption and lactate production with an IC50 of 5–10 μM in MCF-7 cells that exclusively express PKM2
lactateProd↓,
MMP↓, Shikonin is also reported to impair mitochondrial function and increase oxidative stress
ROS↑,

3041- SK,    Promising Nanomedicines of Shikonin for Cancer Therapy
- Review, Var, NA
Glycolysis↓, SHK could regulate immunosuppressive tumor microenvironment through inhibiting glycolysis of tumor cells and repolarizing tumor-associated macrophages (TAMs).
TAMS↝,
BioAv↓, HK is a hydrophobic natural molecule with unsatisfactory solubility, rapid intestinal absorption, obvious “first pass” effect, and rapid clearance, leading to low oral bioavailability.
Half-Life↝, SHK displays a half-life of 15.15 ± 1.41 h and Cmax of 0.94 ± 0.11 μg/ml in rats when administered intravenously.
P21↑, Table 1
ERK↓,
ROS↑,
GSH↓,
MMP↓,
TrxR↓,
MMP13↓,
MMP2↓,
MMP9↓,
SIRT2↑,
Hif1a↓,
PKM2↓,
TumCP↓, Inhibit Cell Proliferation
TumMeta↓, Inhibit Cells Metastasis and Invasion
TumCI↓,

3040- SK,    Pharmacological Properties of Shikonin – A Review of Literature since 2002
- Review, Var, NA - Review, IBD, NA - Review, Stroke, NA
*Half-Life↝, One study using H-shikonin in mice showed that shikonin was rapidly absorbed after oral and intramuscular administration, with a half-life in plasma of 8.79 h and a distribution volume of 8.91 L/kg.
*BioAv↓, shikonin is generally used in creams and ointments, that is, oil-based preparations; indeed, its insolubility in water is usually the cause of its low bioavailability
*BioAv↑, 200-fold increase in the solubility, photostability, and in vitro permeability of shikonin through the formation of a 1 : 1 inclusion complex with hydroxypropyl-β-cyclodextrin.
*BioAv↑, 181-fold increase in the solubility of shikonin in aqueous media in the presence of β-lactoglobulin at a concentra- tion of 3.1 mg/mL
*Inflam↓, anti-inflammatory effect of shikonin
*TNF-α↓, shikonin inhibited TNF-α production in LPS-stimulated rat primary macrophages as well as NF-κB translocation from the cytoplasm to the nucleus.
*other↑, authors found that treatment with shikonin prevented the shortening of the colorectum and decreased weight loss by 5 % while improving the ap- pearance of feces and preventing bloody stools.
*MPO↓, MPO activity was reduced as well as the expression of COX-2, the activation of NF-κB and that of STAT3.
*COX2↓,
*NF-kB↑,
*STAT3↑,
*antiOx↑, Antioxidant Effects of Shikonin
*ROS↓, radical scavenging activity of shikonin
*neuroP↑, shown to exhibit a neuroprotective effect against the damage caused by ischemia/reperfusion in adult male Kunming mice
*SOD↑, it also attenuated neuronal damage and the upregulation of superoxide dismutase, catalase, and glutathione peroxidase activities while reducing the glutathione/glutathione disulfide ratio.
*Catalase↑,
*GPx↑,
*Bcl-2↑, shikonin upregulated Bcl-2, downregulated Bax and prevented cell nuclei from undergoing morphological changes typical of apoptosis.
*BAX↓,
cardioP↑, Two different studies have suggested a possible cardioprotective effect of shikonin that would be related to its anti-inflammatory and antioxidant effects.
AntiCan↑, A wide spectrum of anticancer mechanisms of action have been described for shikonin:
NF-kB↓, suppression of NF-κB-regulated gene products [44],
ROS↑, ROS generation [46],
PKM2↓, inhibition of tumor-specific pyruvate kinase-M2 [47,48]
TumCCA↑, cell cycle arrest [49]
Necroptosis↑, or induction of necroptosis [50],
Apoptosis↑, shikonin at 1 μM induced caspase-dependent apoptosis in U937 cells after 6 h with an increase in DNA fragmentation, intracellular ROS, low mitochondrial membrane potential
DNAdam↑,
MMP↓,
Cyt‑c↑, At 10 μM, shikonin induced a greater release of cytochrome c from the mitochondria and of lactate dehydrogenase,
LDH↝,

3047- SK,    Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL-6/STAT3 signaling pathway
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW48
TumCG↓, SKN inhibited colon cancer cell growth, suppressed both constitutive and IL-6-induced STAT3 phosphorylation, and downregulated the expression of ADAM17
p‑STAT3↓,
ADAM17↓,
Apoptosis↑, SKN promoted cell apoptosis, as evidenced by increased expression levels of cleaved caspase-3 and cleaved PARP in both cell lines
Casp3↑,
cl‑PARP↑,
cycD1/CCND1↓, SKN decreased the expression of cyclin D1 and cyclin E1, thus suggesting the disruption of the cell cycle and the suppression of cell growth
cycE/CCNE↓,
TumCCA↑,
JAK1?, The inhibitory effects of SKN on the phosphorylation of both JAK1 and JAK2 in the two cell lines were also observed
p‑JAK1↓,
p‑JAK2↓,
p‑eIF2α↑, phosphorylation levels of eIF2α were enhanced by SKN (20 µM) in the HCT116 and SW480 colon cancer cells
eff↓, NAC decreased SKN-induced p-eIF2α expression and reversed the SKN-mediated downregulation of ADAM17 protein expression
ROS↑, suppressed the expression of ADAM17 mediated by ROS-associated p-eIF2α expression in the HCT116 and SW480 colon cancer cells
IL6↓, demonstrated that the antitumor effects of SKN on colon cancer cells were associated with its inhibition of the IL-6/STAT3 signaling pathway.

2469- SK,    Shikonin induces the apoptosis and pyroptosis of EGFR-T790M-mutant drug-resistant non-small cell lung cancer cells via the degradation of cyclooxygenase-2
- in-vitro, Lung, H1975
Apoptosis↑, Shikonin induced cell apoptosis and pyroptosis by triggering the activation of the caspase cascade and cleavage of poly (ADP-ribose) polymerase and gasdermin E by elevating intracellular ROS levels
Pyro↑,
Casp↑,
cl‑PARP↑,
GSDME↑,
ROS↑,
COX2↓, shikonin induced the degradation of COX-2 via the proteasome pathway, thereby decreasing COX-2 protein level and enzymatic activity and subsequently inhibiting the downstream PDK1/Akt and Erk1/2 signaling pathways through the induction of ROS produc
PDK1↓,
Akt↓,
ERK↓,
eff↓, Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis
eff↓, NAC pre-treatment inhibited the shikonin-induced activation of the caspase cascade (caspase-8/9/3) and cleavage of PARP and GSDME in H1975 cells
eff↑, Celecoxib augmented the cytotoxic effects of shikonin by promoting the apoptosis and pyroptosis of H1975 cells

1280- SK,    Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells
- in-vitro, GC, AGS
ROS↑, shikonin induced the generation of ROS as well as caspase 3-dependent apoptosis.
Casp3↑,
P53↑, shikonin induced p53 expression but repressed Nrf2 expression
NRF2↓, Nrf2/ARE signaling pathway may be inhibited by shikonin treatment, especially at high concentration of 250 nM

1284- SK,    Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy
- in-vitro, Melanoma, RPMI-8226 - in-vitro, Melanoma, U266
Ferroptosis↑, SHK treatment leads to the ferroptosis of MM cells
LDH↓,
ROS↑, Cellular mitochondrial lipid ROS also increased after SHK treatment
Iron↑,
lipid-P↑,
ATP↓, extracellular release of Adenosine 5’-triphosphate (ATP) and High mobility group protein B1 (HMGB1
HMGB1↓,
GPx4↓, Additionally, the ferroptosis markers GPX4 and solute carrier family 7 member 11 (xCT/SLC7A11) were downregulated at both the transcriptional and translational levels after SHK treatment
MDA↑, SHK treatment led to an increase in MDA content in cells. In contrast, the levels of SOD and GSH decreased in cells
SOD↓,
GSH↓,

2009- SK,    Necroptosis inhibits autophagy by regulating the formation of RIP3/p62/Keap1 complex in shikonin-induced ROS dependent cell death of human bladder cancer
- in-vitro, Bladder, NA
TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
selectivity↑, and has no toxicity on normal bladder epithelial cells
*toxicity∅,
Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
ROS↑,
p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
Keap1↑,
*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

2008- SK,  Cisplatin,    Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
ChemoSen↑, combination of shikonin and cisplatin exhibited synergistic anticancer efficacy
selectivity↑, and achieved greater selectivity between cancer cells and normal cells.
i-ROS↑, By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway.
DNAdam↑,
MMP↓,
TumCCA↑, induction of G2/M cell cycle arrest
eff↓, NAC and GSH were used in our experiment. The MTT results revealed that scavenging of ROS fully attenuated combined treatment-induced cell growth inhibition against HCT116 cell
*toxicity↓, combined treatment showed less cytotoxicity toward NCM460 normal human colon mucosal epithelial cells

2007- SK,    Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells
- in-vitro, lymphoma, U937 - in-vitro, BC, MCF-7 - in-vitro, BC, SkBr3 - in-vitro, CRC, HCT116 - in-vitro, OS, U2OS - NA, Nor, RPE-1
tumCV↓, We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines.
selectivity↑, structure of mitochondria show marked differences between cancer cells and normal cells
Dose↝, Shikonin inhibited proliferation by 50% in nearly all cancer cell lines at concentrations below 10 μM after 24 h.
other↑, mitochondrion itself is a possible target of the compound
MMP↓, Breakdown of the Mitochondrial Membrane Potential
ROS↑, ROS production shortly after cellular shikonin uptake, and ROS levels continuously increased for at least 1 h after exposure to shikonin
DNAdam↑, Induction of ROS, oxidative DNA damage, and elevated intracellular Ca2+ levels by shikonin
Ca+2↑,
Casp9↑, Caspase 9 is activated after the release of cytochrome c from the mitochondria
Cyt‑c↑,
*toxicity↓, RPE-1-GFP-EB3 (normal) cells were treated with 25 μM shikonin. shikonin treatment did cause a strong slowdown and finally a complete disappearance of EB3 particles within 3 min of application

2010- SK,    Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway
- in-vitro, Lung, H1975 - in-vitro, Lung, H1650 - in-vitro, Nor, CCD19
EGFR↓, Shikonin is a potent inhibitor of EGFR
selectivity↑, Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU).
Casp↑, Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis
PARP↑,
Apoptosis↑,
ROS↑, intensity of ROS by greater than 10-fold
eff↓, NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin.
selectivity↑, the IC50 value of Shikonin in CCD19 (normal cells) is approximately 4-fold higher than that of HCC827, H1650 and H1975.

1342- SK,    RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species
- in-vitro, GBM, NA - in-vivo, NA, NA
RIP1↑,
RIP3↑,
DNAdam↑, DNA DSBs in vitro and in vivo
ROS↑,
GSH↓, depletion of GSH

1343- SK,    Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis
- in-vitro, Ovarian, A2780S - in-vivo, NA, A2780S
*BioAv↓, clinical use is limited by poor tumor targeting and low bioavailability
ROS↑,
GSH↓,
TumCG↓,

1344- SK,    Novel multiple apoptotic mechanism of shikonin in human glioma cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683 - in-vitro, GBM, M059K
ROS↑,
GSH↓,
MMP↓,
P53↑, upregulation of p53,
cl‑PARP↑,
Catalase↓,
SOD1↑,
Bcl-2↓,
BAX↑,
eff↓, Pretreatment with NAC, PFT-α, or cyclosporin A causes the recovery of shikonin-induced apoptosis.

1345- SK,    The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway
- in-vitro, AML, HL-60
CD14↑,
CD11b↑,
ROS↑, Shikonin result in the predominance of cell death because the oxidative stress is more severe and overcome the antioxidative capacity of Nrf2/ARE pathway, resulting in cell death.
GSH↓,
GSH/GSSG↓,
GPx↑, mRNA expression levels of GPX and CAT were markedly upregulated by Shikonin in a dose-dependent manner
Catalase↓, Shikonin causes apoptosis in human glioma cells by interrupting intracellular redox homeostasis, which included CAT downregulation
Diff↑, Shikonin-induced HL-60 cell differentiation

1346- SK,    An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683
NRF2↓, ROS production by shikonin resulted in the inhibition of nuclear translocation of Nrf2
ROS↑, ROS generation from mitochondrial complex II
Apoptosis↑,
Cyt‑c↑, release cytochrome c to the cytosol
GSH↓,
MMP↓,
P53↑,
HO-1⇅, In Hs683 cells, the expressions of γ-GCS and HO-1 were slightly inhibited by shikonin at 3 h. However, shikonin increased the expressions of γ-GCS, catalase, SOD-1 and HO-1 at 24 h.

1312- SK,    Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells
- in-vitro, OS, 143B
ROS↑, Taken together, our results reveal that shikonin increased ROS generation and ERK activation, and reduced Bcl2, which consequently caused the cells to undergo apoptosis.
p‑ERK↑, phosphorylated ERK was apparently increased in response to shikonin treatment for 24 and 48 h.
Bcl-2↓,
cl‑PARP↑, PARP cleavage, another well known characteristic of apoptosis, was also found in shikonin-treated cells.
Apoptosis↑,
TumCCA↑, 4 and 8mM shikonin for 24 h obviously caused G2/M phase arrest
Bcl-2↑, shikonin also decreased Bcl-2 expression, and decreased the pro-caspase 3
proCasp3↓,

1050- SK,    Shikonin improves the effectiveness of PD-1 blockade in colorectal cancer by enhancing immunogenicity via Hsp70 upregulation
- in-vitro, Colon, CT26
HSP70/HSPA5↑,
ROS↑, upregulation of Hsp70 was dependent on ROS induced by SK
PKM2↓,

1073- SK,  Chemo,    Natural Compound Shikonin Is a Novel PAK1 Inhibitor and Enhances Efficacy of Chemotherapy against Pancreatic Cancer Cells
- in-vitro, PC, PANC1 - in-vitro, PC, Bxpc-3
PAK1↓, significantly inhibited the activity of PAK1 kinase
TumCP↓,
Apoptosis↑,
ChemoSen↑, shikonin sensitized pancreatic cancer cells to chemotherapeutic
ROS↑, Moreover, shikonin has been shown to trigger ROS-based mitochondria-mediated apoptosis and significantly inhibited tumor growth in a human colon cancer SW480 xenograft mouse model [18]

4891- Sper,    Spermidine as a promising anticancer agent: Recent advances and newer insights on its molecular mechanisms
- Review, Var, NA - Review, AD, NA
TumCCA↑, Spermidine specifically interferes with the tumour cell cycle, resulting in the inhibition of tumor cell proliferation and suppression of tumor growth.
TumCP↓,
TumCG↓,
*Inflam↓, health improving effects, that includes remarkable anti-inflammatory effects
*antiOx↑, It is also a potent antioxidant, and reportedly improves the respiratory function
*neuroP↑, Dietary intake of spermidine reduces the risk of neurodegeneration, metabolic diseases, heart ailments, and cancer.
*cognitive↑, spermidine-induced autophagy slows the rate of cognitive decline due to its ability to clear amyloid-beta plaques in the brain
*Aβ↓,
*mitResp↑, Spermidine supplementation also enhances mitochondrial metabolism, and translational activity.
AntiCan↑, anticancer properties of spermidine are of particular interest as it is known to reduce the cancer-related mortality in humans
TumCD↑, in addition to impacting their discourse with the immune effectors that result in expediting the identification of tumor-associated antigens and eventually cancer cell death
TumAuto↑, Inhibition of acetyltransferase EP300 by spermidine is known to induce autophagy, which is one of the desirable approaches in the treatment of cancer.
*AntiAge↑, Lifelong oral spermidine administration is reported to extend the lifespan in mice by 25%, as evidenced by genetic investigations.
LC3B-II↑, Western blotting experiments have showed a surge in the levels of LC3 II/LC3 I, Atg5, and Beclin 1 proteins in spermidine administered HeLa cells.
ATG5↑,
Beclin-1↑,
mt-ROS↑, Spermidine induces mitochondrial reactive oxygen species (mtROS) mediated M2-polarization by producing a surge in the levels of H2O2 and mitochondrial peroxide in the presence of spermidine.
H2O2↑,
Apoptosis↑, Spermine is known to induce apoptosis in primary human cells as well as the malignant tumor cells by producing a surge in the intracellular level of reactive oxygen species (ROS)
*ROS↑,
ChemoSen↑, A combination of 5-fluorouracil and spermine analogues N 1 , N 11 -diethylnorspermine (DENSPM) (6, Figure 5) at concentrations 1.25, 2.5, 5, and 10 μM or α-difluoromethylornithine (DFMO) led to a synergistic killing of HCT116 colon carcinoma cells
MMP↓, and loss of membrane potential of mitochondria followed by a subsequent release of cytochrome c
Cyt‑c↑,

4892- Sper,  erastin,    Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer
- in-vitro, Pca, PC3 - in-vivo, Pca, NA
Ferroptosis↑, Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe2+ levels in vitro
lipid-P↑,
Iron↑, Strikingly, Spd remarkedly increased the erastin-induced Fe2+ levels, and sustained the Fe2+ levels upon cotreatment
eff↑, Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice.
HO-1↑, heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe2+, is significantly upregulated in response to Spd and erastin cotreatment.
NRF2↑, Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1.
ROS↑, The production of lipid ROS induced by the combination treatment
AntiTum↑, Spd promotes anti-tumor efficacy of erastin in mice
eff↓, The results demonstrated that GSH and NAC completely suppressed ROS production induced by Spd plus erastin, associated with restoration of cell survival

4894- Sper,    Application of Spermidine in Cancer Research Models: Notes and Protocols
- Review, Var, NA
TumAuto↑, recent studies highlight the anti-neoplastic properties of exogenous spermidine, primarily through the induction of autophagy and enhancement of anti-tumor immunity
AntiTum↑,
Apoptosis↑, plays a role in inducing apoptosis (programmed cell death) and modulating the tumor microenvironment
ROS↑, Spermidine can induce apoptosis through the intrinsic mitochondrial pathway. This involves the generation of reactive oxygen species (ROS), deregulation of mitochondrial membrane potential
MMP↓,
Cyt‑c↑,

4897- Sper,    Spermidine as a promising anticancer agent: Recent advances and newer insights on its molecular mechanisms
- Review, Var, NA
Inflam↓, Spermidine is a natural biomolecule which has been reported to possess a broad spectrum of health improving effects, that includes remarkable anti-inflammatory effects
TumAuto↑, Spermidine-mediated autophagy inhibits activation of apoptosis in cancer cells
Apoptosis↑, Spermidine-induced apoptosis
ROS↑, Spermine is known to induce apoptosis in primary human cells as well as the malignant tumor cells by producing a surge in the intracellular level of reactive oxygen species (ROS
MMP↓, disruption in the mitochondrial membrane potential causes the release of apoptosis-triggering molecules, such as cytochrome c
Cyt‑c↑,
Bcl-2↓, decrease in the Bcl-2 expression

1017- SSE,    Selenite induces apoptosis in colorectal cancer cells via AKT-mediated inhibition of β-catenin survival axis
- vitro+vivo, CRC, NA
Akt↓, selenite exerted a remarkable inhibitory effect on activation of AKT
β-catenin/ZEB1↓,
cycD1/CCND1↓,
survivin↓,
Apoptosis↑,
ROS↑, reactive oxygen species (ROS) was a crucial upstream signal for selenite-triggered inhibition of AKT/β-catenin

1018- SSE,    Selenite-induced autophagy antagonizes apoptosis in colorectal cancer cells in vitro and in vivo
- vitro+vivo, CRC, HCT116 - vitro+vivo, CRC, SW480
TumAuto↑,
LC3s↑, expression of autophagy marker LC3 was increased
TumW↓,
Weight∅, no obvious effect on the body weight of the mice
Beclin-1↑,
p62↓,
ROS↑, concluded that selenite-induced apoptosis and autophagy may be caused by ROS

1002- SSE,  Osi,  Adag,    Selenite as a dual apoptotic and ferroptotic agent synergizes with EGFR and KRAS inhibitors with epigenetic interference
- in-vitro, Lung, H1975 - in-vitro, Lung, H385
Apoptosis↑,
Ferroptosis↑,
DNMT1↓,
TET1↑,
TumCCA↑, G2/M arrest
cl‑PARP↑,
cl‑Casp3↑, H1975 cells only
Cyt‑c↑,
BIM↑,
NOXA↑,
Apoptosis↑,
ROS↑, Selenite is associated with oxidative stress
ER Stress↑, H1975 cells only
UPR↑, H1975 cells only

4739- SSE,  Chemo,  Rad,    Therapeutic Benefits of Selenium in Hematological Malignancies
- Review, Var, NA
ChemoSen↑, Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers.
radioP↑,
QoL↑, This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients.
Risk↓, selenium levels in patients have been correlated with various cancers
*selenoP↑, Selenium is present in all mammals and is utilized by selenoproteins
TumCP↓, It has been reported that Se possesses anti-proliferative, anti-inflammatory, and anti-viral activities in addition to immune altering properties and has been implicated in various cancers
Inflam↓,
ChemoSen↑, Selenium-based compounds exhibit chemopreventive or chemotherapeutic properties through regulation of various processes such as cell cycle arrest, apoptosis, angiogenesis, etc.
TumCCA↑,
Apoptosis↑,
angioG↓,
Dose⇅, The amount of the selenium agent administered can influence whether prooxidant or antioxidant activity is observed.
ROS↑, Selenium-based compounds have been shown to exhibit chemopreventive and anticancer properties through prooxidant activities and the regulation of cellular redox homeostasis by altering thiol groups in multiple metabolic pathways, stimulating the prod
eff↑, The potency of selenium in an in vitro model of lung adenocarcinoma was increased with the addition of fish oil
Risk↓, In clinical trials, it has been observed that selenium and vitamin C supplementation decrease the incidence and mortality of gastric and lung cancer
eff∅, A selenium supplementation did not negatively impact the efficacy of chemotherapy
CSCs↓, Selenium Is Potent in Leukemia Stem Cells through In Vitro and In Vivo AML/CML Models
ROS↑, higher intracellular oxidative stress (or levels of ROS) in chronic or acute myeloid leukemia stem cells

4742- SSE,    Antitumor Effects of Selenium
- Review, Var, NA - Review, Arthritis, NA - Review, Sepsis, NA
*antiOx↓, Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy.
*Inflam↓,
Risk↓,
TumCI↓,
TumMeta↓,
radioP↑,
chemoP↑,
Apoptosis↑, (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus
ROS↑,
DNAdam↑,
Dose↑, In our study, advanced cancer patients can tolerate until 5000 μg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short
selectivity↑, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells.
*other↓, Se-methylselenocysteine (MSeC) is most abundant in garlic, broccoli, walnut, and some other plant products.
*BioAv↑, Most Se compounds are readily absorbed from the diet and are mainly metabolized in the liver.
ROS↑, Methylselenol induced apoptosis by ROS production, subsequently altered mitochondrial membrane potential, and, further, induced caspases’ activity.
MMP↓,
Casp↑,
*Imm↑, Se activates immune functions via the activation of IL-2 receptor [59].
*Pain↓, Supplementation with 200 μg Se in a group of rheumatoid arthritis patients for three months significantly reduced pain and joint involvement
Sepsis↓, Se plays an important role in defense against acute illness, such as sepsis syndrome
MMP2↓, Several experiments by our group demonstrate that selenite inhibits tumor invasion by blocking MMP-2 and -9 expression
MMP9↓,
*Half-Life↓, a short half-life of sodium selenite and more accumulation of the Se in the cancer cells may be more toxic in cancer cells than that in normal cells.

4723- SSE,    Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4
- in-vitro, CRC, HCT116
TumCP↓, In vitro experiments using HCT116 cells showed that Na₂SeO₃ treatment inhibited proliferation, increased intracellular Fe2⁺, MDA, and ROS levels, and reduced mitochondrial membrane potential.
Iron↑,
MDA↑,
ROS↑,
MMP↓,
NRF2↓, Western blotting further revealed the downregulation of Nrf2 and Gpx4 proteins upon selenium treatment
GPx4↓,
Ferroptosis↑, Our research findings indicate that sodium selenite may induce ferroptosis by regulating the Nrf2/Gpx4 axis, highlighting its potential as a dual nutrient and pharmacological drug for the treatment of CRC.

4718- SSE,    High-Dose Selenium Induces Ferroptotic Cell Death in Ovarian Cancer
- in-vitro, Ovarian, NA
TumCP↑, Here, we observed that high-dose sodium selenite (SS) significantly decreased the proliferation and increased the death of ovarian cancer cells, mediated by an increased generation of reactive oxygen species.
ROS↑,
GPx↓, high-dose SS decreased the levels of glutathione peroxidase (GPx), a selenoprotein with antioxidant properties, without altering other selenoproteins.
lipid-P↑, Furthermore, high-dose SS triggered lipid peroxidation and ferroptosis, a type of iron-dependent cell death, due to dysregulated GPx4 pathways.
Ferroptosis↑,
Dose↑, effective dose (1000–2000 μg/kg) of SS for anticancer effects in an ovarian cancer mouse model through tail injection three times per week for 2 weeks

5081- SSE,    Application Notes and Protocols: Selenite as a Selenium Source in Cell Culture Media Supplementation
- Review, Var, NA
Dose↝, The effects of sodium selenite on cultured cells are dose-dependent. Low concentrations can be protective and support growth, while higher concentrations can induce cytotoxicity, particularly in cancer cell lines.
ROS↑, Sodium selenite supplementation can significantly impact intracellular signaling pathways, primarily through the generation of reactive oxygen species (ROS).
Akt↓, nhibition of pro-survival pathways like AKT/mTOR, ultimately resulting in cell cycle arrest and apoptosis.[
mTOR↓,
TumCCA↑,
Apoptosis↑,

5080- SSE,    Sodium Selenite Regulates the Proliferation and Apoptosis of Gastric Cancer Cells by Suppressing the Expression of LncRNA HOXB-AS1
- in-vitro, GC, HGC27 - in-vitro, GC, NCI-N87
AntiTum↑, The in vivo antitumor effect of sodium selenite on gastric carcinoma has been demonstrated.
HOXB-AS1↓, Na2SeO3 downregulated the expression of HOXB-AS1 in the human gastric cancer (HGC) cell lines, HGC-27, NCI-N87, and KATO III cells, while inhibiting their proliferation and invasion and inducing apoptosis.
TumCP↓,
TumCI↓,
Apoptosis↑,
BAD↓, the expression of apoptosis-related (Bad, Bcl-2, and cleaved-caspase-3) and invasion-related (MMP2, E-cadherin, and N-cadherin) proteins, indicating increased apoptosis and decreased invasion.
Bcl-2↓, f Bcl-2, MMP2, and N-cadherin proteins was significantly downregulated
cl‑Casp3↑,
MMP2↓,
E-cadherin↑,
N-cadherin↓,
ROS↑, Na2SeO3 can increase ROS levels and inhibit the NF-κB signaling pathway, effectively inhibiting the growth, metastasis, and inducing apoptosis of renal cell carcinoma both in vitro and in vivo [41]
NF-kB↓,

5079- SSE,  Rad,    The solvent and treatment regimen of sodium selenite cause its effects to vary on the radiation response of human bronchial cells from tumour and normal tissues
- in-vitro, Lung, A549 - in-vitro, Nor, BEAS-2B
chemoP↑, Sodium selenite is often given to moderate the side effects of cancer therapy to enhance the cellular defence of non-cancerous cells.
eff↝, the effect of sodium selenite on radiation response is strongly dependent on the respective experimental in vitro conditions and ranges from lead to an initially suspected but ultimately no real radioprotection
ROS↑, The selenite-mediated ROS generation
MMP↓, Selenite leads to a decrease in the mitochondrial membrane potential and to the release of cytochrome c into the cytosol, which ultimately activates the apoptotic pathway
Cyt‑c↑,
TumCG↓, In our study, the growth of A549 tumour cells was more sensitive to sodium selenite than the normal BEAS-2B cells.
RadioS↝, However, in our study, no general difference in radiosensitivity between the tumour (A549) and normal (BEAS-2B) cells under the influence of sodium selenite could be observed.
other↝, results support the previous results on the potential for the use of sodium selenite in radiation therapy, but also illustrate the urgent need and importance of further elucidating the mechanisms of action of sodium selenite

5078- SSE,  Rad,    Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer
- Trial, Pca, NA
Half-Life↝, The half-life of selenite was 18.5 hours.
OS↑, Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression.
Pain↓, Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11–78%.
PSA↓,
GSH↓, selenite depletes cells of an important antioxidant, glutathione (GSH), and results in the generation of superoxide, a highly reactive and toxic radical that results in the generation of reactive oxygen species (ROS).
ROS↑,
selectivity↑, 1) prostate cancer cells are more sensitive to selenium (sodium selenite)-induced apoptosis than normal prostate epithelial cells
TumCG↓, 2) Selenite induces significant growth inhibition of well-established prostate cancer tumors in mice at doses that have no detectable toxicity when administered both ip and po, a
AR↓, 3) Selenite disrupts androgen receptor (AR) signaling, with inhibition of AR expression
Dose↑, This simulation reveals that only the higher dose levels (33 mg and 49.5 mg) reach the desired therapeutic range after a single dose.
ChemoSen↑, In another study of selenite (0.2 mg/kg per day for 7 days) in combination with chemotherapy, addition of selenite resulted in a significant increase in the percentage of apoptotic lymphoma cells and clinical response compared to patients treated wit
RadioS↑, sodium selenite was studied in 15 patients with advanced/metastatic tumors receiving concurrent sodium selenite with palliative radiation therapy.

5075- SSE,    Sodium selenite inhibits proliferation and metastasis through ROS‐mediated NF‐κB signaling in renal cell carcinoma
- vitro+vivo, RCC, 786-O
TumCP↓, treatment with SSE resulted in significant inhibition of cell proliferation and migration.
TumCMig↓,
Apoptosis↑, SSE induced apoptosis via the endogenous apoptotic pathway.
ROS↑, SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling.
NF-kB↓,
eff↓, Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine(NAC) reversed the effect of SSE on cells.
E-cadherin↑, SSE treatment significantly increased the expression of E-cadherin and cleaved caspase-3, decreased the expression of VEGF.
cl‑Casp3↑,
VEGF↓,
MMP9↓, we found that SSE increased the expression of E-cadherin while as decreased the expression of MMP-9
EMT↓, suggesting that SSE may inhibit the metastasis of RCC by regulating EMT and extracellular matrix degradation
MMP↓, we found that SSE decreased mitochondrial membrane potential and increased the intracellular ROS, which suggested that SSE induced mitochondrial damage
mtDam↑,
BAX↑, we detected the pro-apoptotic proteins Bax, Caspase-3, and found that SSE increased their expression.
Bcl-2↓, we detected anti-apoptotic proteins Bcl-2, and found that SSE decreased its expression.

5074- SSE,    Application of Sodium Selenite in the Prevention and Treatment of Cancers
- Review, Var, NA
Imm↑, A less recognized, albeit even more essential role of selenite is in its stimulation of the cellular immune system
angioG↑, certain studies indicate that selenite may inhibit angiogenesis, and help to repair the damaged DNA fragments.
DNArepair↑,
NK cell↑, most important function of this compound in the fighting of cancer may be the direct activation of natural killer (NK) cells.
ROS↑, thus selenite Se4+ exhibits an ability to undergo oxidation and reduction reactions (the so-called redox reactions)
AntiCan↑, It should be emphasized that the use of high doses of sodium selenite exhibits promising anticancer effects, as described in numerous preclinical studies
selectivity↑, Numerous studies demonstrated higher selenite cytotoxicity against cancer cells when compared to normal cells, using a comparable dose of this element
ER Stress↑, sodium selenite can cause cell death by an independent pathway of mitochondrial apoptosis, endoplasmic reticulum stress (caused by the presence of (non)unfolded proteins), processes of autophagy, or necrosis.
TumAuto↑,
necrosis↑,
toxicity↝, Sodium selenite may be toxic when taken orally at higher doses, yet it is well tolerated by other routes such as intravenous, intraperitoneal and/or transdermal
Dose↑, As demonstrated recently by Swedish scientists, considerably higher doses of selenium are well tolerated by patients with cancer, in the case when sodium selenite is administered intravenously.

5091- SSE,    Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite
- in-vitro, GBM, U87MG - in-vitro, Cerv, HeLa - in-vitro, BC, MCF-7 - in-vitro, Pca, PC3 - in-vitro, CRC, HT-29 - in-vitro, Nor, SVGp12
Ferroptosis↑, In this study, for the first time, we demonstrate that sodium selenite (SS), a well-established redox-active selenium compound, is a novel inducer of ferroptosis in a variety of human cancer cells.
xCT↓, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO).
GSH↓,
GPx4↓,
Iron↑, SS induces iron accumulation via O2•−-dependent process
lipid-P↑,
ROS↑, SS-induced ferroptotic responses are achieved via ROS, in particular superoxide (O2•−) generation.
eff↓, Antioxidants such as superoxide dismutase (SOD) and Tiron not only scavenged O2•− production, but also markedly rescued SLC7A11 down-regulation, GSH depletion, GPx4 inactivation, iron accumulation, LPO, and ferroptosis.
TumCP↓, SS inhibits the proliferation of human cancer cells
TumCD↑, SS induces non-apoptotic, non-autophagic and non-necroptotic cell death in human cancer cells

5093- SSE,    Pharmacological mechanisms of the anticancer action of sodium selenite against peritoneal cancer in mice
- in-vivo, Var, NA
AntiCan↑, Prior studies in mice show that sodium selenite administered intraperitoneally is highly effective in inhibiting cancer cells implanted in the peritoneal cavity.
eff↑, We found that intraperitoneal delivery of selenite to cancer cells in the peritoneal cavity of mice rapidly and robustly killed the cancer cells, with a therapeutic efficacy higher than that of cisplatin.
selectivity↑, 1) Favorable drug distribution: selenite increased selenium levels in the cancer cells by 250-fold, while in normal tissues only by 7-fold.
ROS↑, 2) Optimal selenium form: selenite was converted in the cancer cells mainly into selenium nanoparticles (SeNPs), which are more efficient than selenite in producing reactive oxygen species (ROS).
Dose↝, we found that the maximum tolerated dose (MTD) of i.p. injection of sodium selenite was 4 mg Se/kg, with no death (Fig. 1A) but marked body weight loss
Trx↓, The powerful effect of i.p. injected selenite is associated with a highly selective Se distribution in favor of intraperitoneal cancer cells, wherein endogenously formed SeNPs efficiently hijack the Trx- and Grx-coupled GSH systems to produce ROS to
GSH↓,

5111- SSE,    Sodium selenite induces apoptosis via ROS-mediated NF-κB signaling and activation of the Bax-caspase-9-caspase-3 axis in 4T1 cells
- in-vitro, BC, 4T1
ROS↑, SSE treatment causes a transient increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling and p65
NF-kB↓,
p65↓,
mtDam↑, the accumulation of ROS caused mitochondrial dysfunction, leading to the activation of caspase-9 and -3, thereby resulting in apoptosis.
Casp9↑,
Casp3↑,
Apoptosis↑,
eff↓, However, modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine (NAC)reversed these events.

5109- SSE,    Selenium compounds activate ATM-dependent DNA damage response via the mismatch repair protein hMLH1 in colorectal cancer cells
- in-vitro, CRC, HCT116
ROS↑, We show that hMLH1 complementation sensitizes HCT 116 cells to methylseleninic acid, methylselenocysteine, and sodium selenite via reactive oxygen species
DNAdam↓, and facilitates the selenium-induced oxidative 8-oxoguanine damage, DNA breaks, G2/M checkpoint response, and ATM pathway activation
ATM↑,
eff↓, Pretreatment of the hMLH1-complemented HCT 116 cells with the antioxidant N-acetylcysteine(NAC) or 2,2,6,6-tetramethylpiperidine-1-oxyl or the ATM kinase inhibitor KU55933 suppresses hMLH1-dependent DNA damage response to selenium exposure.
TumCCA↑, Selenium-induced cell cycle arrest and apoptosis in colon cancer cells has been well studied

5106- SSE,  GSH,    Dual role of glutathione in selenite-induced oxidative stress and apoptosis in human hepatoma cells
- in-vitro, Liver, HepG2
ROS↑, It was found that Se-induced oxidative stress and apoptosis are closely related to the intracellular level of GSH.
Apoptosis↑,
eff↑, Both the increase and depletion of GSH content significantly enhanced Se-induced oxidative stress and apoptosis in HepG2 cells.
GSH↓, our laboratory further demonstrated the formation of ROS, the induction of apoptosis, and the concurrent decrease of GSH

5105- SSE,    Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells
- in-vitro, Pca, LNCaP
TumCD↑, (1) selenite induced cancer cell death and apoptosis by producing superoxide radicals;
Apoptosis↑,
ROS↑,
eff↓, (2) selenite-induced superoxide production, cell death, and apoptosis were inhibited by overexpression of MnSOD, but not by CuZnSOD, CAT, or GPx1;
MMP↓, (3) selenite treatment resulted in a decrease in mitochondrial membrane potential, release of cytochrome c into the cytosol, and activation of caspases 9 and 3
Cyt‑c↑,
Casp3↑,
Casp9↑,
ER Stress↑, Studies have also shown that Se can induce cell death by mitochondrial-independent apoptotic pathways, endoplasmic reticulum stress, autophagy, or necrosis [11, 25, 43, 44]
TumAuto↑,
necrosis↑,
chemoPv↑, which may contribute to chemoprevention of prostate cancer.

5096- SSE,    Selenium Toxicity Accelerated by Out-of-Control Response of Nrf2-xCT Pathway
- in-vitro, BC, MCF-7
xCT↑, Expression of xCT mRNA was remarkably increased in MCF-7 cells after Se treatment, which may further increase Se uptake and oxidative stress.
ROS↑,
NRF2↑, Oxidative stress activates Nrf2 regulon containing GSH biosynthesis enzymes and xCT. Therefore, further Se is taken into the cell, more ROS is generated, and xCT is induced again.

5095- SSE,    Extracellular thiol-assisted selenium uptake dependent on the xc− cystine transporter explains the cancer-specific cytotoxicity of selenite
- in-vitro, Lung, H157
toxicity↝, selenite toxicity is determined by the level of selenium accumulation in cells.
eff↓, MSG and selenite. We found that MSG protected the cells from any toxic effects of selenite,
other↝, Inhibition of the xc− cystine/glutamate antiporter inhibits selenium uptake and selenite toxicity.
ROS↑, sodium selenite has been shown to induce superoxide-mediated mitochondrial damage and subsequent autophagic cell death in 3 malignant glioma cell lines
mtDam↑,

5082- SSE,    Rationale for the treatment of cancer with sodium selenite
- Review, Var, NA
Risk↑, low blood Se levels were found to be associated with an increased incidence and mortality from various types of cancers
antiOx↑, Se compounds, generally considered to be antioxidants
ROS↑, selenite is not an antioxidant, but possesses oxidizing properties in the presence of specific substrates.
Imm↑, Selenite by virtue of oxidizing cell membrane thiols, can prevent the formation of the coat and consequently makes cancer cells vulnerable to the immune surveillance and destruction.
NK cell↑, selenite may directly activate NK cells, as well as inhibit angiogenesis without undesirable decrease in the oxidative potential of cellular environment.
angioG↓,
toxicity↓, postulated that sodium selenite, in view of its relative low toxicity, might become a drug of choice for many types of cancer including leukemia.

5092- SSE,    Redox-Active Selenium Compounds—From Toxicity and Cell Death to Cancer Treatment
- Review, Var, NA
*antiOx↑, Selenium—An Antioxidant with Strong Pro-Oxidant Properties
ROS↑,
GSH↓, Reaction of selenite with glutathione and subsequent generation of superoxide anion
BioAv↓, The most studied and simplest selenium compound, selenite must be administrated intravenously since no or very limited amounts of it will be detected in plasma after oral administration

5090- SSE,    Sodium Selenite Induces Ferroptosis in Non-small Cell Lung Cancer A549 Cells Via Reactive Oxygen Species (ROS)/Glutathione (GSH)/Glutathione Peroxidase4 (GPx4) Axis
- NA, Lung, A549
TumCP↓, sodium selenite could inhibit the proliferation of A549 cells, and the IC50 was 10 10 μmol/L;
ROS↑, sodium selenite could induce ROS accumulation, reduce GSH and MMP levels, increase MDA levels, and downregulate GPX4 expression in A549 cells.
GSH↓,
MMP↓,
GPx4↓,
Iron↑, inducing iron death

5089- SSE,  Se,    Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line
- in-vitro, Pca, LNCaP
ROS↑, Our results demonstrated that oxidative stress was induced by sodium selenite at high concentrations in both acute and chronic treatments, but outcomes were different.
mtDam↑, After acute exposure to selenite, cells exhibited mitochondrial injury and cell death, mainly apoptosis.
TumCD↑,
Apoptosis↑,
TumCCA↑, After chronic exposure to selenite, cells showed growth inhibition caused by cell cycle arrest, increased numbers of mitochondria and levels of mitochondrial enzymes, and only minimal induction of apoptosis
Trx↓, production of ROS, regulation of the Trx redox system, regulation of the cell cycle, and inhibition of angiogenes
angioG↓,
GSH⇅, intracellular levels of GSH were increased at doses of 0.5 and 1.5 uM selenite and decreased at doses of 2 and 2.5 uM selenite
NADPH↓, In addition, GSH and NADPH are consumed
GPx↑, GPX activities in the selenite-adapted cells were significantly increased (2- to 3-fold induction

5088- SSE,    Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite
- in-vitro, BC, MCF-7 - in-vitro, GBM, U87MG - in-vitro, Pca, PC3 - in-vitro, Cerv, HeLa - in-vitro, GBM, A172
Ferroptosis↑, Sodium selenite selectively induces ferroptosis in multiple human cancer cells.
ROS↑, Superoxide is the ROS molecule responsible for the sodium selenite-induced ferroptosis.
Iron↑, Sodium selenite induces iron accumulation via superoxide dependent mechanism
xCT↓, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO)
GSH↓,
GPx4↓,
lipid-P↑,
TumCP↓, SS inhibits the proliferation of human cancer cells
selectivity↑, Surprisingly, SS had minimal toxicity on SVG P12 cells compared to U87MG human malignant glioma cells

5087- SSE,    Sodium Selenite Alleviates Breast Cancer-Related Lymphedema Independent of Antioxidant Defense System
- Trial, BC, NA
eff↑, Compared to the baseline, at 2 weeks, 75.0% of participants in clinical stage showed improvement, while there was no change in the CTRL group
Inflam↓, Selenite’s effect on lymphedema may be associated with non-antioxidant properties, such as anti-inflammation and immune function.
Imm↑, As sodium selenite is transformed into elemental selenium in cancer, it oxidizes sulfhydryl groups [14], which then disrupts parafibrin, potentially increasing immune recognition towards cancer cells
ROS↑, Effect of Sodium Selenite Supplementation on Blood Parameters is Indicative of Oxidative Stress
*NK cell↑, Oral sodium selenite supplementation (200 μg/day for 8 weeks) in healthy university students increased cytotoxic lymphocytes and NK cell activities

5086- SSE,    Sodium Selenite Induces Superoxide-Mediated Mitochondrial Damage and Subsequent Autophagic Cell Death in Malignant Glioma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, T98G - in-vitro, GBM, A172
TumAuto↑, selenite induces autophagy in which mitochondria serve as the main target.
ROS↑, high levels of superoxide anion were generated
TumCD↑, Sodium selenite induces nonapoptotic cell death in human glioma cells
tumCV↓, 1 to 7 μmol/L selenite decreased viability in the tested glioma cell lines
selectivity↑, suggesting that selenite is preferentially cytotoxic to malignant glioma cells over normal astrocytes.
MMP↓, selenite induced a significant loss of MMP beginning 4 h after treatment
eff↓, Moreover, selenite-induced AVO formation was almost completely inhibited by CuDIPS, MnTBAP, or NAC but not by PEG-catalase
MitoP↑, Collectively, these results show that selenite induces excessive mitophagy.

5085- SSE,    Intravenous Infusion of High Dose Selenite in End-Stage Cancer Patients: Analysis of Systemic Exposure to Selenite and Seleno-Metabolites
- Review, Var, NA
toxicity↝, selenite is safe and tolerable with an unexpectable high maximum tolerated dose (MTD) and short half-life.
Half-Life↝, half-life was short (18.5 h)
ROS↑, Selenide efficiently redox cycles with oxygen, producing reactive oxygen species (ROS) until the system is exhausted of thiols and/or NADPH
Thiols↓,
NADPH↓,
toxicity↝, trimethylselenonium may serve as a urinary biomarker for both excessive selenium intake and body burden as well as a toxic dose of selenium
other↝, Selenoprotein P (SELENOP) is a proven biomarker of Se status

5084- SSE,  GEM,    The Antitumor Activity of Sodium Selenite Alone and in Combination with Gemcitabine in Pancreatic Cancer: An In Vitro and In Vivo Study
- in-vitro, PC, PANC1 - vitro+vivo, PC, Panc02
tumCV↓, Our results demonstrated a significant inhibition of pancreatic cancer cell viability with the use of sodium selenite alone and a synergistic effect when associated with GMZ
ChemoSen↑,
TumCG↓, combined therapy not only inhibited tumor growth (65%)
OS↑, but also relative to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival.
MMP↓, sodium selenite induced mitochondrial depolarization
AIF↑, sodium selenite induced a large AIF nuclear location in both PANC-1 and Pan02 cells
GSH↓, selenite-mediated depletion of GSH and TRX
Trx↓,
ROS↑, selenite depletes GSH and reduced thioredoxin (TRX-H), leaving the cell defenseless against reactive oxygen species (ROS) and increasing them
AntiTum↑, sodium selenite should be considered as a promising antitumor agent against pancreatic cancer, either alone or in combination with GMZ.

5083- SSE,    Sodium Selenite as an Anticancer Agent
- Review, Var, NA
AntiCan↑, only an inorganic sodium selenite with four-valent Se, and not that with six-valent (selenate) cation shows anticancer activity.
ROS↑, Thus selenite (Se+4) can undergo redox reaction, for example with protein's sulfhydryl groups expressed on the surface of tumor cells.

1575- statins,  Citrate,    Inhibition of Lung Cancer Growth: ATP Citrate Lyase Knockdown and Statin Treatment Leads to Dual Blockade of Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol-3-Kinase (PI3K)/AKT Pathways
- in-vitro, NSCLC, A549
eff↑, we find that statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which act downstream of ACL in the cholesterol synthesis pathway, dramatically enhance the anti-tumor effects of ACL inhibition, even regressing tumors
HMG-CoA↓, statins, inhibitors of (HMG-CoA) reductase
eff↑, statins dramatically enhance the anti-tumor effects of ACL inhibition
AntiTum↑,
EGFR↓, reduce the growth of EGF receptor
eff↑, ACL knockdown cells, H2O2 induced more apoptosis, which was further amplified with statin treatment (Fig. 1I). These data suggest that oxidant stress can tip ACL knockdown cells into apoptosis and that statin treatment magnifies this effect.
ROS↑, suggesting involvement of reactive oxygen species (ROS) in the induction of apoptosis by PI3K inhibitors.
EMT↓, Reversal of EMT
E-cadherin↑, increase in E-cadherin
MUC1↑, Mucin staining in ACL knockdown tumors is markedly increased, further suggesting that differentiation is induced in this condition
p‑ACLY↓, Statin treatment downregulates the phosphorylation of ACL and AKT
p‑Akt↓,
eff↑, . In A549 cells, Na-citrate supplementation caused a slight downregulation of AKT phosphorylation

5328- TFdiG,    Study on mechanism of low bioavailability of black tea theaflavins by using Caco-2 cell monolayer
- in-vitro, NA, Caco-2
BioAv↓, Four theaflavins showed poor bioavailability with the Papp values ranging from 0.44 × 10−7 to 3.64 × 10−7 cm/s in the absorptive transport.
P-gp↑, Moreover, theaflavins increased the expression of P-gp, MRP1, MPR3, and BCRP while decreased the expression of MRP2 at the transcription and translation levels.
MRP1↑,
ROS↑, theaflavins can suppress the adhesion and invasion of hepatoma cells by scavenging hydroxyl radicals and reactive oxygen species (ROS) (Zhang et al., 2000).
*BioAv↓, It is reported that only a small amount of theaflavins can be detected in the plasma and urine samples of healthy volunteers after 2 hours of consumption of 700 mg mixed theaflavins

5331- TFdiG,    Anti-Cancer Properties of Theaflavins
- Review, Var, NA
AntiCan↑, Theaflavins, phenolic components present in black tea, have demonstrated anti-cancer potential in cell cultures in vitro and in animal studies in vivo.
TumCP↓, Theaflavins have been shown to inhibit proliferation, survival, and migration of many cancer cellswhile promoting apoptosis.
TumCMig↓,
Apoptosis↑,
cl‑PARP↑, Treatment with theaflavins has been associated with increased levels of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspases-3, -7, -8, and -9, all markers of apoptosis
cl‑Casp3↑,
cl‑Casp7↑,
cl‑Casp8↑,
cl‑Casp9↑,
BAX↑, and increased expression of the proapoptotic marker Bcl-2-associated X protein (Bax) and concomitant reduction in the antiapoptotic marker B-cell lymphoma 2 (Bcl-2)
Bcl-2↓,
p‑Akt↓, theaflavin treatment reduced phosphorylated Akt, phosphorylated mechanistic target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and c-Myc levels with increased expression of the tumour suppressor p53.
p‑mTOR↓,
PI3K↓,
cMyc↓,
P53↑,
ROS↑, theaflavins inhibited Wt-p53 MCF-7 and ZR-75-1 cell migration in a dose-response manner while upregulating the levels of reactive oxygen species (ROS;
NF-kB↓, Theaflavin treatment inhibited the translocation of NF-kB/p65 to the nucleus of MCF-7 cells
MMP9↓, Additionally, the levels of pro-migratory proteins matrix metalloproteinase (MMP)-2 and MMP-9 were downregulated
MMP2↓,
TumVol↓, Histological examination of tumours revealed that the largest tumour in mice that received black tea extract was 40% smaller than the largest tumour in the control group
PSA↓, TF3 induced the greatest inhibition of testosterone-mediated androgen receptor expression while also suppressing testosterone-induced secretion of prostate-specific antigen (PSA).
TumCCA↑, Theaflavins isolated from black tea caused a dose-dependent inhibition of HT 460 human lung cancer cell viability, paired with G2/M phase cell cycle arrest and induced apoptosis
VEGF↓, F3 exhibited lower rates of proliferation (in a dose-dependent manner) and angiogenesis due to inhibition of VEGF secretion and HIF-1a protein
Hif1a↓,
CDK2↓, downregulation of CDK2 and CDK4 protein expression and CDK2 and cyclin E1 protein expression, respectively.
CDK4↓,
GSH↓, A decrease in cellular GSH content and an increase in ROS levels were observed with TF1 treatment.
Dose↑, The studies summarized in this review showed that, generally, cancer cells must be exposed to micromolar concentrations of theaflavins to observe anti-cancer effects.
BioAv↓, However, micromolar concentrations of theaflavins cannot be achieved through direct ingestion of the compounds themselves
BioAv↓, When two volunteers were administered 30 mg of theaflavins orally—the approximate equivalent of 30 cups of black tea—the maximum concentration of theaflavins detected in serum and urine after two hours were both in the femtomolar range
BioAv↑, Some success has been observed with the use of encapsulated nanoparticles to improve delivery of other poorly soluble polyphenols such as resveratrol, naringenin, curcumin, and carnosol [70,71,72]. This may offer a potential solution to improve the b

5332- TFdiG,    Theaflavin-3,3′-digallate triggers apoptosis in osteosarcoma cells via the caspase pathway
- vitro+vivo, OS, 143B - in-vitro, OS, U2OS
tumCV↓, TF3 significantly reduced the viability of 143B and U2OS cells.
cl‑Casp3↑, TF3 upregulated the expression of cleaved caspase-3 and cleaved caspase-9 in osteosarcoma cells.
cl‑Casp9↑,
p‑γH2AX↑, TF3 increased the levels of phosphorylated histone H2Ax, Bax, Bak1, and cytochrome c, while reducing the levels of Mcl-1 and survivin in osteosarcoma cells.
BAX↑,
Bak↑,
Cyt‑c↑,
Mcl-1↓,
survivin↓,
TumVol↓, TF3 significantly reduced the average tumor volume in the xenograft model.
Wnt↓, TF3 also inhibited the proliferation of ovarian cancer stem cells by suppressing the Wnt/β-Catenin pathway 14.
β-catenin/ZEB1↓,
Dose↝, mice were fed TF3 at experimental concentrations (10 and 20 mg/kg) thrice a week.
ROS↑, TF3 treatment significantly elevated ROS levels in 143B and U2OS cells. Specifically, ROS levels were significantly higher in cells treated with 75 or 100 μM TF3 than in control cells.
eff↓, Moreover, treatment with NAC, an antioxidant, significantly reversed cell viability after TF3 treatment
TumW↓, In the xenograft mouse model, TF3 treatment reduced tumor volume, tumor weight, and Ki-67 expression.
Ki-67↓,

5333- TFdiG,    Theaflavin-3,3′-Digallate Plays a ROS-Mediated Dual Role in Ferroptosis and Apoptosis via the MAPK Pathway in Human Osteosarcoma Cell Lines and Xenografts
- vitro+vivo, OS, MG63
tumCV↓, The results showed that TF3 reduced cell viability, suppressed cell proliferation, and caused G0/G1 cell cycle arrest in both MG63 and HOS cell lines in a concentration-dependent manner.
TumCP↓,
TumCCA↑,
Iron↑, TF3 also altered the homeostatic mechanisms for iron storage in the examined cell lines, resulting in an excess of labile iron
ROS↑, Unsurprisingly, TF3 caused oxidative stress through reduced glutathione (GSH) exhaustion, reactive oxygen species (ROS) accumulation, and the Fenton reaction, which triggered ferroptosis and apoptosis in the cells.
GSH↓,
Fenton↑,
Ferroptosis↑,
Apoptosis↑,
MAPK↑, TF3 also induced MAPK signalling pathways, including the ERK, JNK, and p38 MAPK pathways.
ERK↑,
JNK↑,
p38↑,
TumCG↓, TF3 significantly reduced OS growth in the 20 and 40 mg/kg treatment groups but did not significantly affect body weight
Dose↝,
FTH1↓, TF3 downregulated FTH expression in vivo and in vitro to promote the release of Fe2+ and the generation of ROS that are involved in ferroptosis progression
GPx4↓, and downregulated the expression of GPX4, eventually resulting in ferroptosis.

5222- TQ,    Thymoquinone chemosensitizes colon cancer cells through inhibition of NF-κB
- in-vitro, CRC, COLO205 - in-vitro, CRC, HCT116
tumCV↓, TQ significantly decreased cell viability in COLO205 and HCT116 cells in a dose-dependent manner.
ChemoSen↑, TQ treatment additionally sensitized COLO205 and HCT116 cells to cisplatin therapy in a concentration-dependent manner.
p‑p65↓, TQ treatment significantly decreased the level of phosphorylated p65 in the nucleus, which indicated the inhibition of NF-κB activation by TQ treatment.
NF-kB↓,
VEGF↓, TQ also decreased the expression levels of VEGF, c-Myc and Bcl-2.
cMyc↓,
Bcl-2↓,
ROS↑, TQ-induced apoptosis has been indicated to be mediated by reactive oxygen species generation (29,33,37)

1928- TQ,    Thymoquinone Crosstalks with DR5 to Sensitize TRAIL Resistance and Stimulate ROS-Mediated Cancer Apoptosis
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
TumCP↓, TQ+TRAIL significantly inhibited the protein content-based proliferation of MDA-MB-231 cells more than MCF-7 cells.
DR4↑, synergistic effect of them significantly up-regulated the genetic expressions of DR4, DR5, Cas-8, and FADD genes
DR5↑,
Casp8↑,
FADD↑,
Bcl-2↓, inhibited the genetic expression of the Bcl-2
ROS↑, The induction of the apoptotic genes using the combined therapy was stimulated by the elevation of the reactive oxygen species (ROS); nitric oxide (NO) and malondialdehyde (MDA) levels.
NO↑,
MDA↑,

1929- TQ,    Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells
- in-vitro, Bladder, 5637 - in-vitro, Bladder, T24/HTB-9
tumCV↓, TQ restrains the viability, proliferation, migration and invasion through activating caspase-dependent apoptosis in bladder carcinoma cells
TumCP↓,
TumCI↓,
Casp↑,
ROS↑, mediated by TQ induced ROS increase in bladder carcinoma cells
PD-L1↓, TQ upregulates hsa-miR-877-5p level to reduce PD-L1 expression in 5637 and T24 BC cells
EMT↓, which suppresses the epithelial mesenchymal transition (EMT)
MMP↓, MMP was markedly lowered by TQ in a dose-dependent way
eff↓, MMP was significantly recovered in the combined treatment of TQ and NAC

1930- TQ,    Therapeutic implications and clinical manifestations of thymoquinone
- Review, Var, NA
AntiCan↑, TQ showed anti-cancer, anti-oxidant, and anti-inflammatory properties, validated in various disease models.
antiOx↑,
Inflam↓,
TumCP↓, anti-cancer potential of TQ is goverened by anti-proliferation, cell cycle arrest, apoptosis induction, ROS production, anti-metastasis and anti-angiogenesis, inhibition of cell migration and invasion action
TumCCA↑,
Apoptosis↑,
ROS↑,
TumMeta↓,
TumCI↓,

1931- TQ,  doxoR,    Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms
- in-vivo, AML, NA
eff↑, Q and Dox caused greater inhibition of cell viability and increased sub-G1 cells in both cell lines compared to Dox or TQ alone.
tumCV↓,
TumCCA↑,
ROS↑, combination induced apoptosis by increasing ROS and causing disruption of mitochondrial membrane potential.
MMP↓,
eff↑, Pretreatment with N-acetyl cysteine (NAC) or pan caspase inhibitor significantly inhibited the apoptotic response suggesting that cell death is ROS- and caspase-dependent.
TumVol↓, combination reduced tumor volume in NOD/SCID mice
eff↑, possibility to use up to twofold lower doses of Dox against ATL while exhibiting the same cancer inhibitory effects.
Ki-67↓, However, in TQ and combination treated groups, the expression of Ki-67 was significantly lower

1932- TQ,    Recent Findings on Thymoquinone and Its Applications as a Nanocarrier for the Treatment of Cancer and Rheumatoid Arthritis
- Review, Var, NA
ROS↑, most quoted reports indicate in increase in ROS

1933- TQ,    Thymoquinone: potential cure for inflammatory disorders and cancer
- Review, Var, NA
antiOx↑, Its anti-oxidant/anti-inflammatory effect has been reported in various disease models. Potent free radical and superoxide radical scavenger at both nanomolar and micromolar range, respectively
Inflam↓,
AntiCan↑, anticancer effect(s) of thymoquinone are mediated through different modes of action, including anti-proliferation, apoptosis induction, cell cycle arrest, ROS generation and anti-metastasis/anti-angiogenesis.
TumCCA↑, Thymoquinone was also shown to induce G0/G1 arrest
ROS↑, activation of caspases and generation of ROS.
angioG↓,
Apoptosis↑,
Casp↑,
eff↑, combination of thymoquinone and conventional chemotherapeutic drugs could produce greater therapeutic effect as well as reduce the toxicity of the latter
eff↝, TQ has been reported to exert anti-oxidant activity at lower concentration, but at higher concentration, it showed significant pro-oxidant effects. Whether TQ can act as a pro-oxidant or antioxidant can also be attributed cell type

1934- TQ,    Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: role of reactive oxygen species
- in-vitro, Pca, PC3 - in-vitro, Pca, C4-2B
ROS↑, A dose-dependent increase in ROS generation was clearly evident at this time point. Almost a 3.25-fold increase in ROS levels were observed with 75 and 100 umol/L of TQ in both PC-3 and C4-2B cells.
GSH↓, GSH levels were significantly decreased by 50 and 100 umol/L TQ, showing 35% and 65% reductions in GSH levels
eff↓, Pretreatment with NAC protected PC-3 and C4-2B cells against TQ-induced ROS generation and growth inhibition
AR↓, TQ dose dependently inhibited both total and nuclear AR levels (4–5 fold) and AR-directed transcriptional activity (10–12 fold).

1935- TQ,    Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis
- Review, OS, NA
Apoptosis↑, Nigella sativa, has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation
TumCCA↑,
angioG↓,
TumMeta↓,
ROS↑,
P53↑, TQ upregulated the expression of p53 in a time-dependent manner, promoting apoptosis in MCF-7
Twist↓, TQ to BT 549 cell lines (breast cancer cells) in a dose-dependent fashion reduced the transcription activity of TWIST1, one of the promotors of endothelial-to-mesenchymal transition (EMT)
E-cadherin↑, TQ engagement increased the expression of E-cadherin and decreased the expression of N-cadherin
N-cadherin↓,
NF-kB↓, fig 1
IL8↓,
XIAP↓,
Bcl-2↓,
STAT3↓,
MAPK↓,
PI3K↓,
Akt↓,
ERK↓,
MMP2↓,
MMP9↓,
*ROS↓, prevent cancer formation
HO-1↑, Moreover, TQ could stunt the growth of HCC cell lines through the generation of ROS, heme oxygenase-1 (HO-1)
selectivity↑, application of phytochemicals such as TQ is a promising strategy since these compounds show less toxicity against normal cells.
TumCG↓, Despite inhibiting the growth and viability of different cancer types, TQ has no adverse effects on healthy cells

1936- TQ,    Thymoquinone induces apoptosis and increase ROS in ovarian cancer cell line
- in-vitro, Ovarian, CaOV3 - in-vitro, Nor, WRL68
selectivity↑, TQ induces anti-proliferative activity on Caov-3 with an IC50 of 6.0±0.03 μg/mL, without any cytotoxic activity towards WRL-68 normal hepatocytes.
TumCP↓,
MMP↓, TQ induces decreases in plasma membrane permeability and mitochondrial membrane potential.
Bcl-2↓, significant decrease is observed in Bcl-2 while Bax is down-regulated.
BAX↑,
ROS↑, TQ induced anti-cancer effect involves intrinsic pathway of apoptosis and cellular oxidative stress

2112- TQ,    Crude flavonoid extract of the medicinal herb Nigella sativa inhibits proliferation and induces apoptosis in breastcancer cells
- in-vitro, BC, MCF-7
Apoptosis↑, apoptosis, including cell shrinkage and detachment, nuclear condensation, and DNA damage, were observed after the CFENS treatments
DNAdam↑,
ROS↑, CFENS triggered ROS accumulation, GSH depletion, disruption of mitochondrial membrane potential, activation of caspases-3/7 and -9, and an increase in the Bax/Bcl-2 ratio in MCF-7 cell
GSH↓, GSH level is depleted, whereas GSSG is accumulated, resulting in a decrease in the GSH/GSSG ratio
MMP↓, ROS accumulation also induces outer mitochondrial membrane permeabilization (MMP), which leads to loss of mitochondrial membrane potential (ΔΨm)
Casp3↑,
Casp7↑,
Casp9↑,
Bax:Bcl2↑,
P53↑, CFENS induced cell cycle arrest, upregulated the expression levels of p53 and p21 proteins,
P21↑,
cycD1/CCND1↓, downregulated the expression of cyclin D1.
GSSG↑,
GSH/GSSG↓, GSH level is depleted, whereas GSSG is accumulated, resulting in a decrease in the GSH/GSSG ratio

2124- TQ,    Thymoquinone: an emerging natural drug with a wide range of medical applications
- Review, Var, NA
hepatoP↑, Hepatoprotective
Bax:Bcl2↑, A549 non-small cell lung cancer cells exposed to benzo(a)pyrene plus TQ in vitro
cycD1/CCND1↓,
P21↑,
TRAIL↑,
P53↑,
TumCCA↑, G2/M cell cycle arrest
hepatoP↑, Hepatoprotective effects
*ALAT↓, The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tissue levels of malondialdehyde (MDA), oxidized glutathione (GSSG), and superoxide dismutase (SOD) activity were found to be lower
*AST↓,
*MDA↓,
*GSSG↓,
*COX2↓, N. sativa and TQ treatment also suppressed the expression of the COX-2 enzyme in the pancreatic tissue
*lipid-P↓, Thymoquinone and thymohydroquinone inhibited in vitro non-enzymatic lipid peroxidation in hippocampal homogenates induced by iron-ascorbate (52)
PPARγ↑, In breast cancer cells TQ was able to increase peroxisome proliferator-activated receptor gamma (PPAR-γ) activity
p38↑, Treatment of human breast carcinoma in both in vitro and in vivo models demonstrated antiproliferative and proapoptotic effects of TQ, which are mediated by its inductive effect on p38 and ROS signaling
ROS↑,
ChemoSen↑, TQ possesses anti-tumor effects in breast tumor xenograft mice and it potentiates the antitumor effect of doxorubicin (64).
selectivity↑, TQ is also a microtubule-targeting agent (MTA), and binds to the tubulin-microtubule network, thus preventing microtubule polymerization and causing mitotic arrest and apoptosis of A549 cells but not of normal HUVEC cells
selectivity↑, No effect on α/β tubulin protein expression was found in normal human fibroblasts used as control cell model. These data indicate that TQ exerts a selective effect on α/β tubulin in cancer cells
*MDA↓, Reduction of tissue MDA levels, and increased SOD levels
*SOD↑,

2123- TQ,    Thymoquinone suppresses growth and induces apoptosis via generation of reactive oxygen species in primary effusion lymphoma
- in-vitro, lymphoma, PEL
Akt↓, TQ treatment results in down-regulation of constitutive activation of AKT via generation of reactive oxygen species (ROS)
ROS↑,
BAX↓, and it causes conformational changes in Bax protein, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol.
MMP↓,
Cyt‑c↑,
eff↑, subtoxic doses of TQ sensitized PEL cells to TRAIL via up-regulation of DR5
Casp9↑, TQ-induced signaling causes caspase-9/3 activation and PARP cleavage in PEL cells
Casp3↑,
cl‑PARP↑,
DR5↑, TQ-induced ROS generation regulates up-regulation of DR5

2122- TQ,    Review on Molecular and Therapeutic Potential of Thymoquinone in Cancer
- Review, Var, NA
ChemoSen↓, Chemosensitization by TQ is mostly limited to in vitro studies, and it has potential in therapeutic strategy for cancer
*ROS↓, its scavenging ability against freeradicals, including reactive oxygen species (ROS;
*GSH↑, TQ reduces the cellular oxidative stress by inducing glutathione (GSH)
RenoP↑, TQ protects the kidney against ifosfamide, mercuric chloride, cisplatin, and doxorubicin-induced damage by preventing renal GSH depletion and antilipid peroxidation
hepatoP↑, TQ ameliorated hepatotoxicity of carbon tetrachloride as seen by the significant reduction of the elevated levels of serum enzymes and significant increase of the hepatic GSH content
COX2↓, TQ induces inhibition of PGE2 and COX-2, in a COX-2 overexpressing HPAC cells (PC cells).
NF-kB↓, NF-κB is a molecular target of TQ in cance
chemoPv↑, TQ is a chemopreventive agent for prostate cancer
neuroP↑, The beneficial effect of TQ as a neuroprotective agent in inhibiting viability of human neuroblastoma cell line SH-SY5Y
TumCCA↑, TQ, it reportedly induces G1 cell cycle arrest in osteosarcoma cancer cells (COS31) as well as in human colon cancer cells (HCT-116),
P21↑, TQ caused a dramatic increase in p21WAF1 , (Cip1), and p27 (Kip1) and blocked the progression of synchronized LNCaP cells from G1 to S phase,
p27↑,
ROS↑, TQ on p53 deficient lymphoblastic leukemia Jurkat cells and found TQ treatment produced intracellular ROS pro- moting a DNA damage-related cell cycle arrest and triggered apoptosis
DNAdam↑,
MUC4↓, in pancreatic cancer cells and it was found that TQ downregulates MUC-4 expression through the proteasomal pathway

2121- TQ,    ROS">Thymoquinone Inhibits Tumor Growth and Induces Apoptosis in a Breast Cancer Xenograft Mouse Model: The Role of p38 MAPK and ROS
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
p‑p38↑, Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells
ROS↑,
TumCP↓, These inductions were found to be responsible for TQ’s anti-proliferative and pro-apoptotic effect
eff↑, TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin
XIAP↓, TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograf
survivin↓,
Bcl-xL↓,
Bcl-2↓,
Ki-67↓, Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors
*Catalase↑, TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues.
*SOD↑,
*GSH↑,
hepatoP↑,
p‑MAPK↑, TQ significantly up-regulated the phosphorylation of various MAPKs in MCF-7 cells
JNK↓, The increase of JNK and p38 protein phosphorylation was found to be maximal at 12 h
eff↓, N-acetylcysteine (NAC) prevents TQ-induced ROS production

2120- TQ,    ROS-mediated_suppression_of_STAT3">Thymoquinone induces apoptosis of human epidermoid carcinoma A431 cells through ROS-mediated suppression of STAT3
- in-vitro, Melanoma, A431
ROS↑, The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining.
Apoptosis↑, Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3
P53↑,
BAX↑,
MDM2↓,
Bcl-2↓,
Bcl-xL↓,
Casp9↑,
Casp7↑,
Casp3↑,
STAT3↓, Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment.
cycD1/CCND1↓,
survivin↓,
eff↓, The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ

2119- TQ,    Dual properties of Nigella Sativa: anti-oxidant and pro-oxidant
- Review, Var, NA
*ROS↓, NS has both anti-oxidant and pro-oxidant properties in different cell types hence should be used carefully because it acts as a cytoprotective or cytotoxic agent in inflammatory and malignant conditions respectively.
ROS↑, malignant conditions
chemoP↑, It is reported that nigella can reduce the toxic effects of anticancer drugs
RenoP↑, NS has been shown to improve multiple organ toxicity in models of oxidative stress
hepatoP↑,
NLRP3↓, NLRP3 inflammasome was inactivated partially by inhibition of ROS in melanoma cells by TQ administration.
neuroP↑, NS oil has been found to be neuroprotective against oxidative stress in epileptogenesis
NF-kB↓, TQ has been shown to exhibit down regulation of NF-κB expression in lung cancer cells and in osteosarcoma cells
P21↑, TQ up regulated the expression of p21 and down regulated the histone deacetylase (HDAC) activity and induced histone hyperacetylation causing induction of apoptosis and inhibition of proliferation in pancreatic cancer cell
HDAC↓,
Apoptosis↑,
TumCP↓,
GSH↓, TQ was found to decrease glutathione (GSH) levels in prostate cancer cells resulting in up-regulated expression of GADD45 alpha
GADD45A↑,
GSK‐3β↑, TQ caused the apoptosis of tumor cells by modulation of wnt signaling through activation of GSK-3β

2127- TQ,    Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways
- Review, GBM, NA
chemoP↑, TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells
ChemoSen↑,
BioAv↑, TQ adds another advantage in overcoming blood-brain barrier
PTEN↑, TQ upregulates PTEN signaling [72, 73], interferes with PI3K/Akt signaling and promotes G(1) arrest, downregulates PI3K/Akt
PI3K↓,
Akt↓,
TumCCA↓,
NF-kB↓, and NF-κB and their regulated gene products, such as p-AKT, p65, XIAP, Bcl-2, COX-2, and VEGF, and attenuates mTOR activity
p‑Akt↓,
p65↓,
XIAP↓,
Bcl-2↓,
COX2↓,
VEGF↓,
mTOR↓,
RAS↓, Studies in colorectal cancer have demonstrated that TQ inhibits the Ras/Raf/MEK/ERK signaling
Raf↓,
MEK↓,
ERK↓,
MMP2↓, Multiple studies have reported that TQ downregulates FAC and reduces the secretion of MMP-2 and MMP-9 and thereby reduces GBM cells migration, adhesion, and invasion
MMP9↓,
TumCMig↓,
TumCI↓,
Casp↑, caspase activation and PARP cleavage
cl‑PARP↑,
ROS⇅, TQ is hypothesized to act as an antoxidant at lower concentrations and a prooxidant at higher concentrations depending on its environment [89]
ROS↑, In tumor cells specifically, TQ generates ROS production that leads to reduced expression of prosurvival genes, loss of mitochondrial potential,
MMP↓,
eff↑, elevated level of ROS generation and simultaneous DNA damage when treated with a combination of TQ and artemisinin
Telomerase↓, inhibition of telomerase by TQ through the formation of G-quadruplex DNA stabilizer, subsequently leads to rapid DNA damage which can eventually induce apoptosis in cancer cells specifically
DNAdam↑,
Apoptosis↑,
STAT3↓, TQ has shown to suppress STAT3 in myeloma, gastric, and colon cancer [86, 171, 172]
RadioS↑, TQ might enhance radiation therapeutic benefit by enhancing the cytotoxic efficacy of radiation through modulation of cell cycle and apoptosis [31]

2129- TQ,  doxoR,    Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells
- in-vitro, BC, MCF-7
ChemoSen↑, TQ greatly inhibits doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation
PTEN↑, TQ treatment increased cellular levels of PTEN proteins
p‑Akt↓, resulting in a substantial decrease of phosphorylated Akt, a known regulator of cell survival.
TumCCA↑, TQ arrested MCF-7/DOX cells at G2/M phase and increased cellular levels of p53 and p21 proteins.
P53↑,
P21↑,
Apoptosis↑, TQ-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspases and PARP cleavage in MCF-7/DOX cells.
MMP↓,
Casp↑,
cl‑PARP↑,
Bax:Bcl2↑, TQ treatment increased Bax/Bcl2 ratio via up-regulating Bax and down-regulating Bcl2 proteins.
eff↓, PTEN silencing by target specific siRNA enabled the suppression of TQ-induced apoptosis resulting in increased cell survival.
DNAdam↓, TQ treatment arrests MCF-7/DOX Cells in G2/M phase and induces DNA damage
p‑γH2AX↑, time-dependent increase in the phosphorylation of H2AX was observed following TQ treatment
ROS↑, DNA damage caused by TQ induced reactive species and oxidative stress.

2084- TQ,    Thymoquinone, as an anticancer molecule: from basic research to clinical investigation
- Review, Var, NA
*ROS↓, An interesting study reported that thymoquinone is actually a potent apoptosis inducer in cancer cells, but it exerts antiapoptotic effect through attenuating oxidative stress in other types of cell injury
*chemoPv↑, antioxidant activity of thymoquinone is responsible for its chemopreventive activities
ROS↑, other studies reported thymoquinone induce apoptosis in cancer cells by exerting oxidative damage
ROS⇅, Another hypothesis states that thymoquinone acts as an antioxidant at lower concentrations and a prooxidant at higher concentrations
MUC4↓, Torres et al. [17] revealed that thymoquinone down-regulates glycoprotein mucin 4 (MUC4)
selectivity↑, thymoquinone was found to inhibit DNA synthesis, proliferation, and viability of cancerous cells, such as LNCaP, C4-B, DU145, and PC-3, but not noncancerous BPH-1 prostate epithelial cells [20].
AR↓, Down-regulation of androgen receptor (AR) and cell proliferation regulator E2F-1 was indicated as the mechanism behind thymoquinone’s action in prostate cancer
cycD1/CCND1↓, expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor (VEGF), was inhibited by thymoquinone, which ultimately increased apoptosis and killed cancer cells
Bcl-2↓,
Bcl-xL↓,
survivin↓,
Mcl-1↓,
VEGF↓,
cl‑PARP↑, induction of the cleavage of poly-(ADP-ribose) polymerase (PARP
ROS↑, In ALL cell line CEM-ss, thymoquinone treatment generated reactive oxygen species (ROS) and HSP70
HSP70/HSPA5↑,
P53↑, thymoquinone can induce apoptosis in MCF-7 breast cancer cells via the up-regulation of p53 expression
miR-34a↑, Thymoquinone significantly increased the expression of miR-34a via p53, and down-regulated Rac1 expression
Rac1↓,
TumCCA↑, In hepatic carcinoma, thymoquinone induced cell cycle arrest and apoptosis by repressing the Notch signaling pathway
NOTCH↓,
NF-kB↓, Evidence revealed that thymoquinone suppresses tumor necrosis factor (TNF-α)-induced NF-kappa B (NF-κB) activation
IκB↓, consequently inhibits the activation of I kappa B alpha (I-κBα) kinase, I-κBα phosphorylation, I-κBα degradation, p65 phosphorylation
p‑p65↓,
IAP1↓, down-regulated the expression of NF-κB -regulated antiapoptotic gene products, like IAP1, IAP2, XIAP Bcl-2, Bcl-xL;
IAP2↑,
XIAP↓,
TNF-α↓, It also inhibited monocyte chemo-attractant protein-1 (MCP-1), TNF-α, interleukin (IL)-1β and COX-2, ultimately reducing the NF-κB activation in pancreatic ductal adenocarcinoma cells
COX2↓,
Inflam↓, indicating its role as an inhibitor of proinflammatory pathways
α-tubulin↓, Without affecting the tubulin levels in normal human fibroblast, thymoquinone induces degradation of α and β tubulin proteins in human astrocytoma U87 cells and in T lymphoblastic leukaemia Jurkat cells, and thus exerts anticancer activity
Twist↓, thymoquinone treatment inhibits TWIST1 promoter activity and decreases its expression in breast cancer cell lines; leading to the inhibition of epithelial-mesenchymal transition (EMT)
EMT↓,
mTOR↓, thymoquinone also attenuated mTOR activity, and inhibited PI3K/Akt signaling in bladder cancer
PI3K↓,
Akt↓,
BioAv↓, Thymoquinone is chemically hydrophobic, which causes its poor solubility, and thus bioavailability. bioavailability of thymoquinone was reported ~58% with a lag time of ~23 min
ChemoSen↑, Some studies revealed that thymoquinone in combination with other chemotherapeutic drugs can show better anticancer activities
BioAv↑, Thymoquinone-loaded liposomes (TQ-LP) and thymoquinone loaded in liposomes modified with Triton X-100 (XLP) with diameters of about 100 nm were found to maintain stability, improve bioavailability and maintain thymoquinone’s anticancer activity
PTEN↑, Thymoquinone also induces apoptosis by up-regulating PTEN
chemoPv↑, A recent study showed that thymoquinone can potentiate the chemopreventive effect of vitamin D during the initiation phase of colon cancer in rat model
RadioS↑, thymoquinone also mediates radiosensitization and cancer chemo-radiotherapy
*Half-Life↝, Thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) has been developed to improve its bioavailability (elimination half-life ~5 hours)
*BioAv↝, calculated absolute bioavailability of thymoquinone was reported ~58% with a lag time of ~23 min by Alkharfy et al.

2094- TQ,    Cytotoxicity of Nigella sativa Extracts Against Cancer Cells: A Review of In Vitro and In Vivo Studies
- Review, Var, NA
ROS↑, Oxidative stress generation leading to cancer cell death
angioG↓, Suppression of angiogenesis and metastasis by inhibiting VEGF and MMPs.
TumMeta↓,
VEGF↓,
MMPs↓,
P53↑, upregulation of p53, Bax, caspases
BAX↑,
Casp↑,
Bcl-2↓, downregulating anti-apoptotic factors (Bcl-2, survivin).
survivin↓,
*ROS↓, antioxidant activity neutralizes reactive oxygen species (ROS)
ChemoSen↑, enhances the efficacy of conventional chemotherapeutics like doxorubicin, cisplatin, and 5-fluorouracil while reducing their toxicity.
chemoP↑,
MDR1↓, helps overcome drug resistance by modulating multidrug resistance (MDR) proteins
BioAv↓, thymoquinone, their absorption and stability are limited due to poor solubility and rapid metabolism
BioAv↑, To improve efficacy, nanoformulations, such as lipid-based carriers and nanoparticles, have been explored

2095- TQ,    Review on the Potential Therapeutic Roles of Nigella sativa in the Treatment of Patients with Cancer: Involvement of Apoptosis
- Review, Var, NA
TumCCA↑, cell cycle arrest, apoptosis induction, ROS generation
Apoptosis↑,
ROS↑,
Cyt‑c↑, release of mitochondrial cytochrome C, an increase in the Bax/Bcl-2 ratio, activations of caspases-3, -9 and -8, cleavage of PARP
Bax:Bcl2↑,
Casp3↑,
Casp9↑,
cl‑PARP↑,
P53↑, increased expressions of p53 and p21,
P21↑,
cMyc↓, decreased expressions of oncoproteins (c-Myc), human telomerase reverse transcriptase (hTERT), cyclin D1, and cyclin-dependent kinase-4 (CDK-4).
hTERT/TERT↓,
cycD1/CCND1↓,
CDK4↓,
NF-kB↓, inhibited NF-κB activation
IAP1↓, (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor)
IAP2↓,
XIAP↓,
Bcl-xL↓,
survivin↓,
COX2↓,
MMP9↓,
VEGF↓,
eff↑, combination of TQ and cisplatin in the treatment of lung cancer in a mouse xenograft model showed that TQ was able to inhibit cell proliferation (nearly 90%), reduce cell viability, induce apoptosis, and reduce tumor volume and tumor weight

2100- TQ,    Dual properties of Nigella Sative: Anti-oxidant and Pro-oxidant
- Review, NA, NA
ROS⇅, Pubmed data indicated that NS has both anti-oxidant and pro-oxidant properties in different cell types
*antiOx↑, NS acts as an anti-oxidant by scavenging ROS [4]. It can ameliorate ischemic reperfusion injury conditions and attenuated ROS in heart [5] intestine [6] and kidney [7]
*SOD↑, improved the activities of various enzymes like superoxide dismutase [SOD] and myeloperoxidase (MPO)
*MPO↑,
*neuroP↑, NS oil has been found to be neuroprotective against oxidative stress in epileptogenesis, pilocarpine-induced seizures [25] and opioid tolerance
*chemoP↑, Anticancer drugs leave toxic effect due to over-production of ROS. NS oil or TQ can potentially up-regulate anti-oxidant mechanisms caused by anticancer drug
*radioP↑, NS seed extracts can protect normal tissue from oxidative damage during radiotherapy of cancer patients [35,36]
NF-kB↓, TQ has been shown to exhibit down regulation of NF-κB expression in lung cancer cells
IAP1↓, Anti-apoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc) and angiogenic genes (matrix metalloproteinase-9 orMMP-9) and vascular endothelial growth factor (VEGF) were down-regulated
IAP2↓,
XIAP↓,
Bcl-xL↓,
survivin↓,
COX2↓,
MMP9↓,
VEGF↓,
ROS↑, TQ causes release of ROS in ABC cells which in turn inhibits NF-κB activity
P21↑, TQ up regulated the expression of p21 and down regulated the histone deacetylase (HDAC) activity and induced histone hyperacetylation causing induction of apoptosis and inhibition of proliferation in pancreatic cancer cell
HDAC↓,
GSH↓, TQ was found to decrease glutathione (GSH) levels in prostate cancer cells resulting in up-regulated expression of GADD45 alpha (growth arrest and DNA damage inducible gene) and AIF
GADD45A↑,
AIF↑,
STAT3↓, TQ suppressed the STAT 3; the signal transducer and activator of transcription which is involved in the abnormal transformation of a number of human malignancies [53].

2106- TQ,    Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy
- Review, Var, NA
Apoptosis↑, The anticancer power of TQ is accomplished by several aspects; including promotion of apoptosis, arrest of cell cycle and ROS generation.
TumCCA↑,
ROS↑,
*Catalase↑, activation of antioxidant cytoprotective enzymes including, CAT, SOD, glutathione reductase (GR) [80], glutathione-S-transferase (GST) [81] and glutathione peroxidase (GPx) - scavenging H2O2 and superoxide radicals and preventing lipid peroxidation
*SOD↑,
*GR↑,
*GSTA1↓,
*GPx↑,
*H2O2↓,
*ROS↓,
*lipid-P↓,
*HO-1↑, application of TQ to HaCaT (normal) cells promoted the expression of HO-1 in a concentration and time-dependent pattern
p‑Akt↓, TQ could induce ROS which provoked phosphorylation and activation of Akt and AMPK-α
AMPKα↑,
NK cell↑, TQ was outlined to enhance natural killer (NK) cells activity
selectivity↑, Many researchers have noticed that the growth inhibitory potential of TQ is particular to cancer cells
Dose↝, Moreover, TQ has a dual effect in which it can acts as both pro-oxidant and antioxidant in a dose-dependent manner; it acts as an antioxidant at low concentration whereas, at higher concentrations it possess pro-oxidant property
eff↑, Pro-oxidant property of TQ occurs in the presence of metal ions including copper and iron which induce conversion of TQ into semiquinone. This leads to generation of reactive oxygen species (ROS) causing DNA damage and induction of cellular apoptosis
GSH↓, TQ for one hour resulted in three-fold increase of ROS while reduced GSH level by 60%
eff↓, pre-treatment of cells with N-acetylcysteine, counteracted TQ-induced ROS production and alleviated growth inhibition
P53↑, TQ provokes apoptosis in MCF-7 cancer cells by up regulating the expression of P53 by time-dependent manner.
p‑STAT3↓, TQ inhibited the phosphorylation of STAT3
PI3K↑, via up regulation of PI3K and MPAK signalling pathway
MAPK↑,
GSK‐3β↑, TQ produced apoptosis in cancer cells and modulated Wnt signaling by activating GSK-3β, translocating β-catenin
ChemoSen↑, Co-administration of TQ and chemotherapeutic agents possess greater cytotoxic influence on cancer cells.
RadioS↑, Treatment of cells with both TQ and IR enhanced the antiproliferative power of TQ as observed by shifting the IC50 values for MCF7 and T47D cells from ∼104 and 37 μM to 72 and 18 μM, respectively.
BioAv↓, TQ cannot be used as the primary therapeutic agent because of its poor bioavailability [177,178] and lower efficacy
NRF2↑, TQ to HaCaT cells promoted the expression of HO-1 in a concentration and time-dependent pattern. This was achieved via increasing stabilization of Nrf2

2108- TQ,    Anti-cancer properties and mechanisms of action of thymoquinone, the major active ingredient of Nigella sativa
- Review, Var, NA
HDAC↓, Intraperitoneal injection of TQ (10 mg/kg) for 18 days was associated with significant 39% inhibition of LNM35 xenograft tumor growth, with a significant increase in caspase-3 activity and a significant decrease in histone deacetylase-2 (HDAC2)
TumCCA↑, TQ treatment caused a G0/G1 cell-cycle arrest due to decreased cyclin D1 level and increased expression of p16, a CDK inhibitor (Gali-Muhtasib et al., 2004b)
cycD1/CCND1↓,
p16↑,
P53↑, increased expression of p53,
Bax:Bcl2↑, TQ significantly induced apoptosis in both cell lines by increasing the Bax/Bcl-2 ratio and decreasing Bcl-xL
Bcl-xL↓,
NF-kB↓, 25 mM TQ was accompanied by down-regulated expression of NF-kB-targeted anti-apoptotic factors (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin)
IAP1↓,
IAP2↓,
XIAP↓,
survivin↓,
COX2↓, and proliferative factors (cyclin D1, COX-2, and c-Myc) due to suppressed NF-kB signaling
cMyc↓,
ROS↑, TQ-induced oxidative damage,
Casp3↑, TQ-induced activation of caspase-3, poly (ADP-ribose) polymerase (PARP) cleavage, and the release of cytochrome c from mitochondria into the cytoplasm
cl‑PARP↑,
Cyt‑c↑,
STAT3↓, TQ (5-20 uM) significantly suppressed the constitutive as well as IL-6-induced STAT3, but not STAT5, activation in U266 cells and RPMI-8226 cells

2109- TQ,    Thymoquinone Induces Mitochondria-Mediated Apoptosis in Acute Lymphoblastic Leukaemia in Vitro
- in-vitro, AML, CEM
Apoptosis↓, TQ encouraged apoptosis with cell death-transducing signals by a down-regulation of Bcl-2 and up-regulation of Bax
Bcl-2↓,
BAX↑,
ROS↑, Moreover, the significant generation of cellular ROS, HSP70 and activation of caspases 3 and 8 were also observed in the treated cells.
HSP70/HSPA5↑,
Casp3↑,
Casp8↑,

2110- TQ,    Nigella sativa seed oil suppresses cell proliferation and induces ROS dependent mitochondrial apoptosis through p53 pathway in hepatocellular carcinoma cells
- in-vitro, HCC, HepG2 - in-vitro, BC, MCF-7 - in-vitro, Lung, A549 - in-vitro, Nor, HEK293
P53↑, N. sativa exerts anticancer activity by mitochondrial apoptosis via p53 pathway.
lipid-P↑, Induction of lipid peroxidation, and depletion of glutathione level were also observed.
GSH↓, decrease in the level of MMP was also observed in HepG2 cells after NSO exposure for 24 h
ROS↑, ROS generation and reduced MMP suggest role of oxidative stress in cell death.
MMP↓,
BAX↑, Upregulation of p53, Bax, caspase-3 and caspase-9 and downregulation of Bcl-2 gene
Casp3↑,
Casp9↑,
Bcl-2↓,
tumCV↓, exhibited significant decrease in the percentage cell viability of HepG2, MCF-7 and A-549 cells in a concentration-dependent manner.
selectivity↑, The IC50 values of NSO obtained by MTT assay were 46.2 μg/ml for MCF-7, 44.6 μg/ml for HepG2, 245 μg/ml for A-549 and 1136 μg/ml for HEK293(normal) cell lines

3413- TQ,    Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src‑mediated phosphorylation of EGF receptor tyrosine kinase
- in-vitro, CRC, HCT116
tumCV↓, TQ significantly reduced the viability of human colon cancer HCT116 cells in a concentration- and time-dependent manner
Apoptosis↓, TQ induced apoptosis, which was associated with the upregulation of Bax and inhibition of Bcl-2 and Bcl-xl expression
BAX↑,
Bcl-2↓,
Casp9↑, TQ also activated caspase-9,-7, and -3, and induced the cleavage of poly-(ADP-ribose) polymerase (PARP).
Casp7↑,
Casp3↑,
cl‑PARP↑,
STAT3↓, TQ attenuated the expression of STAT3 target gene products, such as survivin, c-Myc, and cyclin-D1, -D2, and enhanced the expression of cell cycle inhibitory proteins p27 and p21.
survivin↓,
cMyc↓,
cycD1/CCND1↓,
p27↑,
P21↑,
EGFR↓, TQ attenuated the phosphorylation of upstream kinases, such as Janus-activated kinase-2 (JAK2), Src kinase and epidermal growth factor receptor (EGFR) tyrosine kinase
ROS↑, According to this study, TQ-induced cytotoxicity in DLD-1 colon cancer cells was associated with the generation of reactive oxygen species, activation of extracellular signal-regulated kinase and c-Jun-N-terminal kinase, and the cleavage of caspase-7

3412- TQ,    Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells
- in-vitro, Melanoma, SK-MEL-28 - in-vivo, NA, NA
Apoptosis↑, Q treatment induced apoptosis in SK-MEL-28 cells
JAK2↓, Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment
STAT3↓,
cycD1/CCND1↓, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin
survivin↓,
ROS↑, TQ increased the levels of reactive oxygen species (ROS)
eff↓, , whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis.

3411- TQ,    Anticancer and Anti-Metastatic Role of Thymoquinone: Regulation of Oncogenic Signaling Cascades by Thymoquinone
- Review, Var, NA
p‑STAT3↓, Thymoquinone inhibited the JAK2-mediated phosphorylation of STAT3 on the 727th serine residue in SK-MEL-28 cells
cycD1/CCND1↓, levels of cyclin D1, D2, and D3 were reported to be reduced in STAT3-depleted SK-MEL-28 cells
JAK2↓, The JAK2/STAT3 pathway is inactivated by thymoquinone in B16-F10 melanoma cells
β-catenin/ZEB1↓, Levels of β-catenin and Wnt/β-catenin target genes, such as c-Myc, matrix metalloproteinase-7, and Met, were found to be reduced in thymoquinone-treated bladder cancer cells.
cMyc↓,
MMP7↓,
MET↓,
p‑Akt↓, Thymoquinone dose-dependently reduced the levels of p-AKT (threonine-308), p-AKT (serine-473), p-mTOR1, and p-mTOR2 in gastric cancer cells.
p‑mTOR↓,
CXCR4↓, Thymoquinone decreased the surface expression of CXCR4 on multiple myeloma cells
Bcl-2↓, Thymoquinone time-dependently decreased BCL-2 levels and simultaneously enhanced BAX levels
BAX↑,
ROS↑, Thymoquinone-mediated ROS accumulation triggered conformational changes in BAX that sequentially resulted in the activation of the mitochondrial apoptotic pathway
Cyt‑c↑, Thymoquinone effectively increased the release of cytochrome c into the cytosol
Twist↓, Thymoquinone downregulated TWIST1 and ZEB1 and simultaneously upregulated E-cadherin in SiHa and CaSki cell lines [82].
Zeb1↓,
E-cadherin↑,
p‑p38↑, Thymoquinone-induced ROS enhanced the phosphorylation of p38-MAPK in MCF-7 cells.
p‑MAPK↑,
ERK↑, The thymoquinone-induced activation of ERK1/2
eff↑, FR180204 (ERK inhibitor) significantly reduced the viability of thymoquinone and docetaxel-treated cancer cells [
ERK↓, Thymoquinone inhibited the proliferation, migration, and invasion of A549 cells by inactivating the ERK1/2 signaling cascade
TumCP↓,
TumCMig↓,
TumCI↓,

3414- TQ,    Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells
- in-vitro, RCC, Caki-1
tumCV↓, TQ significantly reduced the cell viability and induced apoptosis in Caki cells as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, and -3 and PARP and the inhibition of Bcl-2 and Bcl-xl expression.
Apoptosis↑,
P53↑,
BAX↑,
Cyt‑c↑,
cl‑Casp9↑,
cl‑Casp3↑,
cl‑PARP↑,
Bcl-2↓,
Bcl-xL↓,
p‑STAT3↓, TQ inhibited the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) in Caki cells by blocking the phosphorylation of upstream Janus-activated kinase-2 (JAK2) kinases.
p‑JAK2↓,
STAT3↓, TQ attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, and D2.
survivin↓,
cycD1/CCND1↓,
ROS↑, Treatment with TQ generated ROS in these renal cancer cells.
eff↓, Pretreatment of cells with ROS scavenger N-acetyl cysteine (NAC) abrogated the inhibitory effect of TQ on the JAK2/STAT3 signaling and rescued cells from TQ-induced apoptosis

3403- TQ,    A multiple endpoint approach reveals potential in vitro anticancer properties of thymoquinone in human renal carcinoma cells
- in-vitro, RCC, 786-O
tumCV↓, TQ treatment clearly decreased cell viability in a concentration- and time-dependent manner.
ROS↑, TQ concentrations from 1 to 20 uM moderately increased ROS levels in approximately 20-30% comparing to control cells
TumCCA↑, an increase in the sub-G1 population was observed, especially at 30 μM,
eff↓, The co-treatment with GSH increases the cell viability of TQ-exposed cells
TumCI↓, As depicted in Fig. 8 (A-B), the % of invasion of 786-O cells treated with TQ (1 uM, 10 h) significantly decreased to 75.2% of controls

3424- TQ,    Thymoquinone Is a Multitarget Single Epidrug That Inhibits the UHRF1 Protein Complex
- Review, Var, NA
DNMT1↓, In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex
HDAC1↓,
TumCCA↑, inhibition of cell division, promotion of cell cycle arrest, activation of ROS production, induction of apoptosis and inhibition of tumor angiogenesis and metastasis
ROS↑,
Apoptosis↑,
angioG↓,
TumMeta↓,
selectivity↑, When compared to its effects on cancer cells, TQ has no or only mild cytotoxic effects on matched normal cells, such as normal human fibroblast cells [
BioAv↓, poor pharmacokinetics and chemical stability of TQ
BioAv↓, TQ is heat and light-sensitive, and it has poor solubility in aqueous media, which affects its biodistribution
HDAC1↓, T-ALL TQ decreased in the expression of HDAC1, 4 and 9
HDAC4↓,
UHRF1↓, TQ induces auto-ubiquitination of UHRF1 and subsequent degradation in cancer cells [23] by targeting its RING domain, which is the only domain of the UHRF1 structure that exhibits enzymatic activity
selectivity↑, via a specific inhibition of UHRF1 expression levels in cancer cells without affecting its expression in normal human cells.
G9a↓, TQ could quite possibly inhibit G9a and/or delocalize it from chromatin through its effects on UHRF1.

3425- TQ,    Advances in research on the relationship between thymoquinone and pancreatic cancer
Apoptosis↑, TQ can inhibit cell proliferation, promote cancer cell apoptosis, inhibit cell invasion and metastasis, enhance chemotherapeutic sensitivity, inhibit angiogenesis, and exert anti-inflammatory effects.
TumCP↓,
TumCI↓,
TumMeta↓,
ChemoSen↑,
angioG↓,
Inflam↓,
NF-kB↓, These anticancer effects predominantly involve the nuclear factor (NF)-κB, phosphoinositide 3 kinase (PI3K)/Akt, Notch, transforming growth factor (TGF)-β, c-Jun N-terminal kinase (JNK)
PI3K↓,
Akt↓,
TGF-β↓,
Jun↓,
p38↑, and p38 mitogen-activated protein kinase (MAPK) signaling pathways as well as the regulation of the cell cycle, matrix metallopeptidase (MMP)-9 expression, and pyruvate kinase isozyme type M2 (PKM2) activity.
MAPK↑, activation of the JNK and p38 MAPK
MMP9↓,
PKM2↓, decrease in PKM2 activity
ROS↑, ROS-mediated activation
JNK↑, activation of the JNK and p38 MAPK
MUC4↓, downregulation of MUC4;
TGF-β↑, TQ led to the activation of the TGF-β pathway and subsequent downregulation of MUC4
Dose↝, Q acts as an antioxidant (free radical scavenger) at low concentrations and as a pro-oxidant at high concentrations.
FAK↓, TQ can inhibit several key molecules such as FAK, Akt, NF-κB, and MMP-9 and that these molecules interact in a cascade to affect the metastasis of pancreatic cancer
NOTCH↓, TQ involved in increasing chemosensitivity consist of blocking the Notch1/PTEN, PI3K/Akt/mTOR, and NF-κB signaling pathways, reducing PKM2 expression, and inhibiting the Warburg effect.
PTEN↑, it also restored the PTEN protein that had been inhibited by GEM
mTOR↓,
Warburg↓, reducing PKM2 expression, and inhibiting the Warburg effect.
XIAP↓,
COX2↓,
Casp9↑,
Ki-67↓,
CD34↓,
VEGF↓,
MCP1↓,
survivin↓,
Cyt‑c↑,
Casp3↑,
H4↑,
HDAC↓,

3422- TQ,    Thymoquinone, as a Novel Therapeutic Candidate of Cancers
- Review, Var, NA
selectivity↑, TQ selectively inhibits the cancer cells’ proliferation in leukemia [9], breast [10], lungs [11], larynx [12], colon [13,14], and osteosarcoma [15]. However, there is no effect against healthy cells
P53↑, It also re-expressed tumor suppressor genes (TSG), such as p53 and Phosphatase and tensin homolog (PTEN) in lung cancer
PTEN↑,
NF-kB↓, antitumor properties by regulating different targets, such as nuclear factor kappa B (NF-Kb), peroxisome proliferator-activated receptor-γ (PPARγ), and c-Myc [1], which resulted in caspases protein activation
PPARγ↓,
cMyc↓,
Casp↑,
*BioAv↓, Due to hydrophobicity, there are limitations in the bioavailability and drug formation of TQ.
BioAv↝, TQ is sensitive to light; a short period of exposure results in severe degradation, regardless of the solution’s acidity and solvent type [27]. It is also unstable in alkaline solutions because TQ’s stability decreases with rising pH
eff↑, Encapsulating TQ with CS improves the uptake and bioavailability of TQ but has low encapsulation efficiency (35%)
survivin↓, TQ showed antiproliferative and pro-apoptotic potency on breast cancer through the suppression of anti-apoptotic proteins, such as survivin, Bcl-xL, and Bcl-2
Bcl-xL↓,
Bcl-2↓,
Akt↓, treating doxorubicin-resistant MCF-7/DOX cells with TQ inhibited Akt and Bcl2 phosphorylation and increased the expression of PTEN and apoptotic regulators such as Bax, cleaved PARP, cleaved caspases, p53, and p21 [
BAX↑,
cl‑PARP↑,
CXCR4↓, inhibited metastasis with significant inhibition of chemokine receptor Type 4 (CXCR4), which is considered a poor prognosis indicator, matrix metallopeptidase 9 (MMP9), vascular endothelial growth factor Receptor 2 (VEGFR2), Ki67, and COX2
MMP9↓,
VEGFR2↓,
Ki-67↓,
COX2↓,
JAK2↓, TQ at 25, 50 and 75 µM inhibited JAK2 and c-Src activity and induced apoptosis by inhibiting the phosphorylation of STAT3 and STAT3 downstream genes, such as Bcl-2, cyclin D, survivin, and VEGF, and upregulating caspases-3, caspases-7, and caspases-9
cSrc↓,
Apoptosis↑,
p‑STAT3↓,
cycD1/CCND1↓,
Casp3↑,
Casp7↑,
Casp9↑,
N-cadherin↓, downregulated the mesenchymal genes expression N-cadherin, vimentin, and TWIST, while upregulating epithelial genes like E-cadherin and cytokeratin-19.
Vim↓,
Twist↓,
E-cadherin↑,
ChemoSen↑, The combined treatment of 5 μM TQ and 2 μg/mL cisplatin was more effective in cancer growth and progression than either agent alone in a xenograft tumor mouse model.
eff↑, TQ–artemisinin hybrid therapy (2.6 μM) showed an enhanced ROS generation level and concomitant DNA damage induction in human colon cancer cells, while not affecting nonmalignant colon epithelial at 100 μM
EMT↓, TQ inhibits the survival signaling pathways to reduce carcinogenesis progress rate, and decreases cancer metastasis through regulation of epithelial to mesenchymal transition (EMT).
ROS↑, Apoptosis is induced by TQ in cancer cells through producing ROS, demethylating and re-expressing the TSG
DNMT1↓, inhibits DNMT1, figure 2
eff↑, TQ–vitamin D3 combination significantly reduced pro-cancerous molecules (Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF and HSP-90) a
EZH2↓, reduced angiogenesis by downregulating significant angiogenic genes such as versican (VCAN), the growth factor receptor-binding protein 2 (Grb2), and enhancer of zeste homolog 2 (EZH2), which participates in histone methylatio
hepatoP↑, Moreover, TQ improved liver function as well as reduced hepatocellular carcinoma progression
Zeb1↓, TQ decreases the Twist1 and Zeb1 promoter activities,
RadioS↑, TQ combined with radiation inhibited proliferation and induced apoptosis more than a TQ–cisplatin combination against SCC25 and CAL27 cell lines
HDAC↓, TQ has inhibited the histone deacetylase (HDAC) enzyme and reduced its total activity.
HDAC1↓, as well as decreasing the expression of HDAC1, HDAC2, and HDAC3 by 40–60%
HDAC2↓,
HDAC3↓,
*NAD↑, In non-cancer cells, TQ can increase cellular NAD+
*SIRT1↑, An increase in the levels of intracellular NAD+ led to the activation of the SIRT1-dependent metabolic pathways
SIRT1↓, On the other hand, TQ induced apoptosis by downregulating SIRT1 and upregulating p73 in the T cell leukemia Jurkat cell line
*Inflam↓, TQ treatment of male Sprague–Dawley rats has reduced the inflammatory markers (CRP, TNF-α, IL-6, and IL-1β) and anti-inflammatory cytokines (IL-10 and IL-4) triggered by sodium nitrite
*CRP↓,
*TNF-α↓,
*IL6↓,
*IL1β↓,
*eff↑, The TQ–piperin combination has also decreased the oxidative damage triggered by microcystin in liver tissue and reduced malondialdehyde (MDA) and NO, while inducing glutathione (GSH) levels and superoxide dismutase (SOD), catalase (CAT), and glutathi
*MDA↓,
*NO↓,
*GSH↑,
*SOD↑,
*Catalase↑,
*GPx↑,
PI3K↓, repressing the activation of vital pathways, such as JAK/STAT and PI3K/AKT/mTOR.
mTOR↓,

3423- TQ,    Epigenetic role of thymoquinone: impact on cellular mechanism and cancer therapeutics
- Review, Var, NA
AntiCan↑, Thymoquinone is a natural product with anticancer activity.
Inflam↓, Thymoquinone has been shown to exert anti-inflammatory, antidiabetic, antihypertensive, antimicrobial, analgesic, immunomodulatory, spasmolytic, hepatoprotective, renal-protective, gastroprotective, bronchodilatory, antioxidant and antineoplastic eff
hepatoP↑,
RenoP↑,
BAX↑, Thymoquinone can upregulate proapoptotic genes and proteins, such as Bax/Bak, or downregulate antiapoptotic genes and proteins, such as Bcl-2, Bcl-xL, among others, as well as modulating the caspase pathway
Bak↑,
Bcl-2↓,
Bcl-xL↓,
ROS↑, through the generation of reactive oxygen species (ROS)
P53↑, overexpressed or activated by thymoquinone; for example, p53, PTEN, p21, p27 and breast cancer type 1 susceptibility protein (BRCA1), among others,
PTEN↑,
P21↑,
p27↑,
BRCA1↑,
PI3K↓, (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/ERK, have been found to be inhibited by thymoquinone
Akt↓,
MAPK↓,
ERK↓,
p‑ERK↓, thymoquinone reduces ERK phosphorylation and matrix metalloproteinase (MMP) secretion by downregulating focal adhesion kinase (FAK)
MMPs↓,
FAK↓,
Twist↓, downregulates Twist1 and Zeb1 transcription factors, and thus inhibits epithelial to mesenchymal transition (EMT) and subsequently inhibits cancer metastasis
Zeb1↓,
EMT↓,
TumMeta↓,
angioG↓, thymoquinone can inhibit angiogenesis by interfering with essential steps of neovascularization, such as suppressing proangiogenic vascular endothelial growth factor (VEGF)
VEGF↓,
HDAC↓, HDACs are usually overexpressed in MCF-7 breast cancer cells, and thymoquinone can act as a HDAC inhibitor (HDACi) that potently induces apoptosis through inducing acetylation of histones and inhibiting deacetylation of histones.
Maspin↑, thymoquinone reactivates HDAC target genes (p21 and Maspin), inducing the upregulation of Bax
SIRT1↑, thymoquinone can upregulate SIRT1 expression in neonatal rat cardiomyocytes and consequently deacetylates p53; thus, it can act as an apoptosis inducer
DNMT1↓, Collectively, they suggested that thymoquinone induces methylation of DNA via binding with DNMT1 and suppressing its expression,
DNMT3A↓, thymoquinone decreases the expression of some important epigenetic proteins like DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B, KMT2A,B,C,D,E and UHRF1 in Jurkat cells,
HDAC1↓,
HDAC4↓,

3571- TQ,    The Role of Thymoquinone in Inflammatory Response in Chronic Diseases
- Review, Var, NA - Review, Stroke, NA
*BioAv↓, TQ has poor bioavailability and is hydrophobic, prohibiting clinical trials with TQ alone.
*BioAv↑, TQ nanoparticle formulation shows better bioavailability than free TQ,
*Inflam↓, anti-inflammatory effects of TQ involve multiple complex signaling pathways as well as molecular mechanisms
*antiOx↑, antioxidant activity from the inhibition of oxidative stress
*ROS↓,
*GSH↑, GSH prevented ROS-mediated oxidative stress damage
*GSTs↑, TQ was found to exhibit antioxidant properties by increasing the levels of GSH and glutathione-S-transferase enzyme alpha-3 (GSTA3)
*MPO↓, TQ significantly reduced the disease activity index (DAI) and myeloperoxidase (MPO) activity, protecting the internal microenvironment of the colon.
*NF-kB↓, TQ reduced NF-κB signaling gene expression while alleviating the increase of COX-2 in skin cells induced by 12-O-tetradecanoylphorbol-13-acetate
*COX2↓,
*IL1β↓, reduced the expression of inflammatory factors such as IL-1β, TNF-α, IFN-γ, and IL-6
*TNF-α↓,
*IFN-γ↓,
*IL6↓,
*cardioP↑, TQ may exhibit substantial effects in the control of inflammation in CVD
*lipid-P↓, TQ reduces lipid accumulation and enhances antioxidant capacity and renal function.
*TAC↑,
*RenoP↑,
Apoptosis↑, Breast cancer TQ induces apoptosis and cell cycle arrest; reduces cancer cell proliferation, colony formation, and migration;
TumCCA↑,
TumCP↓,
TumCMig↓,
angioG↓, Colorectal Cancer (CRC) TQ inhibits the angiogenesis
TNF-α↓, Lung cancer TQ inhibits tumor cell proliferation by causing lung cancer cell apoptosis to significantly arrest the S phase cell cycle and significantly reduce the activity of TNF-a and NF-κB
NF-kB↓,
ROS↑, Pancreatic cancer TQ significantly increases the level of ROS production in human pancreatic cancer cells
EMT↓, TQ initiates the miR-877-5p and PD-L1 signaling pathways, inhibiting the migration and EMT of bladder cancer cells.
*Aβ↓, TQ significantly reduced the expression of Aβ, phosphorylated-tau, and BACE-1 proteins.
*p‑tau↓,
*BACE↓,
*TLR2↓, Parkinson’s disease (PD) TQ inhibits activation of the NF-κB pathway. TQ reduces the expression of TLR-2, TLR-4, MyD88, TNF-α, IL-1β, IFN-β, IRF-3, and NF-κB.
*TLR4↓,
*MyD88↓,
*IRF3↓,
*eff↑, TQ pretreatment produced a dose-dependent reduction in the MI area and significantly reduced the elevation of serum cardiac markers caused by ISO.
eff↑, Curcumin and TQ induced apoptosis and cell cycle arrest and reduced cancer cell proliferation, colony formation, and migration in breast cancer cells
DNAdam↑, nanomedicine with TQ that induced DNA damage and apoptosis, inhibited cell proliferation, and prevented cell cycle progression
*iNOS↓, TQ significantly reduced the expression of COX-2 and inducible nitric oxide synthase (iNOS)

2454- Trip,    Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ
- in-vitro, HNSCC, HaCaT - in-vivo, NA, NA
GSDME-N↑, Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis.
Pyro↑,
cMyc↓, TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells
HK2↓,
BAD↑, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3.
BAX↑,
Casp3↑,
NRF2↓, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis
xCT↓,
ROS↑, and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME.
eff↑, Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model.
Glycolysis↓, TPL treatment repressed c-Myc/HK-II axis and aerobic glycolysis in head and neck cancer cells
GlucoseCon↓, as evidenced by reduced glucose consumption, lactate production and cellular ATP content following TPL treatment
lactateProd↓,
ATP↓,
xCT↓, TPL (50 nM) treatment decreased the protein levels of NRF2 and SLC7A11 (
eff↑, combination of TPL with erastin is a promising strategy for head and neck cancer therapy.

2350- UA,    Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
Akt↓, UA (20 µM) also diminished AKT signaling that affected glycolysis as judged by decreased levels of HK2, PKM2, ATP and lactate.
Glycolysis↓,
HK2↓,
PKM2↓,
ATP↓, 20 µM UA caused a decrease in intracellular ATP and lactate pools
lactateProd↓,
AMPK↑, UA-induced energy stress activated AMPK that resulted in cytotoxic autophagy and apoptosis
TumAuto↑,
Apoptosis↑,
ERK↓, UA-promoted apoptosis was associated with decreased pERK1/2 signals and the depolarization of mitochondrial membrane potential.
MMP↓,
NO↑, 20 µM UA treatment resulted in an increase in nitric oxide levels
ROS↑, UA-induced elevation in total reactive oxygen species (ROS), total superoxide and mitochondrial superoxide production was more potent than BA-mediated oxidative stress
DNAdam↑, UA and BA promoted DNA breaks,

5017- UA,    Ursolic acid disturbs ROS homeostasis and regulates survival-associated gene expression to induce apoptosis in intestinal cancer cells
- in-vitro, Cerv, INT-407 - in-vitro, CRC, HCT116
AntiCan↑, Ursolic acid is a natural compound possessing several therapeutic properties including anticancer potential.
TumCG↓, intestinal cancer cell lines INT-407 and HCT-116. The cells growth and number were decreased in a dose- and time-dependent manner in both the cell lines.
ROS↑, It also increases reactive oxygen species levels in the cells in order to induce apoptosis.
Apoptosis↑,
TumCMig↓, significant inhibitor of cancer cells migration and gene expression of migration markers FN1, CDH2, CTNNB1 and TWIST was also downregulated.
CTNNB1↓,
Twist↓,
Bcl-2↓, Ursolic acid treatment downregulated the gene expression of survival factors BCL-2, SURVIVIN, NFKB and SP1
survivin↓,
NF-kB↓,
Sp1/3/4↓,
BAX↑, while upregulated the growth-restricting genes BAX, P21 and P53.
P21↑,
P53↑,
eff↓, The UA-induced oxidative stress was reversed by 5 mM NAC treatment.
TumCMig↓, Ursolic acid restricts the migration ability of cancer cells

5020- UA,    Anticancer activity of ursolic acid on human ovarian cancer cells via ROS and MMP mediated apoptosis, cell cycle arrest and downregulation of PI3K/AKT pathway
- in-vitro, Ovarian, NA
tumCV↓, Ursolic acid caused significant reduction in the viability of the SKOV-3 ovarian carcinoma cells in a dose-dependent manner,
selectivity↑, IC50 of 35 µM in cancer cells and IC50 of 75 µM in normal cell lines
BAX↑, Ursolic acid inhibited the viability of cancer cells via induction of apoptotic cell death which was associated with increase in Bax and decrease in Bcl-2 levels
Bcl-2↓,
Apoptosis↑, ursolic acid induced apoptotic cell death
ROS↑, Ursolic acid also induced dose-dependent G2/M phase cell cycle arrest along with causing significant upsurge in ROS production.
TumCCA↑,
Akt↓, Western blot analysis revealed that ursolic acid had the potential to inhibit I3K/AKT signalling pathway.
PI3K↓,

5021- UA,    Anticancer effect of ursolic acid via mitochondria-dependent pathways
- Review, Var, NA
Inflam↓, anti-inflammatory effect of UA was linked to attenuation of production of proinflammatory cytokines including tumor necrosis factor α, interleukin (IL)-6 and/or IL-17 (
TNF-α↓,
IL6↓,
IL17↓,
NF-kB↓, UA was associated with suppression of the nuclear factor-κB (NF-κβ) pathway, inhibition of expression of cyclooxygenase-2 (COX-2)
COX2↓,
*AntiDiabetic↑, UA demonstrated an antidiabetic functio
*hepatoP↑, UA can provide hepatoprotective activity against several liver diseases
ALAT↓, UA reduced the serum/plasma levels of alanine transaminase and aspartate transaminase, which are liver disease biomarkers
AST↓,
TumCP↓, UA inhibited tumorigenesis and cancer cell proliferation, modulated apoptosis and cell cycle progression and promoted autophagy
Apoptosis↑,
TumCCA↑,
TumAuto↑,
tumCV↓, UA inhibited the viability and migration of T47D, MCF-7 and MDA-MB-231 breast cancer cells by targeting phosphoinositide-3-kinase/protein kinase B (PI3K/Akt)
TumCMig↓,
Glycolysis↓, Additionally, UA affected glycolysis. The effect was accompanied by decreased levels of ATP, lactate, hexokinase 2 and pyruvate kinase. I
ATP↓,
lactateProd↓,
HK2↓, The Akt inhibition affected glycolysis and markedly decreased levels of HK2, pyruvate kinase M2, ATP and lactate.
PKA↓,
COX2↓, UA may down-regulate the expression of COX-2
mtDam↑, UA significantly enhanced proapoptotic effects and stimulated mitochondrial dysfunction by activating caspases 3, 8 and 9, and downregulated Bcl-2 expression in these cancer cells.
Casp3↑,
Casp8↑,
Casp9↑,
Akt↓, UA downregulated the Akt signaling in three breast cancer cell lines
ROS↑, Derivative 17 significantly increased the production of ROS for 24 h, while 5 and 23 did so for 48 h.
MMP↓, human breast cancer cell line MDA-MB-231, UA decreased the mitochondrial ∆Ψm,
P53↑, regulatory proteins p53 and Bax were upregulated while the antiapoptotic protein Bcl-2 was downregulated following treatment with UA.

5022- UA,    Ursolic Acid’s Alluring Journey: One Triterpenoid vs. Cancer Hallmarks
- Review, Var, NA
TumCP↓, inhibition of cell proliferation, induction of apoptosis, suppression of angiogenesis, inhibition of metastasis, and modulation of the tumor microenvironment
Apoptosis↑,
angioG↑,
TumMeta↓,
BioAv↓, acknowledges hurdles related to UA’s low bioavailability,
Hif1a↓, graphical abstract
Glycolysis↓,
mitResp↓,
Akt↓,
MAPK↓,
ERK↓,
mTOR↓,
P53↑,
P21↑,
E2Fs↑,
STAT3↓,
MMP↓,
NLRP3↓,
iNOS↓,
CHK1↓,
Chk2↓,
BRCA1↓,
E-cadherin↑,
N-cadherin↓,
Casp↑,
p62↓,
LC3II↑,
Vim↓,
ROS↑, administration of UA has effectively modulated the generation of both cellular and mitochondrial ROS
CSCs↓, This, in turn, triggers a response in embryonic CSCs known as DNA damage response (DDR), strongly suggesting the potential for UA-induced cell death
DNAdam↑,
GutMicro↑, UA has shown potential in modulating the composition of the gut microbiota and improving the microenvironment within the digestive system
VEGF↓, UA treatment significantly reduced the expression of VEGF-A and FGF-β in both CRC tumors and HT-29 cells (

4857- Uro,    Evaluation and comparison of the anti-proliferative and anti-metastatic effects of urolithin A and urolithin B against esophageal cancer cells: an in vitro and in silico study
- in-vitro, ESCC, KYSE-30
tumCV↓, The results showed that UA (which had lower IC50 than UB) and UB reduced the viability of both KYSE-30 and YM-1 cells.
selectivity↑, Furthermore, UA and UB exhibited lower toxicity towards normal HFF cells compared to ESCC cells
TumCCA↑, Both UB and the more effective UA induced apoptosis and caused G2/M cell cycle arrest in KYSE-30 and YM-1 cells.
ROS↑, Additionally, UA and UB elevated ROS production and led to a decrease in Bcl-2 expression while increasing the expression of Bax and p21 genes
Bcl-2↓,
BAX↑,
P21↑,
MMP2↓, A decrease in the mRNA expression and enzymatic activity of MMP-2 and MMP-9 was observed following treatment with UA and UB.
MMP9↓,

4856- Uro,    Study on the biological mechanism of urolithin a on nasopharyngeal carcinoma in vitro
- in-vitro, NPC, CNE1 - in-vitro, NPC, CNE2
Apoptosis↑, induced apoptosis, MMP depolarization and increase ROS content at a concentration of 40 μM.
MMP↓,
ROS↑, We found that the content of ROS in CNE1 and CNE2 cells gradually increased with the increase of UroA concentration
E-cadherin↑, UroA up-regulated E-cadherin, Bax/Bcl-2, c-caspase-3 and PARP proteins, while inhibiting COL4A1, MMP2, MMP9, N-cadherin, Vimentin and Snail proteins at 20–60 μM.
BAX↑,
cl‑Casp3↑,
PARP↑,
MMP2↓,
MMP9↓,
N-cadherin↓,
Vim↓,
Snail↓,
eff↓, Moreover, co-treatment of UroA (40 μM) and NAC (5 mM) could reverse the effect of UroA on apoptosis-related proteins.
TumCP↓, UroA inhibited proliferation of NPC cells
TumCMig↓, UroA suppressed the migration and invasion of NPC cells
TumCI↓,
EMT↓, Taken together, these results suggest that UroA inhibits epithelial-mesenchymal transition through the ECM.

4835- Uro,    Urolithin A, induces apoptosis and autophagy crosstalk in Oral Squamous Cell Carcinoma via mTOR /AKT/ERK1/2 pathway
- in-vitro, SCC, NA
TumCD↑, urolithin A markedly induced cell death of OSCC via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1.
ER Stress↑,
Akt↓,
mtDam↓,
p‑mTOR↓,
*BioAv↝, The bioavailability of urolithins widely varies with inter individual gut microbiome composition depending on the presence of several identified species like Clostridium coccoides and Eggerthellacae family
ROS↑, remarkable anticancer effect on progressive Oral squamous cell carcinoma cells due to their ability to induce ER stress, ROS, cell cycle arrest and increased apoptosis through the preferential inhibition of AKT/mTOR/ERK signaling pathway.
TumCCA↑,
Apoptosis↑,
ERK↓,

4841- Uro,    Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells
- in-vitro, CRC, HT29 - in-vitro, CRC, SW480 - in-vitro, CRC, SW-620
TumCP↓, UA was found to inhibit the cell proliferation of CRC cell lines in a dose-dependent and time-dependent manner in HT29, SW480, and SW620 cells.
TumCCA↑, UA resulted in cell cycle arrest in a dose-dependent manner along with alteration in the expression of cell cycle–related protein.
Apoptosis↑, Treatment of CRC cell lines with UA resulted in the induction of apoptosis.
P53↑, increased expression of the pro-apoptotic proteins, p53 and p21.
P21↑,
Bcl-2↓, UA treatment inhibited the anti-apoptotic protein expression of Bcl-2.
Cyt‑c↑, exposure of UA induced cytochrome c release and caspase activation
Casp↑,
ROS↑, UA treatment of HT29 resulted in a significantly increased generation of ROS in a dose-dependent manner at t 24 h
*ROS↓, Moreover, UA treatment exhibited no production of ROS in fibroblast cells; instead, it decreased its accumulation compared to the untreated cells

4854- Uro,    Urolithins: Emerging natural compound targeting castration-resistant prostate cancer (CRPC)
- Review, Pca, NA
AR↓, Urolithins not only inhibit androgen receptor (AR) signaling, a crucial factor in the progression of CRPC,
ROS↓, also play a key role in regulating oxidative stress by their antioxidant properties, thereby inhibiting increased reactive oxygen species, a common feature of the aggressive nature of CRPC.
Apoptosis↑, urolithins induce apoptosis and diminish pro-survival signaling, leading to tumor inhibition
selectivity↑, UroA, have been shown to induce apoptosis specifically in cancer cells while sparing healthy cells, making it a desirable trait for cancer therapies
Dose↑, Interestingly, urolithins are used in concentrations ranging from 1 µM to 100 µM, which is reflective of or more than the concentrations that can be obtained through natural dietary sources.
MDA↓, UroA, UroB, and 8-OMe-UroA have been shown to reduce oxidative stress by lowering ROS production and malondialdehyde (MDA) levels while enhancing the activity of superoxide dismutase (SOD) in hydrogen peroxide- treated human bladder cancer T24 cells
SOD↑,
GPx↑, Similarly, treatment with UroA resulted in decreased intracellular ROS levels and increased SOD, and GSH-Px activity in liver cancer cells (HepG2)
ROS↑, In colon cancer, for instance, UroA increased ROS production, disturbed cellular oxidation, and generated oxidative stress ultimately leading to cellular apoptosis by elevating caspases-3 and −9
Casp3↑,
Casp9↑,

1216- VitC,    Ascorbic acid induces ferroptosis via STAT3/GPX4 signaling in oropharyngeal cancer
- in-vitro, Laryn, FaDu - in-vitro, SCC, SCC-154
Iron↝, impairing iron metabolism
ROS↑,
tumCV↓,
Ki-67↓,
TumCCA↑, accumulation in the G0/G1 phase
Ferroptosis↑,
GSH↓,
ROS↑,
MDA↑,
STAT3↓,
GPx4↓,
p‑STAT3↓,

1819- VitC,  VitK3,    The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy
- Review, Var, NA
Dose?, coadministration of these vitamins (in a ratio of 100:1, for C and K(3), respectively) produced selective cancer cell death.
TumCD↑,
selectivity↑,
H2O2↑, formation of H(2)O(2) during vitamins redox cycling, oxidative stress, DNA fragmentation
ROS↑,
DNAdam↑,

606- VitC,    Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer
- Review, NA, NA
ROS↑, millimolar (mM) concentrations, also functions as a pro-oxidant
H2O2↑,
Fenton↑, elevated copper concentrations ... made cancer cells vulnerable to the ROS-generated selective cytotoxicity of copper and ascorbic acid

605- VitC,    Therapeutic Use of Vitamin C in Cancer: Physiological Considerations
- Review, NA, NA
ROS↑,
ChemoSideEff↓,

599- VitC,    Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment
- Review, NA, NA
H2O2↑,
DNAdam↑,
ROS↑,
Fenton↑,
Apoptosis↑, Moderate concentrations of H2O2 typically induce apoptosis
necrosis↑, higher H2O2 concentrations induce necrosis

598- VitC,    Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly
- Review, NA, NA
H2O2↑,
ROS↑,
TET1↑, DNA demethylation mediated by ten-eleven translocation enzyme activation
DNAdam↑,
G6PD∅, **** patients who receive intravenous ascorbate must be prescreened for glucose 6 phosphate dehydrogenase deficiency

597- VitC,  dietSTF,  GlucDep,    The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness
other↝, action as an electron donor
H2O2↑, ascorbate readily undergoes pH-dependent autoxidation creating hydrogen peroxide (H2O2).
ROS↑, high concentration is pro-oxidant (IV 25–30 mmol/L are safely achieved)

596- VitC,    High-Dose Vitamin C in Advanced-Stage Cancer Patients
- Review, NA, NA
ChemoSideEff↓, reducing cancer-related symptoms, such as fatigue and bone pain
ROS↑, is able to reduce catalytic metals such as Fe3+ to Fe2+ and Cu2+ to Cu+, increasing the pro-oxidant chemistry of these metals and facilitating the generation of reactive oxygen species
H2O2↑, Reactions of ascorbate with oxygen or with free transition metal ions lead to the generation of superoxide, H2O2 and highly reactive oxidants, such as the hydroxyl radical by promoting the Fenton chemistry
Fenton↑,
Hif1a↝, Ascorbate regulates the transcription of hypoxia inducible factor-1α (HIF-1α)
Dose↑, Results obtained from in vitro studies revealed that millimolar ascorbate plasma concentrations, achievable only after intravenous vitamin C administration, are cytotoxic to fast-growing malignant cells.
BioAv↓, For this reason, ascorbate concentration in plasma does not exceed 100 μmol/L when it is supplied orally with food; even with oral supplementation approaching maximum tolerated doses, it is always <250 μmol/L
Dose↝, 100 mg, the concentration of ascorbate in daily fasting plasma reaches a plateau between 50–60 µmol/L [24]. Whereas increasing the daily dose ten times to 1000 mg gives only a slight increase in plasma concentration to 70–85 μmol/L
Half-Life↝, high concentrations are relatively transient due to the rapid clearance by the kidneys resulting in a half-life of about 2 h in circulation
IL1β↓, IVC (15–50 g up to three times a week) resulted in reduced CRP levels (in 76 ± 13% of study participants) and reduced concentration of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-8, tumor necrosis factor TNF-α)
IL2↓,
IL8↓,
TNF-α↓,

627- VitC,    High-Dose Vitamin C for Cancer Therapy
- Review, NA, NA
ROS↑,
PARP↑, ROS activates poly (ADP-ribose) polymerase (PARP), which depletes NAD+
GAPDH↓, Hindering GAPDH can result in an “energy crisis”, due to the decrease in ATP production
DNAdam↑,
ATP↓,

635- VitC,  VitK3,    The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress
- in-vitro, NA, NA
RNR↓, VC/VK3 inhibited RNR mainly by targeting its R2 subunit
GSH↓,
Trx1↓, increased highly oxidized Trx1 (oxidized (and generally less active) means effectively less)
GPx↓, VC/VK3 inhibited glutathione peroxidase activity and led to an elevated level of lipid peroxidation, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway.
lipid-P↑,
AIF↑, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway
ROS↑,

633- VitC,    Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment
- Analysis, NA, NA
Fenton↑,
ROS↑,
EMT↓, Ascorbic acid is also known to inhibit EMT of tumor cells
DNAdam↑,
PARP↑, DNA damage increases PARP activity, thereby decreasing NAD+ levels
NAD↓, NAD+
ATP↓,
Apoptosis↑,

632- VitC,    High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients
- Review, NA, NA
SVCT-2∅, vitamin C entry into cells is tightly regulated by SVCT
ROS↑, well-recognized pro-oxidant effects
Hif1a↓, HIF-1α proteasomal degradation
PARP∅, Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents.
TET2↑, However, the ability of vitamin C to restore TET2 activity seems to depend on N- and C-terminal lysine acetylation and type of TET2 mutations

631- VitC,    Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2
- vitro+vivo, Liver, NA
SVCT-2∅, response to VC was correlated with sodium-dependent vitamin C transporter 2 (SVCT-2) expressions. Most importantly, SVCT-2 was highly expressed in liver CSCs
ROS↑,
DNAdam↑,
ATP↓,
TumCCA↑,
Apoptosis↑,
OS↑, VC use was linked to improved disease-free survival (DFS) in HCC patients
CD133↓, CD133+
EpCAM↓, EpCAM+
OV6↓, OV6+
γH2AX↑, p-H2AX induced by VC

629- VitC,  Cu,  Fe,    The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer
- in-vitro, NA, NA
ROS↑,
DNAdam↑,
NAD↓,

628- VitC,  Mg,    Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation
- in-vivo, Colon, CT26 - in-vitro, NA, MCF-7 - in-vitro, NA, SkBr3
AntiCan↑, combined vit c and Mg
SVCT-2↝, Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment (SVCT-2 expression was not changed)
TumCD↑, MgSO4 and MgCl2 significantly increased the cell deaths caused by vitamin C treatment
ROS↑,
P21↑,
proCasp3↑,
TumVol↓, cotreating with vitamin C and magnesium ions inhibited tumor growth more effectively than treating with only vitamin C (mouse)
DNAdam↑,
NAD↓,

623- VitC,    The Involvement of Ascorbic Acid in Cancer Treatment
- Review, NA, NA
ROS↑,
GLUT1↓, VC may impede glucose transport and adenosine triphosphate (ATP) production
ATP↓,

114- VitC,  QC,    Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
GPx↓, significant reduction of GPx, GR and NQO1 enzymatic activity
GSR↓,
NQO1↓,
NRF2↓, Our study revealed the significant effects of sequential treatment with VC + Q on Nrf2 suppression in prostate cancer cells
ROS↑, The level of ROS had significant reduction up to 18% (P ¼ 0.046) when DU145 cells treated with dose no.1 of VC þ Q to compare with the control

2485- VitC,  TACE,    High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma
- Case Report, HCC, NA
ROS↑, high-dose vitamin C can act as a prooxidant, conferring selective toxic effects on cancer cells.
Dose↝, Twenty grams of vitamin C in 250 mL normal saline was initially administered via an ante-cubital vein twice a week in September 2011. To neutralize acidic pH (3.5-5.0) of vitamin C, it was mixed with NaHCO3, resulting in pH 6.2
Dose↝, high-dose vitamin C administration was continued for more than a year. In July 2013, she finally decided to undergo TACE
TumCG↓, Hepatocellular carcinoma regressed completely after the fourth TACE treatment (
Remission↑, describe a case of regression of multiple pulmonary metastases after treatment with high-dose vitamin C, which enabled a subsequent trial of TACE, eventually leading to complete remission

3138- VitC,    The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity
- in-vitro, RCC, RCC4 - in-vitro, CRC, HCT116 - in-vitro, BC, MDA-MB-435 - in-vitro, Ovarian, SKOV3 - in-vitro, Colon, SW48 - in-vitro, GBM, U251
eff↑, Here, we show that a Warburg effect triggered by activation of the hypoxia-inducible factor (HIF) pathway greatly enhances Vc-induced toxicity in multiple cancer cell lines
Warburg↓,
BioAv↑, HIF increases the intracellular uptake of oxidized Vc through its transcriptional target glucose transporter 1 (GLUT1),
ROS↑, resulting high levels of intracellular Vc induce oxidative stress and massive DNA damage, which then causes metabolic exhaustion by depleting cellular ATP reserves.
DNAdam↑,
ATP↓,
eff↑, Activation of HIF increases the susceptibility to Vc-induced cell toxicity
necrosis↑, High intracellular levels of Vc increase ROS and trigger necrosis in VHL-defective renal cancer cells.
PARP↑, Activation of the PARP Pathway by Vc Depletes Intracellular ATP Reserves in VHL-defective Renal Cancer Cells

3102- VitC,    Two Faces of Vitamin C—Antioxidative and Pro-Oxidative Agent
- Review, Var, NA - Review, Stroke, NA
*radioP↑, evidence that vitamin C has radioprotective properties.
*Dose↝, recommended daily dose of vitamin C is on average 75 mg for women and 90 mg for men
ROS↑, Under conditions of high, millimolar ascorbate concentration, vitamin C catalyzes the reduction of free transition metal ions, which causes the formation of oxygen radicals. elevated iron levels recognized in cancer cells
*neuroP↑, Ascorbate appears to be a significant neuroprotector
other↓, It is believed that high-dose vitamin C supplementation may be protective and reduce the size of ischemia
*ROS↓, Vitamin C appears to quench ROS, which contributes to the stabilization of the mitochondrial membrane
*MMP↑,

3101- VitC,    Vitamin C stimulates or attenuates reactive oxygen and nitrogen species (ROS, RNS) production depending on cell state: Quantitative amperometric measurements of oxidative bursts at PLB-985 and RAW 264.7 cells at the single cell level
- in-vitro, Nor, RAW264.7 - in-vitro, AML, PLB-985
*antiOx↑, widely publicized as a universal anti-oxidant
*ROS↓, H-atom donors or radical scavengers (AA, vitamins E, Q, glutathione, etc.) present in aerobic cells regulate reactive oxygen and nitrogen species (ROS and RNS) by quenching them to avoid RNS and ROS-induced profound damages to surrounding cells and t
*RNS↓,
ROS↑, PLB‑985(cancer) cells that exhibited enhanced ROS production following AA treatment

3107- VitC,    Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment
- Review, Var, NA
Risk↓, VitC supplementation resulted in dose-dependent reductions in all-cause mortality and the risk of various cancers
*ROS↓, Vitamin C (VitC) at the physiological dose (μM) is known to exhibit antioxidant properties.
ROS↑, However, it functions as a prooxidant at the pharmacological dose (mM) achieved by intravenous administration.
VEGF↓, VitC suppressed tumor angiogenesis in colon cancer-bearing mice by downregulating the expression and secretion of VEGF-A and VEGF-D
COX2↓, VitC impairs COX-2 activity and inhibits VEGF mRNA expression in melanoma cells in a time-dependent manner
ER Stress↑, VitC increases the ER stress-mediated breast cancer apoptosis via activation of the IRE-JNK-CHOP signaling pathway, an effect independent of ROS
IRE1↑,
JNK↑,
CHOP↑,
Hif1a↓, On the one hand, VitC directly inhibits HIF-1α-mediated glycolysis-related genes expression and the downstream acidic metabolites
eff↑, ROS generated by VitC treatment exerts a synergistic effect with other glycolysis inhibitors, providing a combined therapeutic strategy
Glycolysis↓,
MMPs↓, VitC inhibits a variety of metalloproteinases (MMPs) mRNA, which degrade ECM and release growth factors that drive tumor metastasis
TumMeta↓,
YAP/TEAD↓, VitC treatment reduces YAP1 expression while upregulating SYNPO-2; therefore, inhibiting metastasis of TNBC
eff↑, VitC enhances the killing efficiency of Hep G2 cells by low-dose sorafenib in vitro.
TET1↑, VitC stimulation of TET2 activity in the renal cell carcinoma

3108- VitC,  QC,    The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells
- in-vitro, BC, MDA-MB-231 - in-vitro, Lung, A549
NRF2↓, significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q
HO-1↓, In the MDA-MB 231 and MCF-7 cell lines, HO1 was significantly suppressed following treatment with VC and Q
ROS↑, It was demonstrated that ROS levels significantly increased in tumor cells treated with VC and Q.
NRF2⇅, it was demonstrated that treatment of MDA-MB 231 cells with 25 µM Q increased the expression of Nrf2, while 50 and 75 µM Q decreased the mRNA levels of Nrf2.

3114- VitC,    Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
- in-vitro, AML, NA
TET2↑, Treatment with vitamin C, a cofactor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs
eff↑, enhances the efficacy of PARP inhibition in suppressing leukemia progression.
ROS↑, High levels of vitamin C can lead to reactive oxygen species (ROS) production via the Fenton reaction
Fenton↑,
Hif1a↓, One study suggested that vitamin C decreases viability of human leukemia cell lines by promoting downregulation of HIF1α and the anti-apoptotic genes, BCL2, BCL2L1, and MCL1

3104- VitC,    Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations
*antiOx↑, Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation
*ROS↓,
*DNAdam↓,
ROS↑, High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells.
TET1↑, Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation (TET) proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells.
CSCs↓,
HIF-1↓, Vitamin C induces degradation of hypoxia-inducible factor, HIF-1, essential for the survival of tumor cells in hypoxic conditions
BioAv↑, Flavonoids may modulate bioavailability of vitamin C. Animal studies with flavonoid-rich extracts or purified plant flavonoids showed an enhanced uptake of vitamin C when it was administered together with flavonoids
selectivity↑, Chen et al. demonstrated that intravenous administration of ascorbic acid at high concentrations was toxic for many types of cancer cells in xenografts in mice with no effect on normal cells

2283- VitK2,    Vitamin K Contribution to DNA Damage—Advantage or Disadvantage? A Human Health Response
- Review, Var, NA
*ER Stress↓, protective effect of vitamin K on blood vessels, by reducing inflammation and stress ER
*toxicity↓, Natural forms of vitamin K–K1 and K2—have only a low potential for toxicity
*toxicity↑, However, K3 may demonstrate harmful potential: synthetic vitamin K3 can lead to liver damage
ROS↑, Like another quinone, doxorubicin, menadione exerts its cytotoxic effects by stimulating the generation of oxidative stress, leading to DNA damage
PI3K↑, In bladder cancer cells (T24), vitamin K2 significantly induces PI3K/Akt phosphorylation and increases expression of HIF-1α, intensifying glucose consumption and lactate formation.
Akt↑,
Hif1a↑,
GlucoseCon↑,
lactateProd↑,
ChemoSen↑, Numerous studies indicate that the K vitamins have an additive or synergistic effect on various chemotherapeutic agents.
eff↑, A strong synergism between K1 and sorafenib has been demonstrated in numerous studies
eff↑, ascorbic acid (AA), has a synergistic effect on K3 [73,122,123]. The AA/K3 association leads to an excessive increase in oxidative stress and a decrease in the potential of the mitochondrial membrane, which is a crucial trigger of tumor cell death

2285- VitK2,    New insights into vitamin K biology with relevance to cancer
- Review, Var, NA
Risk↓, Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies
AntiCan↑, MK4 supplementation on bone loss in women with viral liver cirrhosis.Over 8 years of follow-up, the risk ratio for the development of HCC in the MK4 group compared with the control group was 0.20
eff↑, phase 2 randomized placebo-controlled trial in HCC patients demonstrated that MK4 supplementation (45 mg/day orally) enhanced the efficacy of the multi-kinase inhibitor sorafenib
MMP↓, MK4 mediated apoptosis may also involve binding of MK4 to pro-apoptotic BAK, direct effects on mitochondrial membrane depolarization and reactive oxygen species (ROS)
ROS↑,
Cyt‑c↑, MK4 covalently bound to BAK induces decrease in MMP and cytochrome c release.
eff↓, ROS production can be blocked by N-acetyl-cysteine (NAC) and alpha-tocopherol which can ultimately block MK4 mediated apoptosis.
SXR↑, Activation of SXR by MK4 (The loss of UBIAD1 in prostate cancer cells reduced MK4 synthesis which in turn decreased SXR transcriptional regulation)

2284- VitK2,    Menadione-induced DNA damage in a human tumor cell line
- in-vitro, BC, MCF-7
DNAdam↑, Recently obtained data suggest that the DNA damage in MD-treated MCF-7 cells is directly related to redox cycling and the production of ROS
ROS↑,

2278- VitK2,  VitK3,  VitC,    Vitamin K: Redox-modulation, prevention of mitochondrial dysfunction and anticancer effect
- Review, Var, NA
ChemoSen↑, The analyzed data suggest that vitamin C&K can sensitize cancer cells to conventional chemotherapy, which allows achievement of a lower effective dose of the drug and minimizing the harmful side-effects.
ROS↑, modulation of redox-balance and induction of oxidative stress in cancer cells due to quinone structure of vitamin K.
eff↑, Vitamin C plus K3: A powerful redox-system to sensitize cancer cells towards chemotherapeutics

2279- VitK2,    Vitamin K2 Induces Mitochondria-Related Apoptosis in Human Bladder Cancer Cells via ROS and JNK/p38 MAPK Signal Pathways
- in-vitro, Bladder, T24/HTB-9 - in-vitro, Bladder, J82 - in-vitro, Nor, HEK293 - in-vitro, Nor, L02 - in-vivo, NA, NA
MMP↓, Vitamin K2 induced apoptosis in bladder cancer cells through mitochondria pathway including loss of mitochondria membrane potential, cytochrome C release and caspase-3 cascade.
Cyt‑c↑,
Casp3↑,
p‑JNK↑, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK was detected in Vitamin K2-treated cells
p‑p38↑,
ROS↑, generation of reactive oxygen species (ROS) was detected in bladder cancer cells, upon treatment of vitamin K2
eff↓, the anti-oxidant N-acetyl cysteine (NAC) almost blocked the Vitamin K2-triggered apoptosis
tumCV↓, Vitamin K2 significantly decreased the viability of human bladder cancer T24, J82 and EJ cells in a dose- and time-dependent manner
selectivity↑, On the other hand, viability of human normal cells (L02 and HEK293) was minimally affected after exposed to high concentration (100 μM) of Vitamin K2
*toxicity↓,
TumVol↓, in nude mice, vitamin K2 remarkably inhibited the tumor growth and the tumor volume was gradually reduced after the 11th day, compared with the sustained growth of control group.

2280- VitK2,    Vitamin K2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MDA-MB-468 - in-vitro, AML, HL-60
ROS↑, ROS production by VK2 seems to be located up-stream in the molecular machinery for both the types of cell death execution
p62↓, decreased expression of p62, a substrate of autophagy, was observed during the exposure to VK2
eff↓, In the presence of NAC and melatonin, the cytotoxic effect by VK2 was significantly suppressed in both cell lines.

2281- VitK2,    The biological responses of vitamin K2: A comprehensive review
- Review, Var, NA
*ROS↓, VitK1 and MK-4 prevent oxidative cell death by blocking the activation of 12-LOX and ROS generation
*12LOX↓,
*NF-kB↓, VitK2 modulates osteoblast and osteoclast formation and activity via downregulation of basal and cytokine-induced NF-κB activation
*BMD↑, strengthens bone construction
*hepatoP↑, VitK2 significantly increased serum albumin levels with concurrent reduction of the levels of alanine and aspartate aminotransferases, suggesting that VitK2 enhances liver regeneration.
cycD1/CCND1↓, figure 5
PKCδ↓,
STAT3↓,
ERK↑,
MAPK↓,
ROS↑,
PI3K↝,
Akt↝,
Hif1a↝,
*neuroP↑, An increasing body of evidence suggests the possible role of VitK supplementation as a novel neuroprotective strategy in the maintenance of nerve integrity and normal brain function, including cognition and behavior

1817- VitK2,    Research progress on the anticancer effects of vitamin K2
- Review, Var, NA
TumCCA↑, involving cell-cycle arrest
Apoptosis↑, apoptosis, autophagy and invasion
TumAuto↑,
TumCI↓,
TumCG↓, inhibit the growth of cancer cells
ChemoSen↓, combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects
ChemoSideEff↓,
toxicity∅, VK2 is milder, but causes no side effects, whereas VK1 has the least strong function
eff↑, combination of VK2 and vitamin E suppressed the growth of the primary tumor and obliterated the intraperitoneal dissemination in a 65-year-old man with ruptured HCC
cycD1/CCND1↓, decreases in cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels
CDK4↓,
eff↑, pretreatment with VK2 prior to sorafenib treatment is proven to exert more effective HCC growth inhibition in animals than treatment with either alone
IKKα↓, VK2 can inhibit the IκB kinase (IKK)/IκB/NF-κB pathway
NF-kB↓,
other↑, stimulate the phosphorylation of PKA and activate activating protein 2 (AP-2)
p27↑, VK2 upregulates the expression of p27
cMyc↓, 5 µΜ VK2 exposure inhibited c-MYC expression in HL-60 leukemia cells
i-ROS↑, VK2 treatment increased the intracellular level of the reactive oxygen species (ROS)
Bcl-2↓, VK2 decreases Bcl-2 expression and increases the expression of Bcl-2-associated X protein (Bax)
BAX↑,
p38↑, VK2 activates p38 MAPK to its phosphorylated form
MMP↓, mitochondrial membrane potential was depolarized and caspase-9 was activated
Casp9↑,
p‑ERK↓, VK2 is reported to inhibit ERK phosphorylation by suppressing Ras activation
RAS↓,
MAPK↓, subsequently suppressing the activation of MAPK kinase (MEK)
p‑P53↑, VK2 stimulated the extrinsic apoptosis pathway by increasing p53 phosphorylation
Casp8↑, caspase-8 activation and further activates caspase-3
Casp3↑,
cJun↑, increasing the expression of c-JUN and c-MYC;
MMPs↓, downregulating the expression of matrix metalloproteinases (MMPs)
eff↑, combination of VK2 with other chemotherapy agents can produce stronger effects than the use of either alone
eff↑, combination of vitamin D3 with VK2 on cancer cells can synergistically improve the induction of cellular differentiation and also significantly reduces the risk of hypercalcemia and vascular calcification

1824- VitK2,    Vitamin K and its analogs: Potential avenues for prostate cancer management
- Review, Pca, NA
AntiCan↑, potential anticancer activity in several cancer types including prostate cancer
toxicity∅, VK1 and VK2 are non-toxic even at high doses
Risk↓, Epidemiological studies suggest that there is inverse association between dietary intake of VK (especially menaquinone) and overall cancer incidence
Apoptosis↑, VK2 has anticancer activity through the mechanisms such as induction of apoptosis, production of reactive oxygen species (ROS) and cell cycle arrest
ROS↑,
TumCCA↑,
eff↑, Gilloteaux et al. [90] reported that the combination of VK3 and ascorbic acid induces oxidative stress in DU-145 PCa cells.
DNAdam↑, oxidative stress induce lipid and protein oxidative modifications and DNA damage leading to apoptotic cell death
MMP↓, VK2 induces pro-apoptosis effects by regulating the MMP, in which mechanism VK2 produces superoxide within the mitochondrial membrane, followed by the release cytochrome c, activation of procaspase 3
Cyt‑c↑,
pro‑Casp3↑,
FasL↑, VK3 treatment induced c-myc and also increased both FasL and Fas
Fas↑,
TumAuto↑, VK2 also can induce autophagy
ChemoSen↑, combination of vitamins C and VK3 has been proposed as a non-toxic mixture of drugs active as an adjuvant cancer therapy by increasing chemo- or radiotherapy effects through alteration of deoxyribonuclease activity
RadioS↑,

1816- VitK2,    Role of Vitamin K in Selected Malignant Neoplasms in Women
- Review, Var, NA
TumCP↓, inhibition of proliferation
TumMeta↓, inhibition of the potential for metastasis
TumAuto↑, induction of autophagy or apoptosis
Apoptosis↑,
Apoptosis↑, apoptosis, caspase 3/7 activity, increased levels of reactive oxygen species (ROS),
Casp3↑,
Casp7↑,
ROS↑,
AR↓, decreased androgen receptor expression
EMT↓, Vitamin K3 inhibited the epithelial-mesenchymal transition (EMT) and Wnt
Wnt↓,
MMP↓, vitamin K leads to depolarization of the mitochondrial membrane and a release of cytochrome c into the cytosol
Cyt‑c↑,
NF-kB↓, vitamin K2 can reduce cyclin D1 expression in cancer cells by inhibiting the binding of the nuclear factor κB (NF-κB)
cycD1/CCND1↓,
TumCCA↓, arresting the cell cycle in the G1 phase

1818- VitK2,    New insights on vitamin K biology with relevance to cancer
- Review, Var, NA
TumCG↓, A few small randomized trials support the concept that vitamin K supplementation can retard cancer development and/or progression
ChemoSen↑, phase 2 randomized placebo-controlled trial in HCC patients demonstrated that MK4 supplementation (45 mg/day orally) enhanced the efficacy of the multi-kinase inhibitor sorafenib
toxicity∅, long term vitamin K supplementation is safe and may offer survival benefit in HCC patients.
OS↑,
BMD↑, Primary Outcomes: Bone density
eff↑, In studies where both forms of the vitamin have been compared, MKs generally exerted more potent anticancer effects than PK.
MMP↓, direct effects on mitochondrial membrane depolarization and reactive oxygen species (ROS)
ROS↑,
eff↓, ROS neutralization by antioxidants (N-acetyl cysteine (NAC) and alpha-tocopherol) or BAK knockdown prevented MK4 mediated mitochondrial disruption and apoptosis
ERK↑, activates ERK, JNK/p38 MAPK
JNK↑,
p38↑,
Cyt‑c↑, cytochrome c release
Casp↑, caspase activation
ATP↓, reducing ATP production and increasing lactate production
lactateProd↑,
AMPK↑, which activates AMPK
Rho↓, via inhibition of RhoA
TumCG↓, mouse xenograft studies, treatment with MK4 administered in water at a calculated dose of 20 mg/kg/d significantly reduced growth of established HCCs
BioAv↑, Phylloquinone (K1) is the major dietary form, but it is converted into menaquinone (K2) in tissues.
cardioP↑, optimal vitamin K status is common in adults and may contribute to chronic diseases such as osteoporosis, type 2 diabetes and cardiovascular disease.
Risk↓, Observational studies suggest that low vitamin K intake increases cancer risk(more lowers risk)

1829- VitK2,    Vitamin K: New insights related to senescence and cancer metastasis
- Review, Var, NA
TumCP↓, VK can inhibit the proliferation, growth, and differentiation of cancer cells
TumCG↓,
ChemoSen↑, VK as an adjuvant therapy for cancer (or in combination with traditional chemotherapy drug
ROS↑, VK can regulate the balance of oxidation-reduction reaction(redox) by producing reactive oxygen species (ROS) through the mitochondrial pathway.

1840- VitK2,    The mechanisms of vitamin K2-induced apoptosis of myeloma cells
- in-vitro, Melanoma, NA
TumCG↓, growth inhibition was caused by apoptosis and activation of caspase-3
Apoptosis↑,
Casp3↑,
ROS↑, generation of superoxide
p‑MAPK↑, phosphorylation of MAPK was increased by VK2

1214- VitK2,    Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells
- in-vitro, Bladder, T24/HTB-9 - in-vitro, Bladder, J82
Glycolysis↑, Vitamin K2 renders bladder cancer cells more dependence on glycolysis than TCA cycle
GlucoseCon↑, results suggest that Vitamin K2 is able to induce metabolic stress, including glucose starvation and energy shortage, in bladder cancer cells, upon glucose limitation.
lactateProd↑,
TCA↓, Vitamin K2 promotes glycolysis and inhibits TCA cycle in bladder cancer cells
PI3K↑,
Akt↑,
AMPK↑, Vitamin K2 remarkably activated AMPK pathway
mTORC1↓,
TumAuto↑,
GLUT1↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
HK2↑,
LDHA↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
ACC↓, Vitamin K2 remarkably decreased the amounts of Acetyl coenzyme A (Acetyl-CoA) in T24 cells
PDH↓, suggesting that Vitamin K2 inactivates PDH
eff↓, Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death.
cMyc↓, c-MYC protein level was also significantly reduced in T24 cells following treatment with Vitamin K2 for 18 hours
Hif1a↑, Besides, the increased expression of GLUT-1, HIF-1α, p-AKT and p-AMPK were also detected in Vitamin K2-treated tumor group
p‑Akt↑,
eff↓, 2-DG, 3BP and DCA-induced glycolysis attenuation significantly prevented metabolic stress and rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
eff↓, inhibition of PI3K/AKT and HIF-1α notably attenuated Vitamin K2-upregulated glycolysis, indicating that Vitamin K2 promotes glycolysis in bladder cancer cells via PI3K/AKT and HIF-1α signal pathways.
eff↓, (NAC, a ROS scavenger) not only alleviated Vitamin K2-induced AKT activation and glycolysis promotion, but also significantly suppressed the subsequent AMPK-dependent autophagic cell death.
eff↓, glucose supplementation not only restored c-MYC expression, but also rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
ROS↑, under glucose limited condition, the increased glycolysis inevitably resulted in metabolic stress, which augments ROS accumulation due to lack of glucose for sustained glycolysis.

1827- VitK3,    A biophysical approach to menadione membrane interactions: relevance for menadione-induced mitochondria dysfunction and related deleterious/therapeutic effects
- Analysis, Var, NA
ROS↑, Menadione (MEN), a polycyclic aromatic ketone, was shown to promote cell injury by imposing massive oxidative stress
ChemoSen↑, has been proposed as a promising chemotherapeutic agent for the treatment of cancer diseases.

1828- VitK3,  VitC,    Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C
- in-vivo, GBM, NA
eff↑, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold.
ROS↑, cytotoxic effect of menadione is related to the generation of reactive oxygen species
Dose∅, When used in combination at relatively low doses (M:VC at 10 μM:1 mM) for one week M:VC was able to prevent regrowth

1826- VitK3,    PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug
- in-vitro, Cerv, HeLa - in-vitro, Lung, A549
eff↑, PRX1 knockdown in HeLa and A549 cells conferred enhanced sensitivity to vitK3, reducing substantially the necessary doses to kill cancer cells.
ROS↑, Increased ROS accumulation had a crucial role in vitK3-induced cell death in PRX1 knockdown cells.

1832- VitK3,  VitC,    Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism
- in-vitro, AML, K562
ROS↑, vitamin K3- or vitamin C- induced apoptosis in leukemia cells by oxidative stress
H2O2↑, hydrogen peroxide generation,
NF-kB↑, activation of NF-κB,
P53↑, p53, c-Jun, protease caspase-3 activation
cJun↑,
Casp3↑,
MMP↓, mitochondria depolarization leading to nuclei fragmentation
DNAdam↑,
Dose?, Jurkat and K562 cells are exposed to VC and VK3 in a ratio 1000:1 (10 mM: 10 μM) or 100:1 (300 μM: 3 μM), respectively

1834- VitK3,  PDT,    Effects of Vitamin K3 Combined with UVB on the Proliferation and Apoptosis of Cutaneous Squamous Cell Carcinoma A431 Cells
- in-vitro, Melanoma, A431
eff↑, co-treatment of VitK3 combined with UVB more significantly inhibited the growth and proliferation of A431 cells than either VitK3 or UVB alone.
TumCG↓,
TumCP↓,
ROS↑, ROS and the depolarization of the mitochondrial membrane potential were higher in all the co-treatment groups
MMP↓,

1835- VitK3,  VitC,    Potential therapeutic application of the association of vitamins C and K3 in cancer treatment
- Review, Var, NA
ROS↑, A large body of evidence supports the idea that oxidative stress induced by redox cycling of vitamins C and K(3) in association surpasses cancer cellular defense systems and results in cell death
TumCD↑,
TumCG↓, Combined vitamin C and K(3) administration in vitro and in vivo produced tumor growth inhibition and increased the life-span of tumor-bearing mice.
OS↑,

1837- VitK3,  VitC,    Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death
- in-vivo, Pca, NA
eff↑, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects.
ROS↑, The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses.
TumAuto↑, ROS can induce autophagy

1838- VitK3,  PDT,    Photodynamic Effects of Vitamin K3 on Cervical Carcinoma Cells Activating Mitochondrial Apoptosis Pathways
- in-vitro, Cerv, NA
eff↑, vitamin K3 (Vit K3) serves as a photosensitizer to produce Reactive Oxygen Species (ROS)
ROS↑,
tumCV↓, Vit K3 treatment plus UVA reduced tumor cell viability
TumCG↓, Vit K3 treatment plus UVA can inhibit tumor growth
Apoptosis↑, enhance the apoptosis of cervical cancer cells
cl‑Casp3↑, cleaved caspase-3, cleaved caspase-9, B-cell lymphoma- extra large (Bcl-xl), and cytochrome c (cyt-c) increased obviously,
cl‑Casp9↑,
Bcl-xL↑,
Cyt‑c↑,
Bcl-2↓, (Bcl-2) decreased

1839- VitK3,    Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells
- in-vitro, Pca, NA
TumCP↓, VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis
Apoptosis↑,
TumCCA↑, blocking the cell cycle at G0
ROS↑, associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS)
eff↓, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines
AR↓, VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP
Trx↓,
Bcl-2↓,

5015- Xan,  PEITC,    Comparison of the Impact of Xanthohumol and Phenethyl Isothiocyanate and Their Combination on Nrf2 and NF-κB Pathways in HepG2 Cells In Vitro and Tumor Burden In Vivo
- in-vitro, HCC, HepG2
NRF2↓, Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.
ROS↑, The increased expression of NQO1 (~90%) was associated with increased ROS generation
NF-kB↓, X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression.
COX2↓,
Apoptosis↑, In contrast to single phytochemicals, X + PEITC induced apoptosis.
NRF2↑, All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells
SOD↑,
NQO1↑,

1221- Z,    Unexpected zinc dependency of ferroptosis: what is in a name?
- Analysis, Nor, NA
*Ferroptosis↑, zinc and zinc transporters promote ferroptosis
*ROS↑, zinc can enhance mitochondrial ROS generation
*lipid-P↑, induce lipid peroxidation

604- ZO,    Plant-Mediated Zinc Oxide Nanoparticles: Advances in the New Millennium towards Understanding Their Therapeutic Role in Biomedical Applications
- Review, NA, NA
ROS↑,
Apoptosis↑,
DNAdam↑,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1302

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned ⓘ

DrugR↓, 1,   Irisin↓, 1,   Leptin↓, 1,   Resistin↓, 1,  

Redox & Oxidative Stress ⓘ

4-HNE↑, 1,   antiOx↓, 9,   antiOx↑, 22,   antiOx⇅, 2,   ATF3↓, 1,   ATF3↑, 3,   Catalase↓, 25,   Catalase↑, 7,   Catalase∅, 1,   Ceru↓, 1,   compI↓, 1,   Copper↑, 1,   CYP1A1↓, 4,   CYP1A1↑, 3,   CYP2E1↑, 1,   cystine↓, 1,   DJ-1↓, 1,   ENOX2↓, 1,   Fenton↑, 26,   Ferroptosis↓, 3,   Ferroptosis↑, 63,   frataxin↑, 1,   GCLM↓, 1,   GPx↓, 18,   GPx↑, 7,   GPx1↓, 4,   GPx1∅, 1,   GPx4↓, 45,   GPx4↑, 1,   GSH?, 1,   GSH↓, 170,   GSH↑, 5,   GSH⇅, 2,   GSH∅, 1,   mt-GSH↓, 1,   GSH/GSSG↓, 18,   GSR↓, 5,   GSR↑, 2,   GSSG↓, 1,   GSSG↑, 4,   ox-GSSG↑, 1,   GSTA1↓, 2,   GSTA1↑, 1,   GSTP1/GSTπ↓, 2,   GSTs↓, 5,   GSTs↑, 2,   GSTs↝, 1,   H2O2?, 1,   H2O2↓, 1,   H2O2↑, 40,   i-H2O2↓, 1,   mt-H2O2↑, 1,   HK1↓, 1,   HNE↑, 1,   HO-1↓, 21,   HO-1↑, 29,   HO-1⇅, 1,   HO-2↓, 1,   HO-2↑, 1,   hyperG↓, 1,   ICD↑, 3,   Iron↓, 3,   Iron↑, 37,   Iron↝, 1,   i-Iron↓, 1,   i-Iron↑, 2,   c-Iron↑, 1,   Keap1↓, 2,   Keap1↑, 4,   Keap1↝, 2,   ox-Keap1↓, 1,   rd-Keap1↑, 1,   lipid-P↓, 7,   lipid-P↑, 60,   lipid-P↝, 1,   MAD↓, 1,   MDA↓, 5,   MDA↑, 35,   MGO↑, 1,   Mich↑, 1,   NADH↓, 1,   NADPH/NADP+↓, 2,   NAF1↓, 3,   NFE2L2↑, 1,   NOX4↑, 1,   NQO1↓, 4,   NQO1↑, 5,   Nrf1↑, 1,   NRF2↓, 52,   NRF2↑, 47,   NRF2⇅, 2,   NRF2↝, 1,   NRF2∅, 2,   p‑NRF2↓, 1,   p‑NRF2↑, 1,   OSI↑, 1,   OXPHOS↓, 14,   OXPHOS↑, 9,   OXPHOS⇅, 1,   OXPHOS↝, 2,   mt-OXPHOS↓, 3,   mt-OXPHOS↑, 1,   p66Shc↑, 1,   PAO↑, 1,   PARK2↑, 2,   Prx↓, 3,   Prx↑, 1,   Prx3↑, 1,   Prx4↓, 1,   Prx4↑, 1,   Prx6↑, 1,   PrxI∅, 1,   PrxII↓, 1,   PrxII↑, 1,   PrxII∅, 1,   PYCR1↓, 1,   RNS↓, 2,   RNS↑, 1,   ROS↓, 24,   ROS↑, 1283,   ROS⇅, 15,   ROS↝, 2,   ROS∅, 2,   i-ROS↑, 5,   m-ROS↑, 1,   mt-ROS↑, 34,   RPM↑, 3,   SAM-e↝, 1,   selenoP↓, 1,   selenoP↑, 2,   SIRT3↓, 2,   SIRT3↑, 6,   SOD↓, 37,   SOD↑, 13,   SOD∅, 1,   SOD1↓, 4,   SOD1↑, 3,   SOD2↓, 9,   SOD2↑, 4,   T-SOD↓, 1,   TAC↓, 1,   TAC↑, 1,   TBARS↑, 2,   Thiols↓, 5,   i-Thiols↓, 1,   TKT↝, 1,   TOS↑, 1,   Trx↓, 14,   Trx↑, 1,   Trx1↓, 6,   Trx1↑, 1,   Trx2↓, 2,   TrxR↓, 42,   TrxR1?, 1,   TrxR1↓, 13,   mt-TrxR1↓, 1,   TrxR2↓, 1,   mt-TrxR2↓, 1,   VitC↓, 1,   VitE↓, 1,   xCT↓, 18,   xCT↑, 2,   xCT∅, 1,  

Metal & Cofactor Biology ⓘ

Ferritin↓, 8,   Ferritin↑, 1,   FTH1↓, 7,   FTH1↑, 1,   FTL↑, 1,   IronCh↑, 3,   KLF5↓, 1,   NCOA4↑, 4,   NCOA4↝, 1,   Tf↓, 1,   Tf↑, 2,   TfR1/CD71↓, 2,   TfR1/CD71↑, 1,  

Mitochondria & Bioenergetics ⓘ

ADP:ATP↓, 2,   ADP:ATP↑, 3,   AIF↑, 29,   AIF↝, 1,   ATP↓, 76,   ATP↑, 2,   ATP↝, 1,   ATP∅, 1,   i-ATP↓, 1,   mt-ATP↓, 1,   BCR-ABL↓, 1,   BOK↑, 1,   CDC2↓, 8,   CDC25↓, 18,   CDC25↑, 1,   compIII↓, 1,   compIII↑, 1,   EGF↓, 6,   ETC↓, 12,   ETC↝, 2,   FGFR1↓, 4,   Insulin↓, 2,   MEK↓, 7,   p‑MEK↓, 2,   mitResp↓, 15,   mitResp↑, 3,   MMP?, 1,   MMP↓, 342,   MMP↑, 9,   MMP↝, 1,   Mortalin↓, 1,   MPT↑, 3,   mtDam↓, 1,   mtDam↑, 59,   OCR↓, 16,   OCR↑, 7,   mt-OCR↓, 1,   p42↑, 1,   p‑p42↓, 1,   PGC-1α↑, 1,   PINK1↑, 1,   Raf↓, 6,   e-Raf↓, 1,   c-Raf↓, 1,   SDH↓, 2,   SDH↑, 1,   SSBP1↑, 1,   XIAP↓, 30,  

Core Metabolism/Glycolysis ⓘ

12LOX↓, 7,   6PGD↓, 1,   Ac-histone H3↑, 1,   ACC↓, 1,   ACC↑, 3,   ACLY↓, 3,   p‑ACLY↓, 1,   ACSL4↑, 2,   ACSL4∅, 1,   adiP↑, 1,   AKT1↓, 3,   ALAT↓, 4,   ALAT↝, 1,   ALAT∅, 1,   ALDOA↓, 1,   AminoA↓, 1,   AMP↓, 1,   AMP↑, 1,   AMPK↓, 2,   AMPK↑, 43,   p‑AMPK↑, 7,   ANXA7↑, 2,   ATG7↑, 4,   ATP:AMP↓, 1,   BCAP↓, 1,   CAIX↓, 2,   cMyc↓, 55,   cMyc↑, 2,   p‑cMyc↑, 1,   CREB↓, 1,   CRM↑, 1,   CYP3A4↓, 2,   DHCR24↑, 1,   ECAR↓, 9,   ECAR↝, 1,   ENO1↓, 1,   FABP4↑, 1,   FAO↓, 1,   FASN↓, 9,   FBPase↑, 1,   FDG↓, 1,   G6PD↓, 2,   G6PD∅, 1,   GAPDH↓, 5,   GDH↓, 1,   GLO-I↓, 2,   GLS↓, 1,   glucoNG↓, 1,   glucoNG↑, 1,   glucose↓, 1,   GlucoseCon↓, 31,   GlucoseCon↑, 3,   GlucoseCon∅, 1,   GLUT2↓, 2,   GlutaM↓, 2,   GlutMet↓, 1,   glyC↓, 1,   Glycolysis↓, 76,   Glycolysis↑, 1,   Glycolysis∅, 1,   H2S↑, 1,   ac‑Histones↑, 1,   HK2↓, 41,   HK2↑, 1,   HK2∅, 1,   HMG-CoA↓, 2,   IDH2↓, 1,   IDO1↓, 1,   KeyT↑, 1,   lact/pyru↓, 1,   lactateProd↓, 36,   lactateProd↑, 4,   lactateProd∅, 1,   LAT↓, 1,   LDH?, 1,   LDH↓, 22,   LDH↑, 7,   LDH↝, 1,   LDHA↓, 18,   LDHA↑, 1,   LDHA∅, 1,   LDL↓, 4,   MCT4↓, 2,   MCU↓, 1,   NAD↓, 4,   NAD↑, 1,   NAD↝, 1,   NADH:NAD↓, 1,   NADPH↓, 13,   NADPH↑, 6,   NADPH↝, 1,   NNMT↓, 1,   PCK1↓, 1,   PDH↓, 5,   PDH↑, 6,   PDH↝, 1,   p‑PDH↓, 1,   p‑PDH↑, 1,   PDHA1↓, 1,   PDK1?, 2,   PDK1↓, 13,   p‑PDK1↓, 1,   PDK3↑, 1,   PDKs↓, 8,   PDKs↑, 1,   PFK↓, 9,   PFK1↓, 3,   PFKP↓, 3,   PGK1↓, 1,   PI3K/Akt↓, 7,   PI3K/Akt↑, 1,   PI3K/Akt↝, 1,   PI3k/Akt/mTOR↓, 3,   PKM2↓, 33,   PKM2↑, 1,   POLD1↓, 1,   PPARα↓, 1,   PPARα↑, 1,   cl‑PPARα↓, 1,   PPARγ↓, 2,   PPARγ↑, 5,   PPP↓, 3,   PPP↑, 1,   PSMB5↓, 1,   Pyruv↓, 3,   Pyruv↑, 1,   R5P↝, 1,   RNR↓, 1,   p‑S6↓, 1,   p‑S6K↓, 2,   SIRT1↓, 12,   SIRT1↑, 14,   SIRT2↓, 1,   SIRT2↑, 1,   SLC1A5↓, 1,   SLC25A1↓, 1,   SREBP1↓, 1,   SSAT↑, 1,   TCA?, 1,   TCA↓, 4,   TCA↑, 1,   TS↓, 1,   Warburg↓, 14,   β-oxidation↓, 1,  

Cell Death ⓘ

Akt↓, 153,   Akt↑, 11,   Akt↝, 1,   p‑Akt↓, 44,   p‑Akt↑, 2,   APAF1↑, 3,   Apoptosis?, 5,   Apoptosis↓, 12,   Apoptosis↑, 463,   m-Apoptosis↑, 1,   mt-Apoptosis↑, 5,   ASK1↑, 4,   ATF2↓, 3,   BAD↓, 3,   BAD↑, 15,   p‑BAD↓, 1,   Bak↑, 21,   BAX↓, 8,   BAX↑, 201,   BAX⇅, 1,   Bax:Bcl2↑, 46,   Bcl-2↓, 213,   Bcl-2↑, 3,   Bcl-2∅, 1,   cl‑Bcl-2↑, 1,   Bcl-xL↓, 44,   Bcl-xL↑, 1,   BID↓, 1,   BID↑, 12,   cl‑BID↑, 2,   BIM↑, 15,   Casp↓, 1,   Casp↑, 64,   proCasp↑, 1,   Casp1↓, 1,   cl‑Casp1↑, 1,   Casp10↑, 1,   Casp10∅, 1,   Casp12↑, 8,   cl‑Casp12↑, 1,   cl‑Casp12↝, 1,   pro‑Casp12↓, 1,   Casp2↑, 2,   Casp3?, 3,   Casp3↓, 7,   Casp3↑, 252,   cl‑Casp3↓, 1,   cl‑Casp3↑, 57,   cl‑Casp3∅, 1,   proCasp3↓, 3,   proCasp3↑, 3,   pro‑Casp3↑, 1,   Casp6↑, 2,   Casp7↑, 24,   cl‑Casp7↑, 2,   Casp8↓, 1,   Casp8↑, 52,   Casp8∅, 3,   cl‑Casp8↑, 12,   Casp9?, 1,   Casp9↑, 150,   cl‑Casp9↑, 23,   proCasp9↓, 1,   proCasp9↑, 1,   cFLIP↓, 8,   Chk2↓, 2,   Chk2↑, 4,   p‑Chk2↑, 1,   CK2↓, 8,   Cupro↑, 2,   Cyt‑c↓, 1,   Cyt‑c↑, 190,   Cyt‑c↝, 3,   Diablo↑, 14,   DR4↑, 8,   DR4∅, 2,   DR5↑, 42,   DR5∅, 1,   Endon↑, 4,   FADD↑, 8,   FADD∅, 1,   Fap1↓, 1,   Fas↓, 2,   Fas↑, 25,   FasL↑, 10,   Ferroptosis↓, 3,   Ferroptosis↑, 63,   GRP58↓, 2,   GSDMD↑, 3,   GSDME↑, 1,   cl‑GSDME↑, 1,   GSDME-N↑, 1,   HEY1↓, 1,   HGF/c-Met↓, 2,   hTERT/TERT↓, 15,   IAP1↓, 7,   IAP2↓, 5,   IAP2↑, 1,   cl‑IAP2↑, 1,   ICAD↓, 2,   iNOS↓, 14,   iNOS↑, 3,   JNK↓, 6,   JNK↑, 56,   JNK↝, 1,   p‑JNK↓, 4,   p‑JNK↑, 7,   JWA↑, 1,   lysoMP↑, 1,   MAPK↓, 35,   MAPK↑, 35,   MAPK↝, 3,   p‑MAPK↓, 1,   p‑MAPK↑, 5,   Mcl-1↓, 33,   Mcl-1↑, 2,   MCT1↓, 3,   MDM2↓, 11,   MDM2↑, 1,   p‑MDM2↓, 1,   MKP1↓, 2,   MKP2↓, 2,   MLKL↑, 4,   p‑MLKL↓, 1,   MOMP↓, 1,   MOMP↑, 4,   Myc↓, 7,   Myc↑, 1,   NAIP↓, 1,   Necroptosis↑, 13,   necrosis↑, 14,   NICD↓, 1,   NOXA↑, 6,   oncosis↑, 2,   p27↑, 33,   p38↓, 6,   p38↑, 40,   p‑p38↓, 3,   p‑p38↑, 14,   Paraptosis↑, 5,   PDCD4↑, 1,   proApCas↑, 1,   Proteasome?, 1,   Proteasome↓, 2,   PUMA↑, 9,   PUMA↝, 1,   Pyro↑, 6,   RIP1↓, 3,   RIP1↑, 5,   p‑RIP1↑, 1,   Set9↑, 1,   survivin↓, 67,   Telomerase↓, 16,   TNFR 1↑, 2,   TRAIL↑, 10,   TRAIL⇅, 1,   TRAILR↑, 3,   TRPV1↑, 5,   TumCD↓, 1,   TumCD↑, 51,   YAP/TEAD↓, 3,  

Kinase & Signal Transduction ⓘ

AMPKα↑, 7,   CaMKII ↓, 4,   p‑CaMKII ↓, 1,   cSrc↓, 2,   EF-1α↓, 1,   FOXD3↑, 2,   HER2/EBBR2↓, 14,   p70S6↓, 4,   p‑p70S6↑, 1,   RET↓, 1,   SOX9?, 1,   SOX9↓, 2,   Sp1/3/4↓, 20,   TSC2↑, 2,   p‑TSC2↑, 1,  

Transcription & Epigenetics ⓘ

BowelM↑, 2,   ChrMod↑, 2,   cJun↓, 9,   cJun↑, 3,   p‑cJun↑, 1,   DLEU1↓, 1,   EZH2↓, 4,   H3↓, 2,   H3↑, 2,   p‑H3↓, 1,   p‑H3↑, 1,   ac‑H3↑, 2,   H4↓, 1,   H4↑, 2,   ac‑H4↑, 2,   HATs↓, 3,   HATs↑, 1,   KISS1↑, 1,   miR-21↓, 9,   miR-21↑, 1,   miR-27a-3p↓, 1,   other?, 1,   other↓, 12,   other↑, 17,   other↝, 30,   other∅, 1,   OV6↓, 1,   PhotoS↑, 1,   pRB↑, 1,   p‑pRB↓, 3,   SETBP1↓, 1,   sonoS↑, 2,   tumCV↓, 129,   tumCV↑, 3,   USF1↑, 1,   YMcells↓, 1,  

Protein Folding & ER Stress ⓘ

ATF6↑, 4,   cl‑ATF6↑, 1,   ATFs↑, 1,   CHOP↑, 58,   p‑CHOP↝, 1,   cl‑CHOP↑, 1,   i-CRT↓, 1,   eIF2α↓, 1,   eIF2α↑, 11,   p‑eIF2α↑, 9,   p‑eIF2α↝, 1,   ER Stress↓, 4,   ER Stress↑, 139,   ER Stress↝, 1,   ERStress↑, 2,   GRP78/BiP?, 1,   GRP78/BiP↓, 1,   GRP78/BiP↑, 38,   GRP78/BiP↝, 1,   HSF1↓, 2,   HSP27↓, 3,   HSP27↑, 2,   HSP27↝, 1,   HSP70/HSPA5↓, 6,   HSP70/HSPA5↑, 11,   HSP70/HSPA5⇅, 1,   HSP70/HSPA5↝, 1,   HSP90↓, 11,   HSPs↓, 2,   HSPs↑, 2,   IRE1↑, 6,   PERK↑, 15,   p‑PERK↑, 2,   p‑PERK↝, 1,   UPR↑, 26,   XBP-1↓, 1,   XBP-1↑, 4,  

Autophagy & Lysosomes ⓘ

ATG3↑, 2,   ATG5↑, 9,   autoF↓, 1,   AVOs↑, 1,   Beclin-1↓, 4,   Beclin-1↑, 26,   p‑Beclin-1↑, 1,   BNIP3?, 2,   BNIP3↑, 3,   BNIP3↝, 1,   LAMP2↑, 1,   LC3‑Ⅱ/LC3‑Ⅰ↓, 1,   LC3‑Ⅱ/LC3‑Ⅰ↑, 5,   LC3A↑, 1,   LC3B↑, 7,   LC3B-II↑, 7,   LC3I↑, 1,   LC3II↓, 2,   LC3II↑, 28,   LC3s↓, 1,   LC3s↑, 5,   LC3s↝, 1,   lysosome↝, 1,   MitoP↑, 2,   p62↓, 19,   p62↑, 15,   SESN2↑, 3,   TFEB↑, 1,   TumAuto↓, 2,   TumAuto↑, 106,  

DNA Damage & Repair ⓘ

ATM↑, 6,   p‑ATM↑, 1,   ATR↑, 1,   p‑ATR↑, 1,   BRCA1↓, 1,   BRCA1↑, 2,   BRCA2↑, 1,   CHK1↓, 4,   CHK1↑, 1,   p‑CHK1↑, 2,   DFF45↓, 1,   DFF45↑, 2,   DNA-PK↑, 4,   DNAdam↓, 4,   DNAdam↑, 167,   mt-DNAdam↑, 2,   DNArepair↓, 2,   DNArepair↑, 2,   DNMT1↓, 9,   DNMT1↑, 1,   DNMT3A↓, 2,   DNMTs↓, 4,   m-FAM72A↓, 1,   G9a↓, 1,   GADD45A↑, 4,   HR↓, 2,   MGMT↓, 3,   p16↑, 6,   P53?, 2,   P53↓, 4,   P53↑, 153,   P53↝, 4,   P53∅, 1,   p‑P53↑, 9,   ac‑P53↑, 1,   p53 Wildtype∅, 1,   PARP↓, 3,   PARP↑, 23,   PARP∅, 1,   p‑PARP↑, 3,   cl‑PARP↓, 1,   cl‑PARP↑, 109,   cl‑PARP↝, 1,   cl‑PARP∅, 1,   proPARP↓, 1,   PARP1↑, 2,   cl‑PARP1↑, 2,   PCNA↓, 25,   RAD51↓, 3,   RAD51↑, 1,   SIRT6↓, 1,   SIRT6↑, 1,   TP53↓, 3,   TP53↑, 4,   UHRF1↓, 1,   γH2AX↑, 19,   γH2AX↝, 1,   p‑γH2AX↑, 5,  

Cell Cycle & Senescence ⓘ

CDK1↓, 16,   CDK1↑, 4,   p‑CDK1↓, 2,   p‑CDK1↑, 1,   CDK2↓, 39,   CDK2↑, 3,   CDK4↓, 39,   CDK4↑, 4,   CDK4∅, 1,   Cyc↓, 5,   cycA1/CCNA1↓, 9,   cycA1/CCNA1↑, 2,   CycB/CCNB1↓, 24,   CycB/CCNB1↑, 5,   cycD1/CCND1↓, 91,   cycD1/CCND1↑, 2,   cycD1/CCND1∅, 1,   CycD3↓, 1,   cycE/CCNE↓, 20,   cycE/CCNE↑, 2,   cycE1↓, 2,   E2Fs↓, 2,   E2Fs↑, 1,   p19↑, 1,   P21?, 2,   P21↓, 6,   P21↑, 99,   RB1↑, 3,   p‑RB1↓, 7,   Securin↓, 2,   TumCCA?, 2,   TumCCA↓, 7,   TumCCA↑, 328,  

Proliferation, Differentiation & Cell State ⓘ

p‑4E-BP1↓, 1,   ALDH↓, 9,   ALDH1A1↓, 2,   BMI1↓, 3,   BRAF↝, 1,   CD133↓, 13,   CD24↓, 3,   CD34↓, 2,   CD44↓, 13,   cDC2↓, 3,   CDK8↓, 2,   cFos↓, 9,   cFos↑, 2,   CIP2A↓, 1,   cMET↓, 4,   cMYB↓, 1,   CREBBP↓, 1,   CSCs↓, 71,   CSCs↑, 3,   CSCsMark↓, 2,   CTNNB1↓, 1,   Diff↓, 1,   Diff↑, 7,   EMT↓, 89,   EMT↑, 4,   EP4↑, 1,   EpCAM↓, 1,   ERK↓, 60,   ERK↑, 18,   ERK↝, 1,   p‑ERK↓, 15,   p‑ERK↑, 8,   p‑ERK⇅, 1,   p‑ERK↝, 1,   e-ERK↑, 1,   FGF↓, 2,   FGFR2↓, 1,   FOSL1↑, 1,   FOXM1↓, 3,   FOXO↓, 1,   FOXO↑, 3,   FOXO3↓, 3,   FOXO3↑, 10,   p‑FOXO3↓, 1,   FOXO4↓, 1,   FOXO4↑, 1,   Gli↓, 1,   Gli1↓, 8,   GSK‐3β↓, 12,   GSK‐3β↑, 6,   GSK‐3β↝, 1,   p‑GSK‐3β↓, 5,   p‑GSK‐3β↑, 1,   HDAC↓, 36,   HDAC1↓, 9,   HDAC10↑, 1,   HDAC2↓, 4,   HDAC3↓, 3,   HDAC4↓, 2,   HDAC8↓, 1,   HH↓, 4,   HMGCR↓, 1,   HOXB-AS1↓, 1,   IGF-1↓, 15,   IGF-1R↓, 4,   IGF-1R↑, 1,   IGF-2↑, 1,   IGFBP1↑, 2,   IGFBP3↓, 1,   IGFBP3↑, 4,   IGFBP7↑, 1,   Jun↓, 2,   p‑Jun↑, 1,   Let-7↑, 2,   LRP6↓, 1,   MAP2K1/MEK1↓, 1,   miR-125b↓, 1,   miR-34a↑, 3,   mTOR↓, 97,   mTOR↑, 8,   mTOR⇅, 1,   p‑mTOR↓, 18,   p‑mTOR↑, 1,   mTORC1↓, 10,   p‑mTORC1↓, 1,   mTORC2↓, 4,   mTORC2↑, 1,   n-MYC↓, 1,   Nanog↓, 15,   Nestin↓, 3,   NOTCH↓, 17,   NOTCH1↓, 13,   NOTCH1↑, 3,   NOTCH3↓, 3,   OCT4↓, 13,   P70S6K↓, 2,   P70S6K↑, 1,   p‑P70S6K↓, 2,   p85S6K↓, 1,   P90RSK↓, 2,   PI3K↓, 87,   PI3K↑, 8,   PI3K↝, 1,   p‑PI3K↓, 3,   p‑PI3K↑, 1,   PIAS-3↑, 1,   PTCH1↓, 2,   PTEN↓, 1,   PTEN↑, 34,   PTEN↝, 1,   RAS↓, 13,   Shh↓, 7,   SHP1↑, 1,   Smo↓, 5,   SOX2↓, 13,   Src↓, 3,   p‑Src↓, 1,   STAT↓, 4,   p‑STAT↓, 1,   STAT1↓, 1,   p‑STAT1↓, 1,   STAT3↓, 81,   STAT3↑, 3,   STAT3⇅, 1,   p‑STAT3↓, 19,   p‑STAT3↑, 2,   mt-STAT3↓, 1,   STAT5↓, 2,   STAT6↓, 2,   p‑STAT6↓, 1,   TAZ↓, 1,   TCF↓, 1,   TCF↑, 1,   TCF-4↓, 3,   TOP1?, 1,   TOP1↓, 15,   TOP1↝, 1,   TOP1∅, 1,   TOP2↓, 8,   TRF2↓, 1,   TRPM7↓, 1,   TumCG?, 1,   TumCG↓, 172,   TumCG↑, 3,   tyrosinase↓, 1,   VGCC↓, 1,   VGSC↓, 1,   Wnt?, 1,   Wnt↓, 37,   Wnt↑, 1,   Wnt/(β-catenin)↓, 9,   Wnt/(β-catenin)↑, 1,   ZFX↓, 1,  

Migration ⓘ

5LO↓, 2,   AEG1↓, 1,   Akt2↓, 2,   Alix/AIP‑1↓, 2,   annexin II↓, 1,   AntiAg↓, 1,   AntiAg↑, 4,   AP-1↓, 11,   AP-1↑, 1,   ATPase↓, 1,   AXL↓, 2,   BACH1↑, 1,   Ca+2↓, 7,   Ca+2↑, 91,   Ca+2↝, 6,   i-Ca+2?, 1,   i-Ca+2↑, 3,   CAFs/TAFs↓, 2,   cal2↓, 1,   cal2↑, 2,   CD11b↑, 1,   CD31↓, 1,   Cdc42↓, 2,   Cdc42↑, 1,   CDK4/6↓, 1,   CDKN1C↑, 1,   CEA↓, 1,   CLDN1↓, 4,   CLDN2↓, 2,   COL1↓, 1,   COL3A1↓, 1,   CXCL12↓, 3,   E-cadherin↓, 7,   E-cadherin↑, 49,   ER-α36↓, 6,   F-actin↓, 2,   FAK↓, 21,   p‑FAK↓, 4,   Fibronectin↓, 6,   FOSB↑, 1,   Furin↓, 3,   GLI2↓, 3,   ITGB1↓, 3,   ITGB1↑, 1,   ITGB3↓, 1,   ITGB4↓, 1,   ITGB6↓, 1,   Ki-67↓, 28,   KLF2↓, 1,   LAMP1?, 1,   LAMs↓, 2,   LEF1↓, 2,   LysoPr↑, 1,   MALAT1↓, 5,   MARK4↓, 1,   MET↓, 3,   MET↑, 1,   p‑MET↓, 1,   miR-130a↓, 1,   miR-139-5p↑, 1,   miR-155↓, 2,   miR-22↑, 2,   miR-486↑, 1,   MMP-10↓, 2,   MMP1↓, 8,   MMP13↓, 5,   MMP2↓, 101,   MMP2↑, 1,   proMMP2↓, 1,   MMP3↓, 4,   MMP7↓, 14,   MMP7∅, 1,   MMP9↓, 105,   MMP9↑, 3,   MMP9:TIMP1↓, 1,   MMPs↓, 31,   MUC1↑, 1,   MUC4↓, 3,   N-cadherin↓, 34,   NCAM↑, 1,   NFAT↑, 1,   p‑p44↓, 1,   PAK1↓, 2,   p‑pax↓, 1,   PDGF↓, 5,   PKA↓, 5,   PKCδ↓, 11,   PTP1B↓, 1,   Rac1↓, 2,   RAGE↓, 1,   Rho↓, 6,   RIP3↓, 1,   RIP3↑, 6,   p‑RIP3↑, 2,   ROCK1↓, 4,   ROCK1↑, 1,   Slug↓, 11,   Smad1↑, 2,   SMAD2↓, 2,   SMAD3↓, 3,   SMAD3↑, 1,   SMAD4↓, 2,   SMAD4↑, 1,   p‑SMAD4↓, 1,   Snail?, 1,   Snail↓, 27,   SOX4↓, 1,   SOX4↑, 1,   STAC2↓, 1,   talin↓, 1,   TET1?, 1,   TET1↓, 1,   TET1↑, 6,   TGF-β↓, 24,   TGF-β↑, 4,   TIMP1↓, 3,   TIMP1↑, 9,   TIMP2↓, 2,   TIMP2↑, 10,   Treg lymp↓, 1,   TSC1↑, 1,   TSP-1↑, 4,   TumCA↓, 2,   TumCA↑, 1,   TumCI?, 1,   TumCI↓, 82,   TumCI↑, 1,   TumCMig↓, 96,   TumCMig↑, 2,   TumCP↓, 212,   TumCP↑, 5,   TumCP⇅, 1,   TumMeta↓, 71,   TumMeta↑, 2,   TumPF↓, 1,   Twist↓, 22,   TXNIP↑, 3,   Tyro3↓, 1,   uPA↓, 27,   uPA↝, 1,   uPAR↓, 1,   VCAM-1↓, 1,   Vim?, 1,   Vim↓, 47,   Vim↑, 1,   Zeb1↓, 13,   Zeb1↑, 1,   ZEB2↓, 3,   ZO-1↓, 1,   ZO-1↑, 2,   α-SMA↓, 2,   α-SMA↑, 1,   α-tubulin↓, 2,   β-catenin/ZEB1↓, 45,   β-catenin/ZEB1↑, 2,  

Angiogenesis & Vasculature ⓘ

angioG↓, 94,   angioG↑, 5,   ATF4↓, 1,   ATF4↑, 21,   ATF4↝, 1,   p‑ATF4↝, 1,   ECM/TCF↓, 1,   EGFR↓, 47,   EGFR↑, 1,   p‑EGFR↓, 3,   EGR1↑, 1,   EGR4↓, 1,   Endoglin↑, 1,   eNOS↓, 2,   eNOS↑, 1,   EPR↑, 9,   EPR↝, 1,   HIF-1↓, 9,   HIF-1↑, 2,   Hif1a↓, 79,   Hif1a↑, 9,   Hif1a↝, 2,   Hypoxia↓, 1,   KDR/FLK-1↓, 1,   LOX1↓, 2,   miR-210↓, 1,   NO↓, 5,   NO↑, 15,   NO↝, 1,   PDGFR-BB↓, 1,   PDI↑, 2,   PHDs↓, 1,   REL↑, 1,   TAMS↝, 1,   VEGF↓, 109,   VEGF↑, 1,   VEGFR2↓, 16,   ZBTB10↑, 1,  

Barriers & Transport ⓘ

BBB↓, 1,   BBB↑, 7,   BBB↝, 1,   CellMemb↑, 8,   CTR1↑, 2,   GLUT1↓, 27,   GLUT1↑, 2,   GLUT3↓, 2,   GLUT3↑, 1,   GLUT4↓, 3,   NHE1↓, 2,   P-gp↓, 21,   P-gp↑, 1,   SLC12A5↓, 1,   SMCT1∅, 1,   sonoP↑, 1,   SVCT-2↝, 1,   SVCT-2∅, 2,  

Immune & Inflammatory Signaling ⓘ

ASC↓, 1,   ASC↑, 1,   CCR7↓, 1,   CD14↑, 1,   CD4+↓, 1,   CD4+↑, 3,   cellSen↑, 1,   COX1↓, 3,   COX2↓, 77,   COX2↑, 4,   CRP↓, 3,   CXCL9↓, 1,   CXCR2↑, 1,   CXCR4↓, 12,   DCells↑, 3,   FOXP3↓, 1,   Gal1↑, 1,   HCAR1↓, 1,   HMGB1↓, 2,   i-HMGB1↓, 1,   ICAM-1↓, 2,   IFN-γ↓, 6,   IFN-γ↑, 2,   Igs↓, 1,   Igs↑, 2,   IKKα↓, 7,   IKKα↑, 4,   p‑IKKα↓, 1,   IL1↓, 7,   IL1↑, 2,   IL10↓, 7,   IL10↑, 2,   IL12↓, 1,   IL12↑, 2,   IL17↓, 1,   IL18↑, 1,   IL1β↓, 16,   IL1β↑, 3,   IL2↓, 2,   IL2↑, 3,   IL33↑, 1,   IL4↓, 2,   IL6↓, 43,   IL6↑, 2,   IL8↓, 10,   IL8↑, 3,   Imm↑, 12,   Inflam↓, 36,   IκB↓, 1,   IκB↑, 1,   p‑IκB↓, 1,   JAK↓, 7,   JAK↝, 1,   p‑JAK↓, 1,   JAK1?, 1,   JAK1↓, 6,   p‑JAK1↓, 1,   JAK2↓, 11,   p‑JAK2↓, 3,   M1↑, 1,   M2 MC↓, 2,   M2 MC↑, 1,   Macrophages↓, 1,   MCP1↓, 4,   MIP2↓, 1,   Neut↓, 1,   NF-kB↓, 179,   NF-kB↑, 15,   NF-kB↝, 1,   p‑NF-kB↓, 2,   p‑NF-kB↑, 2,   NK cell↑, 8,   NK cell⇅, 1,   p50↓, 1,   p65↓, 14,   p65↑, 1,   p‑p65↓, 4,   PD-1↓, 3,   PD-L1↓, 8,   PD-L1↑, 3,   PGE1↓, 1,   PGE2↓, 15,   PSA↓, 11,   RANTES?, 1,   SOCS-3↑, 1,   SOCS1↑, 1,   T-Cell↑, 3,   Th1 response↑, 1,   TLR1↑, 1,   TLR2↓, 1,   TLR4↓, 5,   TNF-α↓, 34,   TNF-α↑, 6,  

Cellular Microenvironment ⓘ

ADAM17↓, 1,   NOX↑, 1,   pH↓, 1,   pH↑, 1,   pH↝, 1,   i-pH↓, 1,   i-pH↑, 1,   Temp∅, 1,  

Synaptic & Neurotransmission ⓘ

GABA↑, 1,  

Protein Aggregation ⓘ

NLRP3↓, 5,   NLRP3↑, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 27,   CDK6↓, 18,   CDK6↑, 5,   CDK6∅, 1,   ER(estro)↓, 1,   ERα/ESR1↓, 2,   SXR↑, 1,  

Drug Metabolism & Resistance ⓘ

ABC↓, 2,   BioAv↓, 51,   BioAv↑, 53,   BioAv↝, 12,   BioEnh?, 1,   BioEnh↑, 5,   chemoR↓, 1,   ChemoSen↓, 5,   ChemoSen↑, 213,   ChemoSen⇅, 1,   ChemoSen∅, 3,   CYP1A2↓, 1,   CYP1A2↑, 1,   CYP2A3/CYP2A6↓, 1,   Dose?, 8,   Dose↓, 7,   Dose↑, 24,   Dose⇅, 4,   Dose↝, 69,   Dose∅, 38,   eff?, 2,   eff↓, 245,   eff↑, 429,   eff⇅, 1,   eff↝, 34,   eff∅, 3,   Half-Life?, 1,   Half-Life↓, 13,   Half-Life↑, 3,   Half-Life↝, 15,   Half-Life∅, 2,   MDR1↓, 9,   MRP1↓, 1,   MRP1↑, 1,   P450↓, 7,   P450↝, 1,   RadioS↓, 2,   RadioS↑, 106,   RadioS↝, 1,   selectivity?, 1,   selectivity↓, 5,   selectivity↑, 240,   selectivity↝, 1,   selectivity∅, 1,   TET2↑, 2,  

Clinical Biomarkers ⓘ

ALAT↓, 4,   ALAT↝, 1,   ALAT∅, 1,   ALP↓, 3,   ALP↝, 1,   AR↓, 27,   AST↓, 3,   AST↝, 1,   AST∅, 1,   BG↓, 6,   BloodF↑, 1,   BMD↑, 2,   BP↓, 3,   BRAF↝, 1,   BRCA1↓, 1,   BRCA1↑, 2,   CEA↓, 1,   CRP↓, 3,   E6↓, 4,   E7↓, 4,   EGFR↓, 47,   EGFR↑, 1,   p‑EGFR↓, 3,   ERα/ESR1↓, 2,   EZH2↓, 4,   Ferritin↓, 8,   Ferritin↑, 1,   FOXM1↓, 3,   GutMicro↑, 6,   GutMicro↝, 2,   HER2/EBBR2↓, 14,   hTERT/TERT↓, 15,   IL6↓, 43,   IL6↑, 2,   Ki-67↓, 28,   LDH?, 1,   LDH↓, 22,   LDH↑, 7,   LDH↝, 1,   Maspin↑, 1,   Myc↓, 7,   Myc↑, 1,   NOS2↓, 1,   NSE↓, 1,   PD-L1↓, 8,   PD-L1↑, 3,   PSA↓, 11,   RAGE↓, 1,   RBM3↑, 1,   TP53↓, 3,   TP53↑, 4,  

Functional Outcomes ⓘ

AntiCan↓, 3,   AntiCan↑, 85,   antiNeop↑, 1,   AntiTum↑, 35,   Appetite↑, 1,   breath↑, 1,   cachexia↓, 2,   cardioP↑, 8,   CardioT↓, 1,   chemoP↑, 36,   chemoPv↑, 23,   ChemoSideEff↓, 13,   cognitive↑, 1,   hepatoP↓, 2,   hepatoP↑, 12,   K17↓, 1,   memory↑, 1,   NDRG1↑, 1,   neuroP↓, 1,   neuroP↑, 10,   NKG2D↑, 1,   OS↑, 41,   OS⇅, 1,   Pain↓, 3,   Pin1↓, 2,   QoL↑, 10,   radioP↑, 12,   Remission↑, 5,   RenoP↑, 10,   Risk↓, 20,   Risk↑, 1,   Sleep↑, 1,   Strength↑, 2,   toxicity?, 1,   toxicity↓, 23,   toxicity↑, 2,   toxicity↝, 16,   toxicity∅, 7,   TumVol↓, 36,   TumVol↑, 1,   TumW↓, 16,   Weight↑, 4,   Weight∅, 2,  

Infection & Microbiome ⓘ

AntiFungal↑, 1,   Bacteria↓, 5,   CD8+↑, 6,   Sepsis↓, 2,  
Total Targets: 1360

Pathway results for Effect on Normal Cells:


NA, unassigned ⓘ

EndoR↑, 1,  

Redox & Oxidative Stress ⓘ

antiOx?, 1,   antiOx↓, 5,   antiOx↑, 66,   Catalase↓, 1,   Catalase↑, 22,   Copper↓, 2,   Fenton↓, 2,   Ferroptosis↓, 1,   Ferroptosis↑, 1,   GPx↑, 15,   GPx1↑, 2,   GPx4↑, 1,   GSH↓, 4,   GSH↑, 27,   GSH/GSSG↑, 1,   GSR↑, 4,   GSSG↓, 1,   GSSG∅, 1,   GSTA1↓, 2,   GSTA1↑, 1,   GSTs↑, 6,   H2O2↓, 3,   H2O2↑, 1,   HDL↑, 1,   HNE↓, 1,   HO-1↑, 15,   Iron↓, 3,   Keap1↓, 3,   ox-Keap1↑, 1,   lipid-P↓, 15,   lipid-P↑, 1,   MDA↓, 13,   MDA↑, 3,   MPO↓, 4,   MPO↑, 2,   NQO1↑, 2,   Nrf1↑, 1,   NRF2↓, 1,   NRF2↑, 35,   NRF2↝, 1,   OXPHOS↑, 1,   Prx↑, 1,   Prx4∅, 1,   RNS↓, 1,   ROS?, 2,   ROS↓, 86,   ROS↑, 39,   ROS⇅, 2,   ROS∅, 17,   mt-ROS↓, 1,   mt-ROS↑, 4,   selenoP↑, 4,   SIRT3↑, 1,   SOD↓, 2,   SOD↑, 29,   SOD1↓, 1,   SOD1↑, 3,   SOD2↑, 3,   TAC↑, 1,   TAC∅, 1,   TBARS↓, 1,   Trx↑, 2,   TrxR↑, 1,  

Metal & Cofactor Biology ⓘ

IronCh↑, 10,  

Mitochondria & Bioenergetics ⓘ

ADP:ATP↓, 1,   ATP↓, 1,   ATP↑, 4,   ETC↓, 1,   ETC↝, 1,   mitResp↑, 2,   MMP↓, 4,   MMP↑, 4,   MMP∅, 3,   MPT↑, 1,   mt-OCR↑, 1,   PGC-1α↑, 1,   UCP1↓, 1,  

Core Metabolism/Glycolysis ⓘ

12LOX↓, 1,   Acetyl-CoA↑, 1,   ALAT↓, 5,   AMPK↑, 3,   p‑AMPK↑, 1,   p‑cMyc↑, 1,   CREB↑, 1,   CRM↑, 1,   ECAR↓, 1,   ECAR↑, 1,   FAO↑, 1,   FGF21↑, 1,   glucose↓, 3,   GlucoseCon↑, 4,   Glycolysis↓, 1,   Glycolysis↑, 2,   H2S↑, 2,   HK2↑, 1,   lactateProd↓, 1,   LDH↓, 3,   LDH↑, 1,   LDHA↑, 1,   LDHB↑, 1,   LDL↓, 2,   lipidLev↓, 1,   NAD↑, 2,   NADPH↓, 2,   NADPH∅, 1,   PFK↑, 1,   PKM2↓, 1,   PKM2↑, 1,   PPARα↑, 1,   p‑PPARγ↓, 1,   PPP↓, 1,   SIRT1↑, 3,   SIRT2↑, 1,   TCA↑, 1,  

Cell Death ⓘ

Akt↓, 5,   Apoptosis↓, 4,   Apoptosis↑, 1,   Apoptosis∅, 1,   ASK1↓, 1,   BAX↓, 4,   BAX↑, 1,   Bax:Bcl2↓, 1,   Bax:Bcl2↑, 2,   Bcl-2↓, 1,   Bcl-2↑, 1,   Bcl-2∅, 1,   Casp3?, 1,   Casp3↓, 2,   Casp3↑, 4,   Casp3∅, 1,   cl‑Casp3↑, 1,   Casp8↑, 1,   cl‑Casp8↑, 2,   Casp9↑, 1,   cl‑Casp9↑, 1,   Cyt‑c↓, 1,   Cyt‑c↑, 1,   Cyt‑c∅, 1,   Fas↓, 1,   Fas↑, 2,   Ferroptosis↓, 1,   Ferroptosis↑, 1,   HEY1↑, 1,   HGF/c-Met↑, 1,   iNOS↓, 11,   iNOS↑, 1,   JNK↓, 1,   JNK↑, 2,   p‑JNK↓, 1,   MAPK↓, 4,   MAPK↑, 1,   necrosis↓, 1,   p38↓, 1,   p38↑, 1,   YAP/TEAD↑, 1,  

Transcription & Epigenetics ⓘ

Ach↑, 2,   other?, 1,   other↓, 4,   other↑, 5,   other↝, 9,   TREM-1↓, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,   cl‑eIF2α↑, 1,   ER Stress↓, 1,   GRP78/BiP↓, 1,   GRP78/BiP↑, 1,   HSPs↑, 1,   p‑PERK↑, 1,   UPR↓, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,   LC3II↑, 1,   p62↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 1,   DNAdam↑, 2,   DNAdam∅, 1,   DNArepair↑, 1,   p16↓, 1,   P53↓, 3,   P53↑, 2,   cl‑PARP↑, 2,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK2↓, 2,   CDK4↓, 1,   cycA1/CCNA1↓, 1,   cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   cycE/CCNE↑, 1,   P21↓, 3,   P21↑, 2,   RB1↓, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

Diff↑, 3,   EMT↓, 1,   ERK↓, 1,   ERK↑, 2,   FGF↑, 2,   p‑GSK‐3β↑, 1,   HDAC↓, 1,   HDAC3↓, 1,   IGF-1↓, 2,   IGF-1↑, 1,   IGFBP3↑, 1,   mTOR↓, 3,   NOTCH↑, 1,   PI3K↓, 4,   PTEN↑, 1,   RAS↓, 1,   STAT3↓, 1,   STAT3↑, 1,   TumCG↓, 1,   Wnt↑, 1,  

Migration ⓘ

5LO↓, 2,   AntiAg↑, 6,   Ca+2?, 1,   Ca+2↓, 2,   Ca+2↑, 3,   Ca+2↝, 1,   Ca+2∅, 1,   i-Ca+2↓, 1,   FAK↑, 1,   Ki-67↓, 1,   MMP2↑, 1,   MMP3↓, 1,   MMPs↑, 1,   PDGF↑, 1,   PKCδ?, 1,   PKCδ↓, 1,   TGF-β↓, 2,   TGF-β↑, 1,   TRPC1↑, 1,   TumCP↓, 2,   β-catenin/ZEB1↑, 1,   β-Endo↑, 1,  

Angiogenesis & Vasculature ⓘ

angioG↑, 2,   ATF4↑, 1,   Hif1a↓, 2,   Hif1a↑, 1,   Hif1a∅, 1,   NO↓, 7,   NO↑, 2,   VEGF↓, 1,   VEGF↑, 3,  

Barriers & Transport ⓘ

BBB↑, 7,   BBB↝, 1,   GLUT4↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX1↓, 1,   COX2↓, 14,   CRP↓, 4,   CXCR2↑, 1,   GM-CSF↑, 1,   HMGB1↓, 1,   IFN-γ↓, 1,   IL1↓, 1,   IL1↑, 1,   IL10↓, 1,   IL10↑, 2,   IL17↓, 2,   IL18↓, 1,   IL1β↓, 10,   IL2↓, 1,   IL2↑, 1,   IL22↓, 1,   IL4↑, 1,   IL6↓, 13,   IL6↑, 1,   IL8↓, 3,   Imm↑, 3,   Inflam↓, 60,   Inflam↑, 1,   IP-10/CXCL-10↑, 1,   MCP1↑, 1,   MyD88↓, 1,   NF-kB↓, 12,   NF-kB↑, 1,   NK cell↑, 1,   PGE2↓, 3,   PGE2↑, 1,   Th1 response↓, 1,   Th2↑, 2,   TLR2↓, 1,   TLR4↓, 1,   TNF-α↓, 19,   TNF-α↑, 2,  

Synaptic & Neurotransmission ⓘ

5HT↓, 1,   AChE↓, 2,   BDNF↑, 1,   ChAT↑, 2,   GABA↑, 1,   monoA↑, 1,   p‑tau↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 6,   BACE↓, 1,   NLRP3↓, 1,  

Hormonal & Nuclear Receptors ⓘ

GR↑, 1,   testos↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 37,   BioAv↑, 29,   BioAv↝, 7,   BioEnh↑, 1,   Dose?, 1,   Dose↑, 1,   Dose⇅, 1,   Dose↝, 16,   Dose∅, 1,   eff↓, 4,   eff↑, 21,   eff↝, 2,   Half-Life↓, 5,   Half-Life↑, 2,   Half-Life↝, 7,   Half-Life∅, 1,   P450↓, 1,   selectivity↑, 3,  

Clinical Biomarkers ⓘ

ALAT↓, 5,   ALP↓, 1,   AST↓, 6,   BG↓, 1,   BMD↑, 2,   BP↓, 1,   creat↓, 2,   CRP↓, 4,   GutMicro↑, 7,   IL6↓, 13,   IL6↑, 1,   Ki-67↓, 1,   LDH↓, 3,   LDH↑, 1,  

Functional Outcomes ⓘ

AntiAge↑, 5,   AntiCan↓, 1,   AntiCan↑, 5,   AntiDiabetic↑, 5,   AntiTum↑, 1,   Bone Healing↑, 1,   cardioP↓, 1,   cardioP↑, 19,   CardioT↓, 2,   chemoP↑, 6,   chemoPv↑, 2,   cognitive↑, 9,   hepatoP↑, 19,   memory↑, 11,   motorD↑, 1,   neuroP↓, 1,   neuroP↑, 36,   OS↑, 2,   Pain↓, 1,   radioP↑, 4,   RenoP↑, 7,   toxicity?, 2,   toxicity↓, 53,   toxicity↑, 4,   toxicity↝, 11,   toxicity∅, 21,   Weight↓, 2,   Weight∅, 1,   Wound Healing↑, 1,  

Infection & Microbiome ⓘ

AntiFungal↑, 1,   AntiViral↑, 2,   Bacteria↓, 11,   Inf↓, 1,   IRF3↓, 1,   Sepsis↓, 2,  
Total Targets: 364

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
110 Silver-NanoParticles
58 Magnetic Fields
52 Quercetin
50 Curcumin
45 Shikonin
39 Thymoquinone
39 Vitamin C (Ascorbic Acid)
38 Piperlongumine
37 Berberine
32 Sulforaphane (mainly Broccoli)
32 Selenite (Sodium)
31 Artemisinin
31 Ashwagandha(Withaferin A)
30 Betulinic acid
29 Radiotherapy/Radiation
27 Resveratrol
25 Baicalein
24 Phenethyl isothiocyanate
23 Copper and Cu NanoParticles
23 EGCG (Epigallocatechin Gallate)
23 Fisetin
21 Alpha-Lipoic-Acid
20 Allicin (mainly Garlic)
20 Gambogic Acid
19 Apigenin (mainly Parsley)
19 Juglone
17 Chemotherapy
17 salinomycin
16 Magnetic Field Rotating
15 Lycopene
15 Propolis -bee glue
14 Auranofin
14 doxorubicin
14 Parthenolide
14 Selenium NanoParticles
14 Vitamin K2
13 Cisplatin
13 Honokiol
12 Photodynamic Therapy
12 Capsaicin
12 Chrysin
12 Emodin
12 VitK3,menadione
11 chitosan
11 Ellagic acid
11 Silymarin (Milk Thistle) silibinin
11 Luteolin
10 Dichloroacetate
10 diet FMD Fasting Mimicking Diet
10 Plumbagin
9 5-fluorouracil
9 SonoDynamic Therapy UltraSound
9 Rosmarinic acid
8 Melatonin
8 Selenium
8 Sulfasalazine
8 Graviola
8 Hyperthermia
7 3-bromopyruvate
7 Boswellia (frankincense)
7 Disulfiram
7 Electrical Pulses
7 Hydrogen Gas
7 Phenylbutyrate
7 Propyl gallate
7 Pterostilbene
6 Coenzyme Q10
6 Gold NanoParticles
6 Andrographis
6 immunotherapy
6 Berbamine
6 Boron
6 HydroxyTyrosol
6 Methylene blue
6 Nimbolide
6 Piperine
5 2-DeoxyGlucose
5 Gemcitabine (Gemzar)
5 erastin
5 Hydroxycinnamic-acid
5 Aflavin-3,3′-digallate
5 Garcinol
5 Ursolic acid
5 Urolithin
4 Metformin
4 Docetaxel
4 Caffeic acid
4 Citric Acid
4 diet Methionine-Restricted Diet
4 diet Short Term Fasting
4 Spermidine
3 5-Aminolevulinic acid
3 Glucose
3 Zinc
3 temozolomide
3 Oxygen, Hyperbaric
3 γ-linolenic acid (Borage Oil)
3 Magnolol
3 Naringin
2 Ascorbyl Palmitate
2 Atorvastatin
2 beta-glucans
2 Catechins
2 Date Fruit Extract
2 Ferulic acid
2 Fenbendazole
2 Shilajit/Fulvic Acid
2 Galloflavin
2 Paclitaxel
2 Methyl Jasmonate
2 Magnesium
2 Methylglyoxal
2 Myricetin
2 Niclosamide (Niclocide)
2 Oleuropein
2 Pachymic acid
2 Sanguinarine
2 Psoralidin
2 Iron
1 cetuximab
1 Astragalus
1 entinostat
1 Camptothecin
1 Resiquimod
1 Anzaroot, Astragalus fasciculifolius Bioss
1 Ajoene (compound of Garlic)
1 Sorafenib (brand name Nexavar)
1 Astaxanthin
1 Aloe anthraquinones
1 tamoxifen
1 Butyrate
1 almonertinib
1 D-limonene
1 epirubicin
1 Lapatinib
1 Biochanin A
1 beta-carotene(VitA)
1 Ras-selective lethal 3
1 Carnosic acid
1 Celastrol
1 Vitamin E
1 Black phosphorus
1 chemodynamic therapy
1 methylseleninic acid
1 diet Ketogenic
1 diet Plant based
1 Exercise
1 Gallic acid
1 verapamil
1 hydroxychloroquine
1 HydroxyCitric Acid
1 Rapamycin
1 Ivermectin
1 lambertianic acid
1 MCToil
1 Myrrh
1 Oleocanthal
1 borneol
1 Kaempferol
1 benzo(a)pyrene
1 Hyperoside
1 EMF
1 Oxaliplatin
1 Scoulerine
1 polyethylene glycol
1 Formononetin
1 Osimertinib
1 Adagrasib
1 Glutathione
1 statins
1 triptolide
1 glucose deprivation
1 Transarterial Chemoembolization
1 xanthohumol
1 Zinc Oxide
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:%  Target#:275  State#:%  Dir#:2
  wNotes=on  sortOrder:rid,rpid

 

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