Database Query Results : Artemisinin, , ERK

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
ERK, ERK signaling: Click to Expand ⟱
Source:
Type:
MAPK3 (ERK1)
ERK proteins are kinases that activate other proteins by adding a phosphate group. An overactivation of these proteins causes the cell cycle to stop.
The extracellular signal-regulated kinase (ERK) signaling pathway is a crucial component of the mitogen-activated protein kinase (MAPK) signaling cascade, which plays a significant role in regulating various cellular processes, including proliferation, differentiation, and survival. high levels of phosphorylated ERK (p-ERK) in tumor samples may indicate active ERK signaling and could correlate with aggressive tumor behavior

EEk singaling is frequently activated and is often associated with aggressive tumor behavior, treatment resistance, and poor outcomes.
Scientific Papers found: Click to Expand⟱
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↑,

4278- ART/DHA,    Artemisinin Ameliorates the Neurotoxic Effect of 3-Nitropropionic Acid: A Possible Involvement of the ERK/BDNF/Nrf2/HO-1 Signaling Pathway
- in-vivo, NA, NA
*IL6↓, ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression.
*Casp3↓,
*Casp9↓,
*BDNF↑,
*ERK↑,
*NRF2↑,
*HO-1↑,
*neuroP↑, ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.
*antiOx↑,
*Inflam↓,

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↑,

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.

1148- ART/DHA,    Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Cδ/p38/extracellular signal-regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages
- in-vitro, AML, THP1
MMP9↓,
EMMPRIN↓,
p‑PKCδ↓, artemisinin (20-80 μg/mL) strongly blocked PKCδ/JNK/p38/ERK MAPK phosphorylation
p‑JNK↓,
p‑p38↓,
p‑ERK↓,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 7

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 2,   ROS↑, 3,  

Mitochondria & Bioenergetics ⓘ

ADP:ATP↑, 1,   CDC25↓, 1,   Raf↓, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 2,   p‑CREB↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis↑, 2,   BAX↑, 1,   Casp3↓, 1,   Casp3↑, 1,   Casp8↑, 1,   Casp9↑, 1,   p‑Chk2↓, 1,   p‑Chk2↑, 1,   Ferroptosis↑, 2,   JNK↓, 1,   p‑JNK↓, 1,   MDM2↓, 1,   oncosis↑, 1,   p27↑, 2,   p‑p38↓, 2,   p‑RSK↓, 1,   survivin↓, 2,  

Protein Folding & ER Stress ⓘ

ER Stress↓, 1,   GRP78/BiP↑, 1,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 1,  

DNA Damage & Repair ⓘ

p‑ATM↑, 1,   p‑ATR↑, 1,   p‑CHK1↑, 1,   DNAdam↑, 2,   HR↓, 1,   p16↑, 1,   PCNA↓, 1,   RAD51↓, 1,  

Cell Cycle & Senescence ⓘ

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

Proliferation, Differentiation & Cell State ⓘ

cMET↓, 1,   ERK↓, 3,   p‑ERK↓, 2,   mTOR↓, 1,   PI3K↓, 1,   p‑STAT5↓, 1,   TOP2↓, 1,   Wnt/(β-catenin)↓, 1,  

Migration ⓘ

AP-1↓, 1,   Cdc42↑, 1,   CDK4/6↓, 1,   E-cadherin↑, 1,   EMMPRIN↓, 1,   ITGB1↑, 1,   MMP2↓, 2,   MMP7↓, 1,   MMP9↓, 2,   NCAM↑, 1,   PKCδ↓, 1,   p‑PKCδ↓, 1,   TGF-β↓, 1,   TIMP2↑, 2,   TumCP↓, 1,   TumMeta↓, 1,   uPA↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EGFR↓, 1,   Hif1a↓, 1,   KDR/FLK-1↓, 1,   NO↓, 1,   VEGF↓, 2,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL1↓, 1,   IL6↓, 1,   IL8↓, 1,   MIP2↓, 1,   NF-kB↓, 2,   PD-L1↓, 1,   PGE2↓, 1,   SOCS1↑, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   BioAv↑, 1,   eff↓, 1,   eff↑, 1,   Half-Life↓, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   IL6↓, 1,   PD-L1↓, 1,  

Functional Outcomes ⓘ

TumVol↓, 1,  
Total Targets: 96

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   HO-1↑, 1,   NRF2↑, 1,   ROS↓, 1,  

Cell Death ⓘ

Casp3↓, 1,   Casp9↓, 1,   p‑p38↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,   p‑ERK↓, 1,  

Immune & Inflammatory Signaling ⓘ

IL6↓, 1,   Inflam↓, 2,   NF-kB↓, 1,  

Synaptic & Neurotransmission ⓘ

BDNF↑, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 15

Scientific Paper Hit Count for: ERK, ERK signaling
7 Artemisinin
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#:105  State#:%  Dir#:%
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