Artemisinin / Casp3 Cancer Research Results

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↓(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
Casp3, CPP32, Cysteinyl aspartate specific proteinase-3: Click to Expand ⟱
Source:
Type:
Also known as CP32.
Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death.
As a key protein of apoptosis, caspase-3 can also cleave GSDME and induce pyroptosis. Loss of caspase activity is an important cause of tumor progression.
Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.
Caspase 3 is the main effector caspase and has a key role in apoptosis. In many types of cancer, including breast, lung, and colon cancer, caspase-3 expression is reduced or absent.
On the other hand, some studies have shown that high levels of caspase-3 expression can be associated with a better prognosis in certain types of cancer, such as breast cancer. This suggests that caspase-3 may play a role in the elimination of cancer cells, and that therapies aimed at activating caspase-3 may be effective in treating certain types of cancer.
Procaspase-3 is a apoptotic marker protein.
Prognostic significance:
• High Cas3 expression: Associated with good prognosis and increased sensitivity to chemotherapy in breast, gastric, lung, and pancreatic cancers.
• Low Cas3 expression: Linked to poor prognosis and increased risk of recurrence in colorectal, hepatocellular carcinoma, ovarian, and prostate cancers.
Scientific Papers found: Click to Expand⟱
4438- AgNPs,  ART/DHA,    Biogenic synthesis of AgNPs using Artemisia oliveriana extract and their biological activities for an effective treatment of lung cancer
- in-vitro, Lung, A549
EPR↑, BAX↑, Bcl-2↑, Casp3↑, Casp9↑, DNAdam↑, TumCCA↑, Apoptosis↑,
3382- ART/DHA,    Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?
- Review, Var, NA
AntiCan↑, toxicity↑, Ferroptosis↑, ROS↑, TumCCA↑, BioAv↝, eff↝, Half-Life↓, Ferritin↓, GPx4↓, NADPH↓, GSH↓, BAX↑, Cyt‑c↑, cl‑Casp3↑, VEGF↓, IL8↓, COX2↓, MMP9↓, E-cadherin↑, MMP2↓, NF-kB↓, p16↑, CDK4↓, cycD1/CCND1↓, p62↓, LC3II↑, EMT↓, CSCs↓, Wnt↓, β-catenin/ZEB1↓, uPA↓, TumAuto↑, angioG↓, ChemoSen↑,
5131- ART/DHA,    Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells
- in-vitro, NSCLC, ASTC-a-1
Apoptosis↑, MMP↓, Casp3↑, TumCP↓,
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↓, eff↓, Apoptosis↑, Casp3↑, ROS↑, Cyt‑c↑, MMP↓, Bcl-2↓, BAX↑, MOMP↑, TumCG↓,
573- ART/DHA,    Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model
- vitro+vivo, NA, NA
p‑p38↓, p‑ERK↓, p‑CREB↓, p‑Chk2↓, p‑STAT5↓, p‑RSK↓, SOCS1↑, Apoptosis↑, Casp3↑,
569- ART/DHA,    Dihydroartemisinin exhibits anti-glioma stem cell activity through inhibiting p-AKT and activating caspase-3
- in-vitro, GBM, NA
TumCP↓, Apoptosis↑, TumCCA↑, Casp3↑, p‑Akt↓,
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↑,
2576- ART/DHA,  AL,    The Synergistic Anticancer Effect of Artesunate Combined with Allicin in Osteosarcoma Cell Line in Vitro and in Vivo
- in-vitro, OS, MG63 - in-vivo, NA, NA
eff↑, tumCV↓, Casp3↑, Casp9↑, Apoptosis↑, TumCG↓,
2323- ART/DHA,    Dihydroartemisinin represses esophageal cancer glycolysis by down-regulating pyruvate kinase M2
- in-vitro, ESCC, Eca109 - in-vitro, ESCC, EC9706
PKM2↓, lactateProd↓, GlucoseCon↓, cycD1/CCND1↓, Bcl-2↓, MMP2↓, VEGF↓, Casp3↑, cl‑PARP↑, BAX↑, DNAdam↑, ROS↑,
2321- ART/DHA,    Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma
- in-vitro, ESCC, Eca109 - in-vitro, ESCC, EC9706
Pyro↑, PKM2↓, Casp8↑, Casp3↑, Warburg↓, TumCCA↑, Apoptosis↑,
1079- ART/DHA,    Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2
- in-vitro, GC, BGC-823 - in-vitro, GC, HGC27 - in-vitro, GC, MGC803
TumCP↓, Apoptosis↑, COX2↓, BAX↑, Bcl-2↓, Casp3↑, Casp9↑, MMP↓,

Showing Research Papers: 1 to 11 of 11

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   GPx4↓, 1,   GSH↓, 1,   ROS↑, 4,  

Metal & Cofactor Biology ⓘ

Ferritin↓, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   ATP↓, 1,   MMP↓, 3,  

Core Metabolism/Glycolysis ⓘ

p‑CREB↓, 1,   GlucoseCon↓, 2,   lactateProd↓, 2,   NADPH↓, 1,   PKM2↓, 2,   p‑S6↓, 1,   Warburg↓, 1,  

Cell Death ⓘ

p‑Akt↓, 1,   Apoptosis↑, 8,   BAX↑, 5,   Bcl-2↓, 3,   Bcl-2↑, 1,   Casp3↑, 10,   cl‑Casp3↑, 1,   Casp8↑, 2,   Casp9↑, 4,   p‑Chk2↓, 1,   Cyt‑c↑, 3,   Ferroptosis↑, 1,   MOMP↑, 1,   p‑p38↓, 1,   Pyro↑, 1,   p‑RSK↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 2,  

Autophagy & Lysosomes ⓘ

LC3II↑, 1,   p62↓, 1,   TumAuto↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 2,   p16↑, 1,   cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

CDK4↓, 1,   cycD1/CCND1↓, 2,   TumCCA↑, 4,  

Proliferation, Differentiation & Cell State ⓘ

CSCs↓, 1,   EMT↓, 1,   p‑ERK↓, 1,   mTOR↓, 1,   p‑STAT5↓, 1,   TumCG↓, 2,   Wnt↓, 1,  

Migration ⓘ

E-cadherin↑, 1,   MMP2↓, 2,   MMP9↓, 1,   TumCP↓, 3,   uPA↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EPR↑, 1,   VEGF↓, 2,  

Barriers & Transport ⓘ

GLUT1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   IL8↓, 1,   NF-kB↓, 1,   SOCS1↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,   ChemoSen↑, 1,   eff↓, 1,   eff↑, 1,   eff↝, 1,   Half-Life↓, 1,  

Clinical Biomarkers ⓘ

Ferritin↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   toxicity↑, 1,  
Total Targets: 71

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Casp3, CPP32, Cysteinyl aspartate specific proteinase-3
11 Artemisinin
1 Silver-NanoParticles
1 2-DeoxyGlucose
1 Allicin (mainly Garlic)
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#:42  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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