Database Query Results : , , GSH

GSH, Glutathione: Click to Expand ⟱
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Glutathione (GSH) is a thiol antioxidant that scavenges reactive oxygen species (ROS), resulting in the formation of oxidized glutathione (GSSG). Decreased amounts of GSH and a decreased GSH/GSSG ratio in tissues are biomarkers of oxidative stress.
Glutathione is a powerful antioxidant found in every cell of the body, composed of three amino acids: cysteine, glutamine, and glycine. It plays a crucial role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system.
cancer cells can have elevated levels of glutathione, which may help them survive in the oxidative environment created by the immune response and chemotherapy. This can make cancer cells more resistant to treatment.
While glutathione can be obtained from certain foods (like fruits, vegetables, and meats), its absorption from supplements is debated. Some people take N-acetylcysteine (NAC) or other precursors to boost glutathione levels, but the effects on cancer prevention or treatment are still being studied.
Depleting glutathione (GSH) to raise reactive oxygen species (ROS) is a strategy that has been explored in cancer research and therapy.
Many cancer cells have altered redox states and may rely on GSH to survive. Increasing ROS levels can induce stress in these cells, potentially leading to cell death.
Certain drugs and compounds can deplete GSH levels. For example, agents like buthionine sulfoximine (BSO) inhibit the synthesis of GSH, leading to its depletion.
Cancer cells tend to exhibit higher levels of intracellular GSH, possibly as an adaptive response to a higher metabolism and thus higher steady-state levels of reactive oxygen species (ROS).

"...intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS)..."
"Cancer cells have a high level of GSH compared to normal cells."
"...cancer cells are affluent with high antioxidant levels, especially with GSH, whose appearance at an elevated concentration of ∼10 mM (10 times less in normal cells) detoxifies the cancer cells." "Therefore, GSH depletion can be assumed to be the key strategy to amplify the oxidative stress in cancer cells, enhancing the destruction of cancer cells by fruitful cancer therapy."

The loss of GSH is broadly known to be directly related to the apoptosis progression.
Scientific Papers found: Click to Expand⟱
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

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.

5282- 3BP,  Rad,    3-Bromopyruvate-mediated MCT1-dependent metabolic perturbation sensitizes triple negative breast cancer cells to ionizing radiation
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MDA-MB-468
Glycolysis↓, Metabolomic analyses showed that 3BP causes inhibition of glycolysis
RadioS↑, Overall, MCT1-mediated metabolic perturbation in combination with radiotherapy is shown to be a promising strategy for the treatment of glycolytic tumors such as TNBC, overcoming the selectivity challenges of targeting glycolysis with glucose analogs
eff↑, 3BP is selectively toxic to cells expressing MCT1
GAPDH↓, 3BP inhibits GAPDH but not hexokinase
PPP↑, Pentose phosphate pathway is upregulated in response to 3BP
GSH↓, Glutathione and NADH are depleted at early time points
ECAR↓, prolonged incubation with 20 μM 3BP for 24 h resulted in a statistically significant selective decrease in ECAR

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.

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].

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);

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.

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

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↓,

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↑,

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

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

372- AgNPs,    Investigating oxidative stress and inflammatory responses elicited by silver nanoparticles using high-throughput reporter genes in HepG2 cells: effect of size, surface coating, and intracellular uptake
- in-vitro, Hepat, HepG2
NRF2↑,
GSH↓,

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↑,

398- AgNPs,    Silver nanoparticles induced testicular damage targeting NQO1 and APE1 dysregulation, apoptosis via Bax/Bcl-2 pathway, fibrosis via TGF-β/α-SMA upregulation in rats
- in-vivo, Testi, NA
Bcl-2↓,
Casp3↑,
GSH↓,
MDA↑,
NO↑,
H2O2↑,
SOD↓,

1902- AgNPs,    Modulation of the mechanism of action of antibacterial silver N-heterocyclic carbene complexes by variation of the halide ligand
- in-vitro, NA, NA
TrxR↓, antibacterial silver NHC complexes with halide ligands of the general type (NHC)AgX (X = Cl, Br or I) that showed potent inhibition of purified bacterial thioredoxin reductase (TrxR) and glutathione reductase (GR
GSR↓,
GSH↓, glutathione (GSH) depletion

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↑,

4382- AgNPs,    Silver nanoparticles induce cytotoxicity by a Trojan-horse type mechanism
- in-vitro, Nor, RAW264.7
*GSH↓, AgNPs decreased intracellular glutathione level, increased NO secretion, increased TNF-α in protein and gene level
*NO↑,
*TNF-α↑,
*MMP3↑, increased gene expression of matrix metalloproteinases (MMP-3, MMP-11, and MMP-19).
*MMP11↑,

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

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

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.

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↑,

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.

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].

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↓,

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↓,

2667- AL,    Allicin in Digestive System Cancer: From Biological Effects to Clinical Treatment
- Review, GC, NA
AntiCan↑, Allicin not only protects against tumors but also alleviates the adverse effects of anticancer treatment and enhances the chemotherapeutic response under certain conditions.
ChemoSen↑,
angioG↓, DATS works against tumors by blocking the cell cycle, inhibiting tumor cell proliferation, and inhibiting angiogenesis
chemoP↑,
*GutMicro↑, In addition to against bacteria, allicin has also been shown to modulate the composition of gut microbiota (GM) and increase the diversity of beneficial bacteria in animal models
*antiOx↑, allicin was confirmed to have strong antioxidant properties
other↝, Allicin is a reactive sulfur species (RSS) and a potent thiol-trapping reagent, rapidly reacting with glutathione (GSH) to yield S-allylmercaptoglutathione (GSSA)
GSH↓, Thus, allicin depletes the intracellular GSH pool and reacts with cysteine thiols available in proteins through S-thioallylation
Thiols↓, This reaction is the key to the biological activity of allicin, and the reversible oxidation and reduction of protein-thiols is the core of many processes in cells
*ROS↓, In a hypertrophic heart mouse model, the clearance of intracellular ROS by allicin was measured, and has been shown to reduce the production of ROS and block ROS-dependent ERK1/2, JNK1/2, AKT, NF-κB and Smad signaling, which leads to the inhibition o
*hepatoP↑, Moreover, allicin has been proven to play a hepatoprotective role against acetaminophen (APAP)-induced liver injury by reducing oxidative stress
*Inflam↓, OSCs in garlic has been shown to inhibit the tumor-mediated pro-inflammatory activity by modulating the cytokine pattern in a way that leads to an overall inhibition of NF-κB
*NF-kB↓,

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.

5165- AL,    The human allicin-proteome: S-thioallylation of proteins by the garlic defence substance allicin and its biological effects
- in-vitro, AML, Jurkat - in-vitro, Nor, L929
necrosis↑, Allicin induces apoptosis or necrosis in a dose-dependent manner but biocompatible doses influence cellular metabolism and signalling cascades.
Thiols↓, Oxidation of protein thiols and depletion of the glutathione pool are thought to be responsible for allicin's physiological effects.
GSH↓,
ENO1↓, allicin caused inhibition of enolase activity, an enzyme considered a cancer therapy target.
Zn2+↑, Allicin leads to Zn2+ release in murine EL-4 cells
Glycolysis↓, suggests that allicin can inhibit glycolysis which provides electron donors for ATP generation required for cellular biosynthesis pathways and growth of the cells.
ATP↓,
BioAv↓, achieving therapeutically relevant concentrations of allicin via the oral route is therefore unlikely and more direct routes of application to the desired site of action need to be considered

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↓,

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↓,

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%

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

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

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

3395- ART/DHA,    Artesunate Induces Ferroptosis in Hepatic Stellate Cells and Alleviates Liver Fibrosis via the ROCK1/ATF3 Axis
- in-vitro, NA, HSC-T6
*Ferroptosis↑, Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in vitro
*GSH↓,
*ROCK1↓, Interestingly, the ROCK1 protein level was significantly reduced after Art treatment compared with ROCK2, which raised the probability that ROCK1 was involved in the regulation of ferroptosis in LX2 cells

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

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]

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↑,

3163- Ash,  Rad,    Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis
*radioP↑, Withaferin A (WA) protected only normal lymphocytes, but not cancer cells, against IR-induced apoptosis
selectivity↑,
*Casp3↓, WA treatment led to significant inhibition of IR-induced caspase-3 activation and decreased IR-induced DNA damage to lymphocytes and bone-marrow cells.
*DNAdam↓,
*ROS↓, WA reduced intracellular ROS and GSH levels
*GSH↓,
*NRF2↑, WA induced pro-survival transcription factor, Nrf-2, and expression of cytoprotective genes HO-1, catalase, SOD, peroxiredoxin-2 via ERK.
*HO-1↑,
*Catalase↑,
*SOD↑,
*Prx↑,
*ERK↑, Activated ERK promotes the nuclear translocation and activity of Nrf2

1146- AsP,    Potential use of nanoformulated ascorbyl palmitate as a promising anticancer agent: First comparative assessment between nano and free forms
- in-vivo, Nor, NA
TumCCA↑, G2/M phase
Apoptosis↑,
IL6↓,
STAT3↓,
angioG↓,
TumMeta↓,
VEGF↓,
MMP9↓,
SOD↑,
Catalase↑,
GSH↓,
MDA↓,
NO↓,
*BioAv↑, nano particles

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

2618- Ba,    Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer
- in-vitro, Lung, H1299 - in-vivo, Lung, A549
TumCG↓, Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro.
TumCP↓,
Apoptosis↑,
GLUT1↓, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation
GLS↓,
mTOR↓, mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment
*toxicity∅, baicalein treatment did not result in damage to the mouse organs, including the liver, heart, spleen, lung, or kidney
cl‑Casp9↓, baicalein dose-dependently suppressed the protein levels of Bax, cleaved caspase 9, and cleaved caspase 3 in H1299 and A549 cells
cl‑Casp3↓,
GSH↓, Meanwhile, the levels of glutathione (GSH), S-formylglutathione, and pyroglutamic acid in baicalein-treated A549 cells were downregulated when compared to that in control group
GlutMet↓, These findings indicate that baicalein inhibits cellular glutamine uptake, which is consistent with the findings of metabolomics studies.

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

5506- Ba,    Improved Bioavailability and Hepatoprotective Activity of Baicalein Via a Self-assembled Solutol HS15 Micelles System
- in-vivo, Nor, NA
*AST↓, The in vivo results showed that HS15-BA micelles significantly inhibited the activity of the CCl4-induced liver injury marker enzymes aspartate transaminase (AST) and alanine transaminase (ALT).
*ALAT↓,
*GSH↓, leading to increased L-glutathione (GSH) and superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) activity, while HS15-BA significantly reversed the above changes.
*SOD↓,
*MDA↓,
*hepatoP↑, BA also had a hepatoprotective effect through anti-inflammatory activity;
*Inflam↓,
BioAv↑, In summary, our study confirmed that HS15-BA micelles enhanced the bioavailability of BA, and showed hepatoprotective effects through antioxidant and anti-inflammatory activities.

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↑,

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↓,

739- Bor,    Borax regulates iron chaperone- and autophagy-mediated ferroptosis pathway in glioblastoma cells
- in-vitro, GBM, U87MG - in-vitro, Nor, HMC3
TumCG↓,
TumCP↓,
TumCCA↑, remarkably reduced S phase in the U87-MG cells (opposite on normal cells)
PCBP1↓,
GSH↓,
GPx4↓,
Beclin-1↑,
MDA↑,
ACSL4↑,
Casp3↑,
Casp7↑,
Ferroptosis↑,
*toxicity↓, exhibited selectivity by having an opposite effect on normal cells (HMC3).

738- Bor,    Borax induces ferroptosis of glioblastoma by targeting HSPA5/NRF2/GPx4/GSH pathways
- in-vitro, GBM, U251 - in-vitro, GBM, A172 - in-vitro, Nor, SVGp12
TumCP↓,
GPx4↓, borax treatment decreased GPx4, GSH, HSPA5 and NRF2 levels in U251 and A172 cells while increasing MDA levels and caspase‐3/7 activity.
GSH↓,
HSP70/HSPA5↓,
NRF2↓,
MDA↑,
Casp3↑,
Casp7↑,
Ferroptosis↑, Consequently, borax may induce ferroptosis in GBM cells
selectivity↑, Treating SVG cells with borax concentrations ranging from 0 to 800 μM for 24 h did not result in a significant reduction in viability compared to the control group

729- Bor,    Promising potential of boron compounds against Glioblastoma: In Vitro antioxidant, anti-inflammatory and anticancer studies
- in-vitro, GBM, U87MG - in-vivo, Nor, HaCaT
TOS↑,
TumCG↓,
MDA↑,
SOD↑,
Catalase↑,
TAC↓,
GSH↓,
BRAF↑,
MAPK↓,
PTEN↓, BA application was found more favorable because of its inhibitory effect on PIK3CA, PIK3R1, PTEN and RAF1 genes
Raf↓, RAF1
*toxicity↓, We verified the selectivity of the compounds using a normal cell line, HaCaT and found an exact opposite condition after treating HaCaT cells with BA and BX

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↓,

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

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

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,

2786- CHr,    Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives
- Review, Var, NA
Apoptosis↑, chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells
TumCCA↑,
angioG↓,
TumCI↓,
TumMeta↑,
*toxicity↓,
selectivity↑,
chemoPv↑, Induction of phase II detoxification enzymes, such as glutathione S-transferase (GST) or NAD(P)H:quinone oxidoreductase (QR) is one of the major mechanism of protection against initiation of carcinogenesis
*GSTs↑,
*NADPH↑,
*GSH↑, upregulation of antioxidant and carcinogen detoxification enzymes (glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), GST and QR)
HDAC8↓, inhibits of HDAC8 enzymatic activity
Hif1a↓, Prostate DU145: Inhibits HIF-1a expression through Akt signaling and abrogation of VEGF expression
*ROS↓, chrysin (20 and 40 mg/kg) was shown to exhibit chemopreventive activity by ameliorating oxidative stress and inflammation via NF-kB pathway
*NF-kB↓,
SCF↓, Chrysin has also been reported to have the ability to abolish the stem cell factor (SCF)/c-Kit signaling in human myeloid leukemia cells by preventing the PI3 K pathway
cl‑PARP↑, (PARP) and caspase-3 and concurrently decreasing pro-survival proteins survivin and XIAP
survivin↓,
XIAP↓,
Casp3↑, activation of caspase-3 and -9.
Casp9↑,
GSH↓, chrysin sustains a significant depletion of intracellular GSH concentrations in human NSCLC cells
ChemoSen↑, chrysin potentiates cisplatin toxicity, in part, via synergizing pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and by depleting cellular GSH, an important antioxidant defense
Fenton↑, ability to participate in a fenton type chemical reaction
P21↑, upregulation of p21 independent of p53 status and decrease in cyclin D1, CDK2 protein levels
P53↑,
cycD1/CCND1↓,
CDK2↓,
STAT3↓, chrysin inhibits angiogenesis through inhibition of STAT3 and VEGF release mediated by hypoxia through Akt signaling pathway
VEGF↓,
Akt↓,
NRF2↓, Chrysin treatment significantly reduced nrf2 expression in cells at both the mRNA and protein levels through down-regulation of PI3K-Akt and ERK pathways.

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

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

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.

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

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↓,

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↑,

404- CUR,    Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy
- vitro+vivo, Lung, A549 - vitro+vivo, Lung, H1299
TumAuto↑,
TumCG↓,
TumCP↓,
Iron↑, iron overload
GSH↓, GSH depletion
lipid-P↑, accumulation of intracellular iron and lipid‐reactive oxygen species (ROS), lipid peroxidation
GPx↓, GPX4
mtDam↑, mitochondrial membrane rupture
autolysosome↑,
Beclin-1↑,
LC3s↑,
p62↓,
Ferroptosis↑, via activating autophagy

406- CUR,    Effect of curcumin on normal and tumor cells: Role of glutathione and bcl-2
- in-vitro, BC, MCF-7 - in-vitro, Hepat, HepG2
GSH↓, depletion
Apoptosis↑,
Bcl-2↓, but not HepG2 cells
cMyc↓,

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

409- CUR,    Curcumin Inhibits Glyoxalase 1—A Possible Link to Its Anti-Inflammatory and Anti-Tumor Activity
- in-vitro, Pca, PC3 - in-vitro, BC, MDA-MB-231
GLO-I↓,
GSH↓, 50uM
ATP↓, mostly >50uM

481- CUR,  CHr,  Api,    Flavonoid-induced glutathione depletion: Potential implications for cancer treatment
- in-vitro, Liver, A549 - in-vitro, Pca, PC3 - in-vitro, AML, HL-60
GSH↓, depletion
mtDam↑, mitochondrial dysfunction
MMP↓,
Cyt‑c↑,

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↑,

167- CUR,    Curcumin-induced apoptosis in PC3 prostate carcinoma cells is caspase-independent and involves cellular ceramide accumulation and damage to mitochondria
- in-vitro, Pca, PC3
MAPK↑,
JNK↑,
Casp3↑, Caspase-3, caspase-8, and caspase-9 were activated, and cytochrome c and apoptosis-inducing factor (AIF) were released from mitochondria following curcumin treatment
Casp8↑,
Casp9↑,
AIF↑, released from mitochondria
GSH↓, Curcumin treatment of PC3 cells caused time- and dose-dependent induction of apoptosis and depletion of cellular reduced glutathione (GSH).
eff↓, Exogenous GSH and its precursor N-acetyl-cysteine, but not ascorbic acid (AA) or ebselen, decreased curcumin accumulation in PC3 cells and also prevented curcumin-induced DNA fragmentation.
Apoptosis↑, Curcumin Triggers Apoptosis in Prostate Cancer Cells
DNAdam↑, curcumin-induced DNA fragmentation in PC3 cells was prevented in the presence of exogenous GSH or NAC.

5188- dietMet,    Dietary methionine links nutrition and metabolism to the efficacy of cancer therapies
- in-vivo, Var, NA
AntiAge↑, dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has anti-aging and anti-obesogenic properties, influences cancer outcome through controlled and reproducible changes to one-carbon metabolism.
MethCyc↓, MR reduced the levels of methionine-related metabolites within two days, which were sustained throughout the intervention
TumCG↓, MR inhibited tumour growth in CRC119
ChemoSen↑, However, MR synergized with 5-FU treatment, leading to a marked inhibition on tumour growth
RadioS↑, Strikingly, MR with a focal dose of 20 Gy reduced tumour growth and extended the tumour tripling time by 52%
OS↑,
GSH↓, MR reduced NAC and glutathione in all subjects

5191- dietMet,    Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
- in-vitro, Colon, HT29
ChemoSen↑, Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer
RadioS↑,
Ferroptosis↑, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis
eff↑, Intermittent methionine deprivation also sensitizes tumor cells against CD8+ T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation.
eff↑, Lastly, the triple combination of methionine intermittent deprivation, system xc- inhibitor and PD-1 blockade shows superior antitumor efficacy.
GSH↓, CHAC1 induced by cystine deprivation was required to achieve substantial GSH depletion and to ensure ferroptosis onset.
eff↓, Prolonged methionine deprivation prevents GSH depletion from exceeding the ferroptosis threshold

1896- dietMet,    Dietary methionine links nutrition and metabolism to the efficacy of cancer therapies
- in-vivo, CRC, NA
TumCG↓, Dietary MR rapidly and specifically alters methionine and sulfur metabolism and inhibits tumour growth in colorectal patient-derived xenograft (PDX) models
*GSH↓, MR reduced NAC and glutathione in all subjects
RadioS↑, Strikingly, MR with a focal dose of 20 Gy reduced tumour growth
eff↑, MR synergized with 5-FU treatment, leading to a marked inhibition on tumour growth

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

2269- dietMet,    Mechanisms of Increased In Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice
- in-vivo, Nor, NA
*adiP↑, metabolic responses include reduced adiposity, reduced circulating and tissue lipid levels, increased plasma adiponectin and fibroblast growth factor 21 (FGF-21), and reduced fasting insulin and blood glucose
*FGF↑,
*Insulin↓,
*glucose↓,
*Akt↑, activation of Akt was significantly higher in methionine-restricted HepG2 cells
*GSH↓, MR produces a significant decrease in hepatic GSH
*PTEN↓, MR in HepG2 cells limits the capacity of the cells to reactivate oxidized PTEN, resulting in amplification of insulin activation of Akt by increasing PIP3.
*FGF21↑, MR produced a threefold increase in FGF-21 mRNA that was mirrored by a fourfold increase in serum FGF-21.
*PIP3↑,

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↑,

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

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↓,

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.

5047- erastin,    The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells
- in-vitro, Ovarian, NA
xCT↓, erastin was reported to target and inhibit system xc−, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death.
GSH↓,
Ferroptosis↑,
ChemoSen↑, More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic effects of cisplatin to efficiently eradicate tumor cells.
eff↑, only a very short pre-treatment of erastin suffices to synergize with cisplatin to efficiently induce cancer cell death

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

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

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↑,

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

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

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.

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

2587- LT,    Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
- in-vitro, Lung, A549
NRF2↓, luteolin elicited a dramatic reduction in Nrf2 at both the mRNA and the protein levels, leading to decreased Nrf2 binding to AREs, down-regulation of ARE-driven genes, and depletion of reduced glutathione.
GSH↓,
ChemoSen↑, luteolin significantly sensitized A549 cells to the anticancer drugs oxaliplatin, bleomycin, and doxorubicin.
HO-1↓, ↓HO-1

2588- LT,  Chemo,    Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway
- in-vitro, CRC, HCT116
NRF2↓, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner.
NQO1↓, Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GSTα1/2] expression and decreased reduced glutathione in wild type mouse small intestinal cells.
HO-1↓,
GSH↓,
ChemoSen↑, uteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect.

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

1275- LT,    Mechanism of luteolin induces ferroptosis in nasopharyngeal carcinoma cells
- in-vitro, Laryn, NA
Ferroptosis↑,
MDA↑,
Iron↑,
SOD↓,
GSH↓,
GPx4↓,
SOX4↓,
GDF15↓,

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↑,

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↓,

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)

1273- Myr,    Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4
- vitro+vivo, GC, NA
Ferroptosis↑, (iron and ROS are critical for ferroptosis)
MDA↑,
Iron↑,
GSH↓,
NOX4↑, increased NOX4 expression in tumor tissue (is an enzyme that produces reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂).)
NRF2↓,
GPx4↓,

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

1679- PBG,    Constituents of Propolis: Chrysin, Caffeic Acid, p-Coumaric Acid, and Ferulic Acid Induce PRODH/POX-Dependent Apoptosis in Human Tongue Squamous Cell Carcinoma Cell (CAL-27)
- in-vitro, SCC, CAL27
tumCV↓,
P53↑, Selected Polyphenols Activate p53, PRODH/POX, Caspase 9 and 3 in CAL-27 Cell Line
Casp9↑,
Casp3↑,
GSH↓, chrysin (5 μg/mL), caffeic acid (65 μg/mL), ferulic acid (50 μg/mL), and p-coumaric acid (70 μg/mL). The obtained outcomes revealed a significant decrease in cellular GSH
proline↓, significant decrease in the intracellular proline concentration in case of CAL-27 cells treated with all studied polyphenols

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↑,

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

4964- PEITC,    Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical
- in-vitro, Var, NA
GSH↓, . The primary route of isothiocyanate metabolism is its conjugation with glutathione (GSH), a reaction catalyzed by glutathione S-transferase (GST).
GSTA1↓,
chemoPv↑, a Dietary Cancer Chemopreventive Phytochemical

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

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.

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

5217- PG,    Role of redox signaling regulation in propyl gallate-induced apoptosis of human leukemia cells
- in-vitro, AML, THP1 - in-vitro, AML, Jurkat - in-vitro, AML, HL-60
tumCV↓, PG reduced cell viability in THP-1, Jurkat, and HL-60 leukemia cells and induced apoptosis in THP-1 cells.
Casp3↑, PG activated caspases 3, 8, and 9 and increased the levels of p53, Bax, Fas, and Fas ligand
Casp8↑,
Casp9↑,
P53↑,
BAX↑,
Fas↑,
FasL↑,
MAPK↑, PG activated mitogen-activated protein kinases (MAPKs), inhibited nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and induced intracellular glutathione (GSH) depletion.
NRF2↓,
GSH↓,

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

1772- PG,    Propyl gallate decreases the proliferation of Calu-6 and A549 lung cancer cells via affecting reactive oxygen species and glutathione levels
- in-vitro, Lung, Calu-6 - in-vitro, Lung, A549
ROS⇅, PG either increased or decreased ROS levels, including O2˙− and ˙OH, depending on the incubation doses and times of 1 or 24 h.
TumCP↓, PG dose-dependently decreased the proliferation of Calu-6 and A549 lung cancer cells, which was related to changes in ROS levels and the depletion of GSH.
GSH↓,

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.

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).

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

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.

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

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

2948- PL,    The promising potential of piperlongumine as an emerging therapeutics for cancer
- Review, Var, NA
tumCV↓, inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases,
TumCP↓,
TumCI↓,
angioG↓,
EMT↓,
TumMeta↓,
*hepatoP↑, A study demonstrated the hepatoprotective effects of P. longum via decreasing the rate of lipid peroxidation and increasing glutathione (GSH) levels
*lipid-P↓,
*GSH↑,
cardioP↑, cardioprotective effect
CycB/CCNB1↓, downregulated the mRNA expression of the cell cycle regulatory genes such as cyclin B1, cyclin D1, cyclin-dependent kinases (CDK)-1, CDK4, CDK6, and proliferating cell nuclear antigen (PCNA)
cycD1/CCND1↓,
CDK2↓,
CDK1↓,
CDK4↓,
CDK6↓,
PCNA↓,
Akt↓, suppression of the Akt/mTOR pathway by PL was also associated with the partial inhibition of glycolysis
mTOR↓,
Glycolysis↓,
NF-kB↓, Suppression of the NF-κB signaling pathway and its related genes by PL was reported in different cancers
IKKα↓, inactivation of the inhibitor of NF-κB kinase subunit beta (IKKβ)
JAK1↓, PL efficiently inhibited cell proliferation, invasion, and migration by blocking the JAK1,2/STAT3 signaling pathway
JAK2↓,
STAT3↓,
ERK↓, PL also negatively regulates ERK1/2 signaling pathways, thereby suppressing the level of c-Fos in CRC cells
cFos↓,
Slug↓, PL was found to downregulate slug and upregulate E-cadherin and inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells
E-cadherin↑,
TOP2↓, ↓topoisomerase II, ↑p53, ↑p21, ↓Bcl-2, ↑Bax, ↑Cyt C, ↑caspase-3, ↑caspase-7, ↑caspase-8
P53↑,
P21↑,
Bcl-2↓,
BAX↑,
Casp3↑,
Casp7↑,
Casp8↑,
p‑HER2/EBBR2↓, ↓p-HER1, ↓p-HER2, ↓p-HER3
HO-1↑, ↑Apoptosis, ↑HO-1, ↑Nrf2
NRF2↑,
BIM↑, ↑BIM, ↑cleaved caspase-9 and caspase-3, ↓p-FOXO3A, ↓p-Akt
p‑FOXO3↓,
Sp1/3/4↓, ↑apoptosis, ↑ROS, ↓Sp1, ↓Sp3, ↓Sp4, ↓cMyc, ↓EGFR, ↓survivin, ↓cMET
cMyc↓,
EGFR↓,
survivin↓,
cMET↓,
NQO1↑, G2/M phase arrest, ↑apoptosis, ↑ROS, ↓p-Akt, ↑Bad, ↓Bcl-2, ↑NQO1, ↑HO-1, ↑SOD2, ↑p21, ↑p-ERK, ↑p-JNK,
SOD2↑,
TrxR↓, G2/M cell cycle arrest, ↑apoptosis, ↑ROS, ↓GSH, ↓TrxR
MDM2↓, ↑ROS, ↓MDM-2, ↓cyclin B1, ↓Cdc2, G2/M phase arrest, ↑p-eIF2α, ↑ATF4, KATO III ↑CHOP, ↑apoptosis
p‑eIF2α↑,
ATF4↑,
CHOP↑,
MDA↑, ↑ROS, ↓TrxR1, ↑cleaved caspase-3, ↑CHOP, ↑MDA
Ki-67↓, ↓Ki-67, ↓MMP-9, ↓Twist,
MMP9↓,
Twist↓,
SOX2↓, ↓SOX2, ↓NANOG, ↓Oct-4, ↑E-cadherin, ↑CK18, ↓N-cadherin, ↓vimentin, ↓snail, ↓slug
Nanog↓,
OCT4↓,
N-cadherin↓,
Vim↓,
Snail↓,
TumW↓, ↓Tumor weight, ↓tumor growth
TumCG↓,
HK2↓, ↓HK2
RB1↓, ↓Rb
IL6↓, ↓IL-6, ↓IL-8,
IL8↓,
SOD1↑, ↑SOD1
RadioS↑, ombination with PL, very low intensity of radiation is found to be effective in cancer cells
ChemoSen↑, PL as a chemosensitizer which sensitized the cancer cells towards the commercially available chemotherapeutics
toxicity↓, PL does not have any adverse effect on the normal functioning of the liver and kidney.
Sp1/3/4↓, In vitro SKBR3 ↓Sp1, ↓Sp3, ↓Sp4
GSH↓, In vitro MCF-7 ↓CDK1, G2/M phase arrest ↓CDK4, ↓CDK6, ↓PCNA, ↓p-CDK1, ↑cyclin B1, ↑ROS, ↓GSH, ↓p-IκBα,
SOD↑, In vitro PANC-1, MIA PaCa-2 ↑ROS, ↑SOD1, ↑GSTP1, ↑HO-1

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,

2951- PL,  AF,    Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells
- in-vitro, GBM, U87MG
GSH↓, natural product piperlongumine (PPL) inhibit the GSH system.
eff↑, subsequent efficacy of PLL in combination with Au within a nanomolar range in GSCs. Auranofin (Au), a known TrxR1 inhibitor
GSTP1/GSTπ↓, PPL is a natural alkaloid found in the plant Piper longum Linn that directly inhibits GSTP-1 and exhibits anti-cancer properties

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↓,

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

2955- PL,    Heme Oxygenase-1 Determines the Differential Response of Breast Cancer and Normal Cells to Piperlongumine
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
ROS?, Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells.
*ROS∅,
other⇅, opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1)
HO-1↑, Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells.
*HO-1↑,
NRF2↑, piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species.
Keap1↓, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1)
cl‑PARP↑, Following piperlongumine treatment, cleaved PARP levels increased in time- (Fig. 1D) and dose-dependent
selectivity↑, These data clearly show that piperlongumine has a cancer cell-selective killing effect
GSH↓, piperlongumine can selectively decrease the level of reduced GSH and increase the level of oxidized GSSG, leading to ROS accumulation and subsequent apoptosis in cancer cells
GSSG↑, we observed piperlongumine-mediated depletion of GSH, a reduction in the GSH/GSSG ratio and accumulation of intracellular ROS in MCF-7 cells but not in MCF-10A cells

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

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

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

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

38- QC,    Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
ROS⇅, LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment.
GSH↓,
PI3K/Akt⇅, DU-145↓, PC3↑

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

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

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↓,

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. ****

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 ****

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↓,

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↓,

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

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

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

5045- SAS,    Sulfasalazine, a potent cystine-glutamate transporter inhibitor, enhances osteogenic differentiation of canine adipose-derived stem cells
- in-vivo, Var, NA
xCT↓, Sulfasalazine (SSZ), a drug used to treat rheumatoid arthritis, suppresses xCT expression in cancer cells.
GSH↓, this treatment decreased the intracellular glutathione concentration.
BMPs↑, significantly increased alizarin red staining and its quantification, as well as the concentration-dependent osteogenic differentiation markers (BMP1 and SPP) mRNA expression.
Diff↑, SSZ treatment of CADSCs increased the efficiency of osteogenic differentiation induction in vitro.

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).

5040- SAS,    Structure-Activity-Relationship-Aided Design and Synthesis of xCT Antiporter Inhibitors
- in-vitro, GBM, A172 - in-vitro, Melanoma, A375 - in-vitro, GBM, U87MG - in-vitro, BC, MCF-7
GSH↓, Depletion of glutathione levels varied among the compounds as well as among the cell lines.
toxicity↓, demonstrated minimal toxicity in normal human astrocytes
xCT↓, Sulfasalazine was previously reported to be an efficient inhibitor of the xCT antiporte

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

5036- SAS,    Targeting xCT with sulfasalazine suppresses triple-negative breast cancer growth via inducing autophagy and coordinating cell cycle and proliferation
- vitro+vivo, BC, MDA-MB-231 - in-vitro, BC, MDA-MB-468
xCT↓, we demonstrated that sulfasalazine (SAS), like erastin (a known xCT inhibitor), effectively suppressed the expression and transport function of xCT, resulting in a depletion of glutathione levels in MDA-MB-231 and MDA-MB-468 cells.
GSH↓,
OS↑, We unveiled a positive correlation between xCT and the autophagy-related molecule p62, their co-expression indicating poor survival outcomes in breast cancer patients.
Myc↓, Treatment with SAS or xCT knockdown led to the inhibition of MYC, CDK1, and CD44 expression.
CDK1↓,
CD44↓,
eff↑, Significantly, the combined administration of SAS and rapamycin exhibited a synergistic inhibitory effect on the growth of transplanted breast tumor in mouse models constructed from murine-derived 4T1 cells.
TumCG↓,

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.

4715- Se,    The Interaction of Selenium with Chemotherapy and Radiation on Normal and Malignant Human Mononuclear Blood Cells
chemoP↑, Selenium, a trace element with anticancer properties, can reduce harmful toxicities of chemotherapy and radiotherapy without compromising efficacy.
radioP↑,
selectivity↑, MSA, at lower concentrations, induced protective responses in normal cells but cytotoxic effects in malignant cells, alone and in conjunction with chemotherapy or radiation.
ChemoSen↑, potentially improve efficacy of anticancer treatments.
GSH↓, Furthermore, the depletion of GSH by MSA in malignant THP1 cells was still significantly reduced at 24 h after radiation and chemotherapy treatment, again without the advantage of higher MSA concentrations
*GSH↑, The GSH increase in normal PBMCs was maintained at 24 h when cells were also treated with 2 Gy radiation, cytosine arabinoside (AraC) or doxorubicin (Dox), though the maximum benefit was achieved with 2.5 µM MSA
*DNAdam↓, MSA Reduces DNA Damage in Normal Cells While Increasing DNA Damage in Malignant Cells
DNAdam↑,
eff↑, The simultaneous increase in GSH in normal cells and depletion of GSH in malignant cells may contribute to improving the therapeutic ratio of cancer treatment by reducing normal tissue toxicities while increasing the anticancer efficacy.

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,

2167- SFN,    The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice
- in-vitro, PC, MIA PaCa-2 - in-vitro, PC, PANC1
Casp8↑, activation of caspase-8, loss of mitochondrial membrane potential, and loss of plasma membrane integrity
MMP↓,
Casp3↑, Incubations at higher sulforaphane doses (>10 micromol/L) resulted in cleavage of caspase-3 in the G(1) subpopulation, suggesting that the induction of apoptosis
Apoptosis↑,
GSH↓, PANC-1, was positively correlated with a decrease in cellular glutathione levels,
GSH↑, whereas sustained increases in glutathione observed in MIA PaCa-2 cells

1501- SFN,    The Inhibitory Effect of Sulforaphane on Bladder Cancer Cell Depends on GSH Depletion-Induced by Nrf2 Translocation
- in-vitro, CRC, T24/HTB-9
Dose↝, SFN (2.5 µM) was shown to promote cell proliferation (5.18–11.84%) and migration in T24 cells, whilst high doses of SFN (>10 µM) inhibited cell growth significantly.
NRF2↑, induction effect of SFN on Nrf2 expression at both low (2.5 µM) and high dose (10 µM) was characterized by a bell-shaped curve.
GSH↓, highly dependent on Nrf2-mediated GSH depletion and following production. These findings suggested that a higher dose of SFN is required for the prevention and treatment of bladder cancer.
eff↑, GSH-depleting agent L-Buthionine-sulfoximine abolished the effect of SFN on cell proliferation.

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

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

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

3311- SIL,    Silymarin protects against acrylamide-induced neurotoxicity via Nrf2 signalling in PC12 cells
- in-vitro, Nor, PC12
*antiOx↑, Silymarin (SM) is a well-known antioxidant, anti-inflammatory and anti-cancer compound extracted from the milk thistle.
*Inflam↓,
AntiCan↑,
*ROS↓, SM could reduce ROS and MDA levels and increase GSH levels in AA-induced PC12 cells.
*MDA↓,
*GSH↓,
*NRF2↑, SM could activate Nrf2 signalling and increase the expression of Nrf2, Gpx, GCLC and GCLM in AA-treated PC12 cells.
*GPx↑,
*GCLC↑,
*GCLM↑,

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

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

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.

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↑,

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

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↓,

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↓,

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.

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.

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↓,

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

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

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

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.

5330- TFdiG,  Cisplatin,    Theaflavin-3,3′-Digallate Enhances the Inhibitory Effect of Cisplatin by Regulating the Copper Transporter 1 and Glutathione in Human Ovarian Cancer Cells
- in-vitro, Ovarian, A2780S - in-vitro, Ovarian, OVCAR-3
selectivity↑, Theaflavin-3,3′-digallate (TF3), a black tea polyphenol, showed less cytotoxicity to normal ovarian cells than ovarian cancer cells.
ChemoSen↑, In the present study, combined treatment with TF3 and cisplatin showed a synergistic cytotoxicity against A2780/CP70 and OVCAR3 cells.
DNAdam↑, enhanced DNA damage induced by cisplatin in both cells.
GSH↓, Treatment with TF3 decreased the glutathione (GSH) levels and upregulated the protein levels of the copper transporter 1 (CTR1) in both cells, which led to the enhanced sensitivity of both ovarian cancer cells to cisplatin.
CTR1↑,

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

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.

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).

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

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

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

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

1215- VitC,  immuno,    Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma
- ex-vivo, HCC, NA - in-vivo, HCC, NA
other↓, AA in vivo experiments demonstrated a reduction in liver injury in mice
*GPx4↑,
*GSH↑,
GPx4↓,
GSH↓,
selectivity↑, Based on different the and gpx4 response for normal vs cancer cells

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↓,

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↑,

2592- VitC,    Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line
- in-vitro, CLL, NA
NRF2↓, addition of ascorbic acid to KCL22/SR cells resulted in a decrease in Nrf2-DNA binding and decreases in levels of gamma-GCSl mRNA and GSH.
GSH↓,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 219

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

4-HNE↑, 1,   antiOx↓, 2,   antiOx↑, 2,   antiOx⇅, 1,   ATF3↑, 1,   Catalase↓, 12,   Catalase↑, 2,   compI↓, 1,   Copper↑, 1,   CYP1A1↓, 3,   CYP1A1↑, 1,   CYP2E1↑, 1,   cystine↓, 1,   Fenton↑, 6,   Ferroptosis↓, 2,   Ferroptosis↑, 38,   GPx↓, 11,   GPx↑, 2,   GPx1↓, 1,   GPx4↓, 31,   GPx4↑, 1,   GSH↓, 211,   GSH↑, 1,   mt-GSH↓, 1,   GSH/GSSG↓, 8,   GSR↓, 2,   GSSG↓, 1,   GSSG↑, 5,   GSTA1↓, 1,   GSTP1/GSTπ↓, 2,   GSTs↓, 2,   GSTs↑, 1,   H2O2↑, 11,   mt-H2O2↑, 1,   HO-1↓, 7,   HO-1↑, 8,   HO-1⇅, 1,   Iron↑, 20,   Iron↝, 1,   i-Iron↑, 1,   c-Iron↑, 1,   Keap1↓, 1,   Keap1↑, 1,   lipid-P↑, 26,   lipid-P↝, 1,   MDA↓, 4,   MDA↑, 28,   NADPH/NADP+↓, 1,   NFE2L2↑, 1,   NOX4↑, 1,   NQO1↓, 2,   NQO1↑, 1,   Nrf1↑, 1,   NRF2↓, 19,   NRF2↑, 12,   NRF2⇅, 1,   OXPHOS↓, 1,   mt-OXPHOS↓, 2,   Prx4↑, 1,   PYCR1↓, 1,   RNS↓, 1,   ROS?, 1,   ROS↑, 172,   ROS⇅, 3,   mt-ROS↑, 2,   SAM-e↝, 1,   SIRT3↓, 1,   SOD↓, 16,   SOD↑, 4,   SOD1↑, 2,   SOD2↓, 1,   SOD2↑, 1,   T-SOD↓, 1,   TAC↓, 1,   TBARS↑, 2,   Thiols↓, 6,   i-Thiols↓, 1,   TOS↑, 1,   Trx↓, 4,   Trx1↓, 1,   Trx2↓, 1,   TrxR↓, 10,   TrxR1?, 1,   TrxR1↓, 1,   VitC↓, 1,   VitE↓, 1,   xCT↓, 18,   xCT↑, 1,  

Metal & Cofactor Biology ⓘ

Ferritin↓, 1,   Ferritin↑, 1,   FTH1↓, 5,   FTH1↑, 1,   FTL↑, 1,   NCOA4↑, 3,   Zn2+↑, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 5,   ATP↓, 17,   compIII↓, 1,   EGF↓, 1,   ETC↓, 1,   FGFR1↓, 1,   p‑MEK↓, 1,   mitResp↓, 5,   MMP?, 1,   MMP↓, 50,   MMP↑, 1,   MPT↑, 1,   mtDam↑, 10,   OCR↓, 2,   Raf↓, 2,   SDH↓, 1,   XIAP↓, 8,  

Core Metabolism/Glycolysis ⓘ

Ac-histone H3↑, 1,   ACSL4↑, 2,   AMPK↑, 2,   CAIX↓, 1,   cMyc↓, 9,   CYP3A4↓, 2,   ECAR↓, 1,   ENO1↓, 1,   FAO↓, 1,   G6PD↓, 1,   GAPDH↓, 3,   GLO-I↓, 1,   GLS↓, 1,   GlucoseCon↓, 1,   GlutaM↓, 1,   GlutMet↓, 1,   Glycolysis↓, 17,   ac‑Histones↑, 1,   HK2↓, 10,   lactateProd↓, 2,   LDH↓, 6,   LDH↑, 1,   LDL↓, 1,   MethCyc↓, 1,   NAD↝, 1,   NADPH↓, 3,   PDH↓, 1,   PFKP↓, 2,   PI3K/Akt↓, 1,   PI3K/Akt⇅, 1,   PI3K/Akt↝, 1,   PKM2↓, 4,   PPP↓, 1,   PPP↑, 1,   Pyruv↓, 1,   RNR↓, 1,   SIRT1↓, 1,   SIRT1↑, 1,   SIRT2↑, 1,   TCA↓, 1,   Warburg↓, 1,  

Cell Death ⓘ

Akt↓, 18,   p‑Akt↓, 5,   Apoptosis↓, 2,   Apoptosis↑, 60,   mt-Apoptosis↑, 1,   ASK1↑, 1,   BAD↑, 1,   Bak↑, 1,   BAX↓, 1,   BAX↑, 31,   Bax:Bcl2↑, 7,   Bcl-2↓, 34,   Bcl-xL↓, 5,   BID↑, 2,   BIM↑, 1,   Casp↑, 5,   Casp1↓, 1,   Casp10↑, 1,   Casp12↑, 2,   Casp3↓, 1,   Casp3↑, 44,   cl‑Casp3↓, 1,   cl‑Casp3↑, 4,   cl‑Casp3∅, 1,   proCasp3↑, 2,   Casp6↑, 1,   Casp7↑, 8,   cl‑Casp7↑, 1,   Casp8↑, 11,   cl‑Casp8↑, 1,   Casp9↑, 24,   cl‑Casp9↓, 1,   cl‑Casp9↑, 2,   proCasp9↑, 1,   cFLIP↓, 2,   Chk2↑, 1,   CK2↓, 1,   Cyt‑c↑, 30,   Diablo↑, 1,   DR4↑, 1,   DR5↑, 5,   Fas↑, 7,   FasL↑, 2,   Ferroptosis↓, 2,   Ferroptosis↑, 38,   HGF/c-Met↓, 1,   IAP1↓, 1,   IAP2↓, 1,   iNOS↓, 3,   JNK↑, 7,   p‑JNK↑, 2,   MAPK↓, 3,   MAPK↑, 8,   MAPK↝, 1,   p‑MAPK↑, 1,   Mcl-1↓, 4,   MDM2↓, 2,   p‑MDM2↓, 1,   MOMP↑, 1,   Myc↓, 1,   Necroptosis↑, 2,   necrosis↑, 2,   p27↑, 3,   p38↑, 9,   p‑p38↑, 2,   PUMA↑, 2,   RIP1↑, 3,   survivin↓, 11,   Telomerase↓, 2,   TNFR 1↑, 1,   TRAIL↑, 1,   TRAILR↑, 1,   TumCD↓, 1,   TumCD↑, 8,  

Kinase & Signal Transduction ⓘ

AMPKα↑, 3,   CaMKII ↓, 1,   HER2/EBBR2↓, 1,   p‑HER2/EBBR2↓, 1,   SOX9↓, 1,   Sp1/3/4↓, 5,  

Transcription & Epigenetics ⓘ

H3↓, 1,   H4↓, 1,   other↓, 3,   other↑, 2,   other⇅, 1,   other↝, 3,   p‑pRB↓, 1,   sonoS↑, 1,   tumCV↓, 15,   USF1↑, 1,  

Protein Folding & ER Stress ⓘ

ATF6↑, 3,   ATFs↑, 1,   CHOP↑, 11,   eIF2α↑, 2,   p‑eIF2α↑, 3,   ER Stress↑, 15,   GRP78/BiP↑, 5,   HSP27↓, 1,   HSP70/HSPA5↓, 1,   HSP70/HSPA5↑, 2,   HSP90↓, 1,   IRE1↑, 1,   PERK↑, 4,   UPR↑, 2,   XBP-1↑, 1,  

Autophagy & Lysosomes ⓘ

autolysosome↑, 1,   Beclin-1↑, 2,   p‑Beclin-1↑, 1,   BNIP3↝, 1,   LC3‑Ⅱ/LC3‑Ⅰ↑, 2,   LC3A↑, 1,   LC3B↑, 1,   LC3II↑, 4,   LC3s↑, 1,   p62↓, 4,   p62↑, 2,   TumAuto↑, 10,  

DNA Damage & Repair ⓘ

ATM↑, 1,   CHK1↓, 1,   DFF45↑, 1,   DNAdam↑, 23,   mt-DNAdam↑, 1,   DNArepair↓, 1,   DNMT1↑, 1,   GADD45A↑, 2,   p16↑, 1,   P53↑, 26,   PARP↓, 1,   PARP↑, 1,   cl‑PARP↑, 14,   cl‑PARP∅, 1,   PCNA↓, 6,   SIRT6↓, 1,   γH2AX↑, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 4,   CDK2↓, 4,   CDK4↓, 6,   Cyc↓, 2,   CycB/CCNB1↓, 4,   cycD1/CCND1↓, 10,   cycE/CCNE↓, 1,   P21↓, 1,   P21↑, 15,   RB1↓, 1,   RB1↑, 1,   p‑RB1↓, 1,   TumCCA↓, 1,   TumCCA↑, 42,  

Proliferation, Differentiation & Cell State ⓘ

ALDH↓, 2,   BRAF↑, 1,   BRAF↝, 1,   CD133↓, 1,   CD34↓, 1,   CD44↓, 2,   cFos↓, 1,   cFos↑, 1,   cMET↓, 1,   CSCs↓, 7,   Diff↑, 2,   EMT↓, 14,   EMT↑, 1,   EP4↑, 1,   ERK↓, 8,   ERK↑, 3,   p‑ERK↓, 1,   p‑ERK↑, 1,   FOSL1↑, 1,   FOXM1↓, 1,   FOXO3↑, 3,   p‑FOXO3↓, 1,   GDF15↓, 1,   GSK‐3β↓, 4,   GSK‐3β↑, 2,   p‑GSK‐3β↓, 1,   HDAC↓, 6,   HDAC1↓, 2,   HDAC8↓, 1,   IGF-1↓, 1,   MAP2K1/MEK1↓, 1,   miR-34a↑, 1,   mTOR↓, 12,   p‑mTOR↓, 3,   mTORC2↓, 1,   Nanog↓, 3,   NOTCH1↓, 5,   OCT4↓, 3,   P70S6K↓, 1,   PI3K↓, 8,   PI3K↑, 1,   p‑PI3K↓, 1,   PTEN↓, 2,   PTEN↑, 2,   PTEN↝, 1,   RAS↓, 1,   SCF↓, 1,   SOX2↓, 2,   p‑Src↓, 1,   STAT↓, 1,   STAT1↓, 1,   STAT3↓, 10,   p‑STAT3↓, 4,   STAT6↓, 2,   p‑STAT6↓, 1,   TCF-4↓, 1,   TOP1∅, 1,   TOP2↓, 1,   TumCG↓, 38,   Wnt↓, 3,   Zn2+↑, 1,  

Migration ⓘ

AntiAg↑, 1,   AP-1↓, 1,   AXL↓, 1,   BACH1↑, 1,   Ca+2↓, 2,   Ca+2↑, 6,   Ca+2↝, 1,   CAFs/TAFs↓, 1,   CD11b↑, 1,   Cdc42↓, 1,   CEA↓, 1,   CLDN1↓, 2,   COL1↓, 1,   COL3A1↓, 1,   E-cadherin↓, 2,   E-cadherin↑, 5,   F-actin↓, 1,   FAK↓, 2,   p‑FAK↓, 1,   ITGB1↓, 2,   ITGB6↓, 1,   Ki-67↓, 5,   LEF1↓, 2,   MET↓, 1,   p‑MET↓, 1,   MMP13↓, 2,   MMP2↓, 13,   MMP3↓, 1,   MMP7↓, 1,   MMP9↓, 14,   MMPs↓, 3,   N-cadherin↓, 5,   PCBP1↓, 1,   PKCδ↓, 2,   proline↓, 1,   Rac1↓, 1,   RAGE↓, 1,   Rho↓, 1,   RIP3↑, 3,   ROCK1↓, 1,   Slug↓, 4,   SMAD2↓, 1,   Snail↓, 5,   SOX4↓, 1,   SOX4↑, 1,   TGF-β↓, 1,   TSP-1↑, 1,   TumCA↑, 1,   TumCI↓, 16,   TumCMig↓, 15,   TumCMig↑, 1,   TumCP↓, 34,   TumMeta↓, 9,   TumMeta↑, 1,   TumPF↓, 1,   Twist↓, 3,   Tyro3↓, 1,   uPA↓, 1,   Vim↓, 7,   Vim↑, 1,   Zeb1↓, 2,   ZO-1↓, 1,   ZO-1↑, 1,   β-catenin/ZEB1↓, 8,  

Angiogenesis & Vasculature ⓘ

angioG↓, 17,   ATF4↑, 5,   ATF4↝, 1,   EGFR↓, 5,   EGFR↑, 1,   EGR1↑, 1,   HIF-1↓, 1,   HIF-1↑, 1,   Hif1a↓, 9,   LOX1↓, 1,   NO↓, 2,   NO↑, 6,   REL↑, 1,   TAMS↝, 1,   VEGF↓, 14,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

CTR1↑, 1,   GLUT1↓, 2,   P-gp↓, 6,   SLC12A5↓, 1,  

Immune & Inflammatory Signaling ⓘ

ASC↓, 1,   CD14↑, 1,   COX2↓, 8,   COX2↑, 1,   CXCR4↓, 3,   HMGB1↓, 1,   ICAM-1↓, 2,   IFN-γ↓, 3,   IKKα↓, 4,   IKKα↑, 1,   IL1↓, 3,   IL12↑, 1,   IL1β↓, 1,   IL1β↑, 1,   IL2↓, 1,   IL2↑, 2,   IL6↓, 9,   IL8↓, 5,   Imm↑, 1,   Inflam↓, 7,   JAK1↓, 1,   JAK2↓, 2,   NF-kB↓, 21,   NF-kB↑, 1,   p‑NF-kB↓, 1,   NK cell↑, 1,   p65↓, 1,   p‑p65↓, 1,   PD-1↓, 1,   PD-L1↓, 2,   PGE2↓, 1,   PSA↓, 5,   TLR1↑, 1,   TNF-α↓, 6,   TNF-α↑, 2,  

Cellular Microenvironment ⓘ

pH↝, 1,  

Protein Aggregation ⓘ

NLRP3↓, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 5,   CDK6↓, 3,   ERα/ESR1↓, 1,  

Drug Metabolism & Resistance ⓘ

ABC↓, 1,   BioAv↓, 11,   BioAv↑, 5,   BioAv↝, 1,   BioEnh↑, 1,   ChemoSen↑, 38,   CYP1A2↑, 1,   CYP2A3/CYP2A6↓, 1,   Dose↓, 1,   Dose↑, 2,   Dose⇅, 1,   Dose↝, 14,   Dose∅, 2,   eff?, 1,   eff↓, 40,   eff↑, 55,   eff↝, 3,   Half-Life?, 1,   Half-Life↓, 3,   Half-Life↝, 3,   Half-Life∅, 1,   MDR1↓, 2,   MRP1↓, 1,   P450↓, 2,   RadioS↓, 1,   RadioS↑, 16,   selectivity↓, 1,   selectivity↑, 42,  

Clinical Biomarkers ⓘ

AR↓, 5,   BMPs↑, 1,   BP↓, 1,   BRAF↑, 1,   BRAF↝, 1,   CEA↓, 1,   EGFR↓, 5,   EGFR↑, 1,   ERα/ESR1↓, 1,   Ferritin↓, 1,   Ferritin↑, 1,   FOXM1↓, 1,   HER2/EBBR2↓, 1,   p‑HER2/EBBR2↓, 1,   IL6↓, 9,   Ki-67↓, 5,   LDH↓, 6,   LDH↑, 1,   Myc↓, 1,   NSE↓, 1,   PD-L1↓, 2,   PSA↓, 5,   RAGE↓, 1,  

Functional Outcomes ⓘ

AntiAge↑, 1,   AntiCan↑, 18,   AntiTum↑, 2,   cachexia↓, 1,   cardioP↑, 1,   chemoP↑, 7,   chemoPv↑, 5,   ChemoSideEff↓, 1,   cognitive↑, 1,   hepatoP↑, 3,   memory↑, 1,   neuroP↑, 2,   OS↑, 8,   Pain↓, 1,   Pin1↓, 2,   QoL↑, 1,   radioP↑, 1,   RenoP↑, 1,   Risk↓, 1,   toxicity↓, 5,   toxicity↑, 2,   toxicity↝, 1,   TumVol↓, 4,   TumW↓, 5,  

Infection & Microbiome ⓘ

AntiFungal↑, 1,   Bacteria↓, 2,  
Total Targets: 563

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 10,   Catalase↓, 1,   Catalase↑, 4,   Ferroptosis↑, 1,   GCLC↑, 1,   GCLM↑, 1,   GPx↑, 4,   GPx1↑, 1,   GPx4↑, 1,   GSH↓, 11,   GSH↑, 7,   GSSG∅, 1,   GSTA1↓, 1,   GSTs↑, 3,   H2O2↓, 1,   HO-1↑, 5,   Keap1↓, 2,   lipid-P↓, 6,   MDA↓, 4,   MDA↑, 1,   MPO↓, 1,   MPO↑, 1,   NQO1↑, 1,   NRF2↑, 8,   Prx↑, 1,   ROS↓, 13,   ROS↑, 5,   ROS∅, 4,   mt-ROS↓, 1,   SOD↓, 2,   SOD↑, 6,   SOD1↓, 1,   SOD1↑, 1,   SOD2↑, 1,   TBARS↓, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,   Insulin↓, 1,   MMP↓, 1,  

Core Metabolism/Glycolysis ⓘ

adiP↑, 1,   ALAT↓, 3,   FGF21↑, 2,   glucose↓, 1,   GlucoseCon↑, 1,   Glycolysis↑, 1,   H2S↑, 2,   HK2↑, 1,   LDH↓, 2,   NADPH↑, 1,   PFK↑, 1,   PIP3↑, 1,   PKM2↑, 1,   PPARα↑, 1,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   BAX↑, 1,   Bcl-2↓, 1,   Casp3↓, 2,   Casp3↑, 1,   Ferroptosis↑, 1,   iNOS↓, 1,  

Transcription & Epigenetics ⓘ

other↑, 1,   other↝, 1,  

Autophagy & Lysosomes ⓘ

LC3II↑, 1,   p62↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 2,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,   FGF↑, 1,   IGF-1↓, 1,   mTOR↓, 1,   PI3K↓, 1,   PTEN↓, 1,  

Migration ⓘ

MMP11↑, 1,   MMP3↑, 1,   ROCK1↓, 1,   TumCP↓, 1,  

Angiogenesis & Vasculature ⓘ

ATF4↑, 1,   NO↓, 1,   NO↑, 1,  

Barriers & Transport ⓘ

BBB↑, 1,   GLUT4↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL10↑, 1,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 8,   NF-kB↓, 3,   PGE2↓, 1,   TNF-α↓, 2,   TNF-α↑, 1,  

Hormonal & Nuclear Receptors ⓘ

GR↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 3,   BioAv↑, 5,   Dose↝, 2,   eff↓, 2,   eff↑, 2,   Half-Life↓, 1,   Half-Life↝, 3,  

Clinical Biomarkers ⓘ

ALAT↓, 3,   ALP↓, 1,   AST↓, 3,   BP↓, 1,   creat↓, 2,   GutMicro↑, 3,   IL6↓, 1,   LDH↓, 2,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoP↑, 1,   cognitive↑, 2,   hepatoP↑, 4,   memory↑, 1,   neuroP↑, 4,   OS↑, 1,   radioP↑, 2,   toxicity?, 1,   toxicity↓, 12,   toxicity↝, 2,   toxicity∅, 4,   Weight∅, 1,  

Infection & Microbiome ⓘ

Bacteria↓, 1,  
Total Targets: 119

Scientific Paper Hit Count for: GSH, Glutathione
18 Piperlongumine
16 Silver-NanoParticles
12 Phenethyl isothiocyanate
11 Sulfasalazine
11 Shikonin
10 Curcumin
9 Quercetin
8 Artemisinin
8 Selenite (Sodium)
7 3-bromopyruvate
7 Radiotherapy/Radiation
7 diet Methionine-Restricted Diet
6 Allicin (mainly Garlic)
6 Juglone
6 Propyl gallate
6 Sulforaphane (mainly Broccoli)
6 Thymoquinone
5 Boron
5 erastin
4 Apigenin (mainly Parsley)
4 Copper and Cu NanoParticles
4 Luteolin
4 Vitamin C (Ascorbic Acid)
3 Cisplatin
3 Auranofin
3 Ashwagandha(Withaferin A)
3 Baicalein
3 Chrysin
3 Parthenolide
3 Silymarin (Milk Thistle) silibinin
3 Aflavin-3,3′-digallate
2 2-DeoxyGlucose
2 Selenium
1 cetuximab
1 Astragalus
1 Photodynamic Therapy
1 Camptothecin
1 Glucose
1 Andrographis
1 Ascorbyl Palmitate
1 Aloe anthraquinones
1 Berberine
1 Betulinic acid
1 Ras-selective lethal 3
1 Capsaicin
1 chitosan
1 Citric Acid
1 Black phosphorus
1 SonoDynamic Therapy UltraSound
1 Ellagic acid
1 Emodin
1 Ferulic acid
1 Garcinol
1 Hyperthermia
1 HydroxyTyrosol
1 Chemotherapy
1 Lycopene
1 Melatonin
1 Metformin
1 Magnetic Field Rotating
1 Magnetic Fields
1 Myricetin
1 Naringin
1 Propolis -bee glue
1 Plumbagin
1 Resveratrol
1 Rosmarinic acid
1 salinomycin
1 Scoulerine
1 Selenium NanoParticles
1 Docetaxel
1 Glutathione
1 Gemcitabine (Gemzar)
1 immunotherapy
1 VitK3,menadione
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#:137  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

 

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