condition found tbRes List
ART/DHA, Artemisinin: Click to Expand ⟱
Features:
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:
- Pro-oxidant, mechanism related with iron (hence avoid supplements containing iron? Or perhaps take with iron?)
-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)

-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


PKM2, Pyruvate Kinase, Muscle 2: Click to Expand ⟱
Source:
Type: enzyme
PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells.
-C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A
-PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells.
-inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis.
-PK exists in four isoforms: PKM1, PKM2, PKR, and PKL
-PKM2 plays a role in the regulation of glucose metabolism in diabetes.
-PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy.
– Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP.
– The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms.
– Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation.
– Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions.

– Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers.
– High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage.

PKM2 in carcinogenesis and oncotherapy

Inhibitors of PKM2:
-Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established

Full List of PKM2 inhibitors from Database
-key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells.
Tumor pyruvate kinase M2 modulators

Flavonoids effect on PKM2
Compounds name IC50/AC50uM Effect
Flavonols
1. Fisetin 0.90uM Inhibition
2. Rutin 7.80uM Inhibition
3. Galangin 8.27uM Inhibition
4. Quercetin 9.24uM Inhibition
5. Kaempferol 9.88uM Inhibition
6. Morin hydrate 37.20uM Inhibition
7. Myricetin 0.51uM Activation
8. Quercetin 3-b- D-glucoside 1.34uM Activation
9. Quercetin 3-D -galactoside 27-107uM Ineffective
Flavanons
10. Neoeriocitrin 0.65uM Inhibition
11. Neohesperidin 14.20uM Inhibition
12. Naringin 16.60uM Inhibition
13. Hesperidin 17.30uM Inhibition
14. Hesperitin 29.10uM Inhibition
15. Naringenin 70.80uM Activation
Flavanonols
16. (-)-Catechin gallateuM 0.85 Inhibition
17. (±)-Taxifolin 1.16uM Inhibition
18. (-)-Epicatechin 1.33uM Inhibition
19. (+)-Gallocatechin 4-16uM Ineffective
Phenolic acids
20. Ferulic 11.4uM Inhibition
21. Syringic and 13.8uM Inhibition
22. Caffeic acid 36.3uM Inhibition
23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition
24. Gallic acid 332.6uM Inhibition
25. Shikimic acid 990uM Inhibition
26. p-Coumaric acid 22.2uM Activation
27. Sinapinic acids 26.2uM Activation
28. Vanillic 607.9uM Activation


Scientific Papers found: Click to Expand⟱
2324- ART/DHA,    Research Progress of Warburg Effect in Hepatocellular Carcinoma
- Review, Var, NA
PKM2↓, DHA effectively suppressed aerobic glycolysis and ESCC progression by downregulating PKM2 expression in esophageal squamous cell carcinoma (ESCC) and ESCC cells
GLUT1↓, DHA inhibited leukemia cell K562 proliferation by suppressing GLUT1 and PKM2 levels, thereby regulating glucose uptake and inhibiting aerobic glycolysis
Glycolysis↓,
Akt↓, In LNCaP cells, DHA reduced Akt/mTOR and HIF-1α activity, leading to decreased expression of GLUT1, HK2, PKM2, and LDH and subsequent inhibition of aerobic glycolysis
mTOR↓,
Hif1a↓,
HK2↓,
LDH↓,
NF-kB↓, DHA was also found to inhibit the NF-κB signaling pathway to prevent GLUT1 translocation to the plasma membrane, thereby inhibiting the progression of non-small-cell lung cancer (NSCLC) cells via targeting glucose metabolism

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↓, 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↑,

2322- ART/DHA,    Dihydroartemisinin Regulates Self-Renewal of Human Melanoma-Initiating Cells by Targeting PKM2/LDHARelated Glycolysis
- in-vitro, Melanoma, NA
TumCP↓, DHA inhibits the proliferation of melanoma cells and blocks the cell cycle process.
PKM2↓, DHA reduces ATP production and downregulate PKM2 and LDHA activities without regulating the expression of the PKM2 and LDHA proteins in melanoma cells
LDHA↓,
Glycolysis↓, downregulates glucose metabolism in melanoma cells.

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↑, DHA treatment to ESCC, we found that some dying cells exhibited the characteristic morphology of pyroptosis, such as blowing large bubbles from the cell membrane,
PKM2↓, accompanied by downregulation of pyruvate kinase isoform M2 (PKM2),
Casp8↑, activation of caspase-8/3, and production of GSDME-NT
Casp3↑,
Warburg↓, previous studies, we demonstrated that DHA has anti-esophageal cancer effects by blocking the cell cycle in G0/G1 phase, inducing apoptosis, regulating the NF-κB/HIF-1α/VEGF pathway ... and downregulating the expression of PKM2 to inhibit the Warburg
TumCCA↑,
Apoptosis↑,

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↓, 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↓,

2320- ART/DHA,    Dihydroartemisinin Inhibits the Proliferation of Leukemia Cells K562 by Suppressing PKM2 and GLUT1 Mediated Aerobic Glycolysis
- in-vitro, AML, K562 - in-vitro, Liver, HepG2
Glycolysis↓, DHA prevented cell proliferation in K562 cells through inhibiting aerobic glycolysis.
GlucoseCon↓, Lactate product and glucose uptake were inhibited after DHA treatment.
lactateProd↓,
GLUT1↓, DHA modulates glucose uptake through downregulating glucose transporter 1 (GLUT1) in both gene and protein levels.
PKM2↓, DHA treatment, decreased expression of PKM2 was confirmed in situ.
ECAR↓, ECAR parameters including the glycolytic activity and capacity decreased in a concentration-dependent manner in K562 cells following DHA administration
LDHA↓, DHA treatment downregulated the relative expression of GLUT1, PKM2, LDH-A and c-Myc
cMyc↓,
other↝, The relative changes of PDK1, P53, HIF-1α, HK2, and PFK1 expression were modest, with most genes being altered by less than 2-fold

957- ART/DHA,    Artemisinin inhibits the development of esophageal cancer by targeting HIF-1α to reduce glycolysis levels
- in-vitro, ESCC, KYSE150 - in-vitro, ESCC, KYSE170
TumCP↓,
TumMeta↓,
Glycolysis↓,
N-cadherin↓,
PKM2↓,
Hif1a↓,


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

Results for Effect on Cancer/Diseased Cells:
Akt↓,2,   angioG↓,1,   Apoptosis↑,2,   AXL↓,1,   BAX↑,1,   Bcl-2↓,2,   Beclin-1↑,1,   Ca+2↑,1,   CAFs/TAFs↓,1,   Casp3↑,2,   Casp8↑,1,   CDK2↓,1,   CDK4↓,1,   CDK6↓,1,   cMyc↓,1,   COX2↓,1,   cycD1↓,1,   cycE↓,1,   Cyt‑c↑,1,   DNAdam↑,1,   DR5↑,1,   ECAR↓,1,   eff↑,6,   EMT↓,1,   ER Stress↑,1,   FADD↑,1,   Fas↑,1,   GlucoseCon↓,3,   GLUT1↓,3,   Glycolysis↓,5,   GRP78/BiP↑,1,   HH↓,1,   Hif1a↓,3,   HK2↓,1,   HSP70/HSPA5↓,1,   IL4↓,1,   JNK↑,1,   Ki-67↓,1,   lactateProd↓,3,   LDH↓,1,   LDHA↓,2,   M2 MC↓,1,   Mcl-1↓,1,   MMP2↓,1,   MMP9↓,1,   mTOR↓,1,   N-cadherin↓,1,   NF-kB↓,1,   other↝,1,   p38↑,1,   cl‑PARP↑,2,   PI3K↓,1,   PKM2↓,7,   PPARγ↑,1,   Pyro↑,1,   ROS↑,2,   Slug↓,1,   Snail?,1,   p‑STAT3↓,1,   TGF-β↓,1,   TumAuto↑,1,   TumCCA↑,1,   TumCP↓,3,   TumMeta↓,2,   Twist↓,1,   uPA↓,1,   VEGF↓,2,   VEGFR2↓,1,   Warburg↓,1,   Zeb1↓,1,   ZEB2↓,1,  
Total Targets: 71

Results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: PKM2, Pyruvate Kinase, Muscle 2
7 Artemisinin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:34  Target#:772  State#:%  Dir#:%
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