Database Query Results : Artemisinin, , ROS

ART/DHA, Artemisinin: Click to Expand ⟱
Features:

Artemisinin — a plant-derived sesquiterpene lactone endoperoxide (from Artemisia annua) best known as the parent scaffold for artemisinin-class antimalarials and widely investigated as a tumor-selective redox/iron-reactive cytotoxic agent. It is a small-molecule natural product (drug-like phytochemical) whose major clinical derivatives include artesunate (water-soluble), artemether/arteether (lipophilic), and the active metabolite dihydroartemisinin (DHA). In oncology literature the abbreviation set commonly includes ART (artemisinin), AS (artesunate), and DHA (dihydroartemisinin); many mechanistic claims are derivative-specific and exposure/iron-context dependent.

Primary mechanisms (ranked):

  1. Iron-dependent activation of the endoperoxide bridge causing ROS/lipid peroxidation stress and tumor-selective cytotoxicity (iron-high contexts)
  2. Ferroptosis sensitization/induction via iron handling and lipid peroxidation programs (often linked to ferritin/lysosome biology; context-dependent)
  3. Mitochondrial dysfunction with ΔΨm loss and intrinsic apoptosis signaling (downstream of oxidative stress)
  4. ER stress / UPR activation (stress-amplification axis)
  5. Hypoxia–metabolism suppression (HIF-1α and glycolysis program attenuation; model-dependent)
  6. Pro-survival inflammatory signaling suppression (e.g., NF-κB / STAT3 axes; model-dependent)

Bioavailability / PK relevance: Oral artemisinin has variable and generally limited systemic exposure with a short half-life on the order of hours; many anticancer in-vitro concentrations exceed typical achievable free-plasma levels without formulation strategies. Artesunate is rapidly converted to DHA; in an FDA label dataset (IV artesunate for severe malaria), artesunate has a very short half-life (~0.3 h) and DHA ~1.3 h, emphasizing exposure-time constraints and the need to interpret “ART/AS/DHA” PK separately.

In-vitro vs systemic exposure relevance: Many reported anticancer effects are driven by oxidative stress at micromolar in-vitro conditions and may be difficult to reproduce systemically without targeted delivery, local administration, or combination strategies that increase intratumoral iron/ROS burden (context-dependent).

Clinical evidence status: Cancer use remains investigational (preclinical-dominant with small/early human studies). Multiple registered clinical studies have evaluated artesunate/derivatives in oncology settings (e.g., phase I solid tumor IV artesunate; small/phase II-style neoadjuvant/adjunct trials), but there is no major regulatory approval for cancer indications; artesunate is approved/used clinically for severe malaria.

Artemisinin a compound in a Chinese herb that may inhibit tumor growth and metastasis Artemisinin (antimalarial drugs)
Artesunic acid (Artesunate) , Dihydroartemisinin (DHA), artesunate, arteether, and artemether, SM735, SM905, SM933, SM934, and SM1044

The induction of OS in tumor cells via the production of ROS is the key mechanism of ART against cancer.
combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.

Summary:
- One of the strongest tumor-selective pro-oxidants, mechanism related with iron. Synergizes with iron-rich tumors
-ROS seems to affect both cancer and normal cells
- Delivery of artemisinin in conjugate form with transferrin or holotransferrin (serum iron transport proteins) have been shown to greatly improve its effectiveness.
- Potential direct inhibitor of STAT3
- Artemisinin synergized with the glycolysis inhibitor 2DG (2-deoxy- D -glucose)
ART Combined Therapy: Allicin, Resveratrol, Curcumin, VitC (but not orally at same time), Butyrate , 2-DG, Aminolevulinic AcidG
-possible problems with liver toxicity??

-Artesunate (ART), an artemisinin compound, is known for lysosomal degradation of ferritin, inducing oxidative stress and promoting cancer cell death.

Pathways:
- Increasing reactive oxygen species (ROS) production. This oxidative stress can cause the loss of mitochondrial membrane potential, leading to cytochrome c release and subsequent activation of caspase cascades.
- Downregulate HIF-1α
- By impairing glycolysis, artemisinin might force cells to rely on oxidative phosphorylation (OXPHOS) for energy production.
- Inhibit GLUT1 (glucose uptake), HK2, PKM2 (slow the glycolytic flux, thereby reducing the energy supply)
- Minimal NRF2 activation

-Artemisinin has a half-life of about 3-4 hours, Artesunate 40 minutes and Artemether 12 hours. Peak plasma levels occur in 1-2 hour.
BioAv 21%, poor-good solubility. Artesunate (ART), a water soluble derivative of artemisinin. concentrations higher in blood, colon, liver, kidney (highly perfused organs)
Pathways:
- induce ROS production, iron dependent (affect both cancer and normal cells)
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Both Lowers (and raises) AntiOxidant defense in Cancer Cells: NRF2↓(contary), SOD↓, GSH↓ Catalase↓ GPx↓
- Small evidence of Raising AntiOxidant defense in Normal Cells: ROS">ROS↓(contary), NRF2↑, SOD↑(contary), GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, ECAR↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓,
- some small indication of inhibiting Cancer Stem Cells : CSC↓, Hh↓, β-catenin↓, sox2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, RadioSensitizer, Others(review target notes),

- Selectivity: Cancer Cells vs Normal Cells
Often synergistic with ROS-based chemo

Artemisinin-class (ART/AS/DHA) mechanisms relevant to cancer biology

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Iron-activated endoperoxide chemistry and ROS burden ROS↑, lipid peroxidation↑, macromolecular damage↑ (iron-high contexts) ROS↔ to ↑ (dose-dependent) P Pro-oxidant, tumor-biased cytotoxic stress Core premise: iron availability (labile iron pool, heme/Fe²⁺ context) gates potency and selectivity; derivative and formulation matter.
2 Ferroptosis susceptibility Ferroptosis↑ (context-dependent), lipid-ROS↑ Ferroptosis↔ (context-dependent) R Non-apoptotic death program engagement or sensitization Evidence supports artemisinin-compounds as ferroptosis sensitizers/inducers in multiple models; often tied to iron handling and lipid peroxidation control nodes.
3 Ferritin and lysosome axis Ferritin turnover↑ / lysosomal iron↑ (model-dependent) → ROS↑ ↔ (model-dependent) R Iron mobilization that amplifies oxidative injury DHA/derivatives have been reported to engage ferritin/lysosome-related processes that increase reactive iron, supporting ferroptotic and apoptotic stress amplification.
4 Mitochondria and MPTP ΔΨm↓, mitochondrial ROS↑, Cyt-c release↑, apoptosis↑ Stress responses↔ to ↑ (dose-dependent) R Intrinsic apoptosis downstream of redox injury Mitochondrial impairment is commonly reported as a downstream execution route after ROS/iron activation; can intersect with ferroptosis via redox spillover.
5 ER stress and UPR ER stress↑, UPR↑ ↔ to ↑ (stress-dose dependent) R Proteostasis collapse / stress signaling Often co-occurs with ROS-driven injury; may contribute to growth arrest and death pathway crosstalk.
6 HIF-1α axis HIF-1α↓ (model-dependent) ↔ G Anti-hypoxic adaptation Reported suppression of hypoxia programs may reduce angiogenic and glycolytic adaptation in some tumors.
7 Glycolysis and glucose transport Glycolysis↓, GLUT1/HK2/PKM2↓ (model-dependent) ↔ (context-dependent) G Metabolic constraint Metabolic effects vary by cell state; can synergize with glycolysis inhibitors in model systems.
8 STAT3 axis STAT3↓ (model-dependent) ↔ G Pro-survival transcriptional attenuation Reported in subsets of studies; may contribute to reduced proliferation/survival signaling.
9 NF-κB and inflammatory signaling NF-κB↓, inflammatory cytokine programs↓ (model-dependent) Inflammation↓ (context-dependent) G Anti-inflammatory / pro-differentiation pressure Can be beneficial for tumor microenvironment modulation, but directionality and net effect depend on immune context.
10 NRF2 axis NRF2↔ (model-dependent; adaptive resistance possible) NRF2↔ to ↑ (context-dependent) G Redox adaptation gatekeeper NRF2 status can determine sensitivity vs resistance to ROS/ferroptosis; combinations that blunt NRF2 defenses are often proposed experimentally.
11 Clinical Translation Constraint Short exposure window; achievable concentrations may be below many in-vitro active ranges; heterogeneity in iron/redox state; derivative-specific PK Off-target oxidative stress risk (dose/formulation dependent) G Limits systemic reproducibility Interpret ART vs AS vs DHA separately; artesunate→DHA conversion is rapid and half-lives are short (route-dependent). Targeted delivery and combination strategies are common translational approaches.

TSF legend: P: 0–30 min    R: 30 min–3 hr    G: >3 hr
ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)

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

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

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

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

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

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

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

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




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



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






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






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






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






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






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






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






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






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






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






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






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






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






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






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






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






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






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






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






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






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






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






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






ROS">Piperine
+±[D][F]ROS-secondary






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






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






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






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






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






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






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






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
3388- ART/DHA,    Keap1 Cystenine 151 as a Potential Target for Artemisitene-Induced Nrf2 Activation
- in-vitro, Lung, A549 - in-vitro, Nor, GP-293 - in-vitro, BC, MDA-MB-231
NRF2↑, ATT upregulated Nrf2 in the MB231 cells . ATT increased Nrf2 levels at low doses ranging from 1 to 5 μM
ROS∅, ATT does not increase ROS production and cannot active Nrf2 by inducing oxidative stress

3666- ART/DHA,    Artemisinin Attenuates Amyloid-Induced Brain Inflammation and Memory Impairments by Modulating TLR4/NF-κB Signaling
- NA, AD, NA
*Inflam↓, Artemisinin has potent anti-inflammatory and immune activities.
*neuroP↑, Artemisinin inhibited neuroinflammation and exerted neuroprotective effects by regulating the Toll-like receptor 4 (TLR4)/Nuclear factor-kappa B (NF-κB) signaling pathway.
*TLR4↓,
*NF-kB↓,
*memory↑, reversing spatial learning and memory deficits.
*ROS↓, Artemisinin Decreased the Production of ROS and iNOS in BV2 Cells
*iNOS↓,
*COX2↓, Artemisinin treatment decreased the expression of COX2 and iNOS
*cognitive↑, Artemisinin Improved the Cognitive Impairment of AD Model Mice

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

3393- ART/DHA,    Artemisinin-derived artemisitene blocks ROS-mediated NLRP3 inflammasome and alleviates ulcerative colitis
- in-vivo, Col, NA
*ROS↓, Artemisitene inhibits ROS (especially mtROS) production and NLRP3 inflammasome assembly.
*NLRP3↓,
*Inflam↓, artemisitene significantly attenuated inflammatory response in DSS-induced ulcerative colitis

3392- ART/DHA,    Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways
- in-vitro, Nor, Hep3B - in-vivo, NA, NA
*Inflam↓, anti-inflammatory effects of artemisinin in TPA-induced skin inflammation in mice.
*NF-kB↓, artemisinin significantly inhibited the expression of NF-?B reporter gene induced by TNF-? in a dose-dependent manner
*ROS↓, artemisinin significantly impaired the ROS production and phosphorylation of p38 and ERK,
*p‑p38↓,
*p‑ERK↓,

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

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

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

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

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↑,

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

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

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

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

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

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

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

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

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

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

3667- ART/DHA,    Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia
- Review, Sepsis, NA
*cognitive↑, artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests
*neuroP↑, attenuated neuronal damage and microglial activation in the hippocampus.
*TNF-α↓, artemisinin (40 μΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6)
*IL6↓,
*NF-kB↓, artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway;
*AMPK↑,
*ROS↓, artemisinin protects neuronal HT-22 cells from oxidative injury by activating the Akt pathway
*Akt↑,
*MCP1↓, artemisinin reversed the LPS-induced increases in the chemokines MCP-1 and MIP-2
*MIP2↓,
*TGF-β↑, Artemisinin also significantly increased the mRNA and protein expression of TGF-β
*Inflam↓, The AMPKα1 pathway is involved in the anti-inflammatory effect of artemisinin

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

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

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

4992- ART/DHA,    Dihydroartemisinin Increases the Sensitivity of Acute Myeloid Leukemia Cells to Cytarabine via the Nrf2/HO-1 Anti-Oxidant Signaling Pathway
- in-vitro, AML, HL-60
Apoptosis↑, The combination of Ara-C and DHA synergistically promoted the apoptosis and differentiation of HL-60 cells
Diff↑,
ROS↓, Mechanistically, synergistic cytotoxic effects of Ara-C/DHA on HL-60 cells may be mediated by decreasing intracellular ROS levels
HO-1↓, However, DHA only caused the down-regulation of HO-1, whereas the expression level of nuclear Nrf2 was unaffected.
NRF2∅,

4991- ART/DHA,  doxoR,    Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy
- in-vivo, Nor, H9c2
*cardioP↑, In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes.
*ROS↓,
*Ferroptosis↓,
*NRF2↑,
Keap1↓, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

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

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

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

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

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

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

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

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

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

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

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

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


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 38

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Fenton↑, 3,   Ferroptosis↑, 14,   GPx4↓, 6,   GPx4↑, 1,   GSH↓, 7,   HO-1↓, 1,   Iron↓, 1,   Iron↑, 5,   i-Iron↓, 1,   Keap1↓, 1,   lipid-P↑, 6,   MDA↑, 1,   NRF2↓, 1,   NRF2↑, 4,   NRF2∅, 1,   ROS↓, 1,   ROS↑, 31,   ROS∅, 1,   xCT∅, 1,  

Metal & Cofactor Biology ⓘ

Ferritin↓, 4,   NCOA4↑, 1,   NCOA4↝, 1,   Tf↓, 1,   Tf↑, 1,   TfR1/CD71↓, 1,  

Mitochondria & Bioenergetics ⓘ

ADP:ATP↑, 1,   AIF↑, 1,   ATP↓, 1,   CDC25↓, 1,   MMP↓, 2,   Raf↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACSL4∅, 1,   AMP↓, 1,   AMPK↑, 2,   cMyc↓, 3,   GlucoseCon↓, 3,   Glycolysis↓, 1,   lactateProd↓, 3,   NADPH↓, 1,   PKM2↓, 2,   PPARγ↑, 1,   p‑S6↓, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Akt↓, 3,   Apoptosis↓, 1,   Apoptosis↑, 8,   BAX↑, 4,   Bcl-2↓, 3,   Casp12↑, 1,   Casp3↓, 1,   Casp3↑, 3,   cl‑Casp3↑, 1,   Casp8↑, 2,   Casp9↑, 3,   p‑Chk2↑, 1,   Cyt‑c↑, 5,   DR5↑, 1,   FADD↑, 1,   Fas↑, 1,   Ferroptosis↑, 14,   JNK↓, 1,   JNK↑, 1,   Mcl-1↓, 1,   MDM2↓, 1,   MOMP↑, 2,   Myc↓, 1,   necrosis↑, 2,   oncosis↑, 2,   p27↑, 2,   p38↑, 1,   survivin↓, 3,   YAP/TEAD↓, 1,  

Transcription & Epigenetics ⓘ

other↝, 1,   tumCV↓, 3,  

Protein Folding & ER Stress ⓘ

CHOP↑, 2,   eIF2α↑, 2,   ER Stress↓, 1,   ER Stress↑, 6,   GRP78/BiP↑, 5,   HSP70/HSPA5↓, 1,   HSP70/HSPA5↑, 1,   PERK↑, 2,   UPR↑, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↑, 1,   LC3II↑, 2,   p62↓, 1,   TumAuto↑, 10,  

DNA Damage & Repair ⓘ

p‑ATM↑, 1,   p‑ATR↑, 1,   p‑CHK1↑, 1,   DNAdam↑, 5,   HR↓, 2,   p16↑, 2,   P53↑, 1,   cl‑PARP↑, 2,   PCNA↓, 1,   RAD51↓, 2,  

Cell Cycle & Senescence ⓘ

CDK1↑, 1,   CDK2↓, 2,   CDK2↑, 1,   CDK4↓, 3,   CDK4↑, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 4,   cycE/CCNE↓, 2,   cycE1↓, 1,   E2Fs↓, 1,   P21↑, 1,   TumCCA↑, 7,  

Proliferation, Differentiation & Cell State ⓘ

CD133↓, 1,   CD44↓, 1,   cMET↓, 1,   CREBBP↓, 1,   CSCs↓, 1,   CSCs↑, 1,   Diff↑, 2,   EMT↓, 2,   ERK↓, 3,   HH↓, 1,   mTOR↓, 4,   mTOR↑, 2,   Nanog↓, 1,   OCT4↓, 1,   P70S6K↑, 1,   PI3K↓, 2,   STAT3↓, 1,   p‑STAT3↓, 1,   TOP2↓, 1,   TRF2↓, 1,   TumCG↓, 3,   Wnt↓, 1,   Wnt/(β-catenin)↓, 1,   Wnt/(β-catenin)↑, 1,  

Migration ⓘ

AP-1↓, 1,   AXL↓, 1,   Ca+2↑, 1,   CAFs/TAFs↓, 1,   Cdc42↑, 1,   CDK4/6↓, 1,   E-cadherin↑, 3,   ITGB1↑, 1,   Ki-67↓, 1,   LysoPr↑, 1,   MMP2↓, 4,   MMP7↓, 1,   MMP9↓, 4,   N-cadherin↓, 1,   NCAM↑, 1,   PKCδ↓, 1,   Slug↓, 1,   Snail?, 1,   TGF-β↓, 2,   TIMP2↑, 2,   TumCI↓, 1,   TumCMig↓, 2,   TumCP↓, 4,   TumCP↑, 1,   TumMeta↓, 2,   Twist↓, 1,   uPA↓, 3,   Vim↓, 1,   Zeb1↓, 1,   ZEB2↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 6,   ATF4↑, 3,   EGFR↓, 1,   Hif1a↓, 2,   KDR/FLK-1↓, 1,   NO↓, 1,   VEGF↓, 5,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 2,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 4,   IL1↓, 1,   IL1β↓, 1,   IL4↓, 1,   IL6↓, 1,   IL8↓, 2,   M2 MC↓, 1,   MIP2↓, 1,   NF-kB↓, 4,   PD-L1↓, 1,   PGE2↓, 1,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 1,   CDK6↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 2,   BioAv↑, 1,   BioAv↝, 1,   ChemoSen↑, 8,   Dose↝, 1,   eff↓, 7,   eff↑, 15,   eff↝, 2,   Half-Life↓, 2,   RadioS↑, 1,   selectivity↑, 3,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   Ferritin↓, 4,   IL6↓, 1,   Ki-67↓, 1,   Myc↓, 1,   PD-L1↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 2,   AntiTum↑, 1,   toxicity↓, 1,   toxicity↑, 1,   TumVol↓, 1,  
Total Targets: 209

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↓, 1,   NRF2↑, 1,   ROS↓, 5,   ROS↑, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,  

Cell Death ⓘ

Akt↑, 1,   Ferroptosis↓, 1,   iNOS↓, 1,   p‑p38↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 1,  

Migration ⓘ

TGF-β↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL6↓, 1,   Inflam↓, 4,   MCP1↓, 1,   MIP2↓, 1,   NF-kB↓, 3,   TLR4↓, 1,   TNF-α↓, 1,  

Protein Aggregation ⓘ

NLRP3↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   Half-Life↓, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   cognitive↑, 2,   memory↑, 1,   neuroP↑, 2,   toxicity↓, 1,  
Total Targets: 28

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
38 Artemisinin
1 5-Aminolevulinic acid
1 Vitamin C (Ascorbic Acid)
1 doxorubicin
1 Resveratrol
1 temozolomide
1 2-DeoxyGlucose
1 Docetaxel
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#:34  Target#:275  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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