condition found tbRes List
VitC, Vitamin C (Ascorbic Acid): Click to Expand ⟱
Features:
High-dose vitamin C: Some studies have suggested that high-dose vitamin C may be effective in treating certain types of cancer, such as ovarian cancer and pancreatic cancer.
Symptoms of vitamin C deficiency include fatigue, weakness, poor wound healing, ecchymoses, xerosis, lower extremity edema, and musculoskeletal pain—most of them are often observed in end-stage cancer patients. -Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters. It is required for the functioning of several enzymes and is important for immune system function.
-Ascorbic Acid, Different levels in different Organs
Homeostasis ranging from about 0.2 mM in the muscle and heart, and up to 10 mM in the brain and adrenal gland. -(Note the Oncomagnetic success in the brain also was then under conditions of high Vitamin C)

-Ascorbic acid is an electron donor
Ascorbic Acid, can be a Pro-oxidant
"The pro-oxidative activity of ascorbic acid (Figure 2) is associated with the interaction with transition metal ions (especially iron and copper). Under conditions of high, millimolar ascorbate concentration, vitamin C catalyzes the reduction of free transition metal ions, which causes the formation of oxygen radicals."
Ascorbic Acid, formation of H2O2 (Hydrogen Peroxide)
Many studies indicate the toxicity of ascorbate to cancer cells. Much evidence indicates that the underlying phenomenon is the pro-oxidative activity of ascorbate, which induces the formation of H2O2 and oxidative stress.
"ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2)"
-High dose VitC therapy may not be for those with kidney problems
-Oral supplement up to 10g/day?
-Direct regulator of TET↑
-caution for (G6PD-) deficient patients receiving vitamin C infusions

-Note plasma half-life 30mins to 1hr, 1.5-2hr elimination half-life.
oral BioAv water soluble, but has limitiations as 100mg yeilds 60uM/L in plasma, but 1000mg only yeilds 85uM/L. mM concentration are required for effectiveness on cancer cells. Hence why IV administration is common. Boosting HIF increases the intracellular uptake of oxidized VitC
Pathways:
- high dose induces ROS production in cancer cells. Otherwise well known antioxidant in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, Caspases↑, DNA damage↑, cl-PARP↑,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ HO1↓ GPx↓
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, NF-κB↓,
- reactivate genes thereby inhibiting cancer cell growth : P53↑, TET↑
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, ERK↓, EMT↓, TET1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, GRP78↑, Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓,
- Others: PI3K↓, AKT↓, STAT↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Hepatoprotective,

- 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⟱
3145- VitC,    Vitamin C inhibits the growth of colorectal cancer cell HCT116 and reverses the glucose‐induced oncogenic effect by downregulating the Warburg effect
- in-vitro, CRC, HCT116
Warburg↓, Notably, as a potential Warburg effect inhibitor, VC suppressed cancer growth in a concentration-dependent manner and further reversed the glucose-induced oncogenic effect.
TumCG↓,
Glycolysis↓,
GlucoseCon↓, 1 h-exposure to 5 mM VC led to an almost 50% reduction in glucose consumption, ATP and lactate contents in cancer cells, with mild impact on normal cells
ATP↓,
lactateProd↓,
selectivity↑, Meanwhile, normal cell had little apparent change
GLUT1↓, (GLUT1, PKM2, and LDHA) were significantly decreased, with p-AMPK/AMPK increased and p-mTOR/mTOR decreased, consistent with the cytotoxicity on 3 kinds of cancer cells
PKM2↓,
LDHA↓,
mTOR↓,

3141- VitC,    High-dose Vitamin C inhibits PD-L1 expression by activating AMPK in colorectal cancer
- in-vitro, CRC, HCT116
Glycolysis↓, Vitamin C inhibits immune evasion by regulating glycolysis
eff↑, VitC suppresses tumor growth and enhances immunotherapy in combination with anti-PD-L1
PD-L1↓, We found that VitC inhibits aerobic glycolysis in HCT116 cells while also downregulating PD-L1 expression.
AMPK↑, VitC's activation of AMPK, which downregulates HK2 and NF-κB, ultimately resulting in reduced PD-L1 expression and increased T cell infiltration.
HK2↓,
NF-kB↓,
Warburg↓, Our research shows that high-dose VitC downregulating the Warburg effect, suppressing CRC growth
tumCV↓, After treatment with VitC, the cell viability of HCT116 cells significantly decreased
GLUT1↓, marked reduction in the mRNA level of glycolysis-related proteins GLUT1, PKM2, and LDHA
PKM2↓,
LDHA↓,
CD4+↑, Our research shows that high-dose VitC increases CD4+ and CD8+ T cell infiltration in tumor tissues by inhibiting PD-L1
CD8+↑,

3136- VitC,    Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer
- in-vitro, Colon, SW48 - in-vitro, Colon, LoVo
ERK↓, Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation.
p‑PKM2↓,
GLUT1↓, As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)
Warburg↓, causing a major blockage of the Warburg effect and therefore energetic stress.
TumCD↑, Vitamin C selectively kills KRAS mutant colon cancer cells alone or in combination with cetuximab
eff↑, Remarkably, treatment of HT29, SW480 and LoVo cells with cetuximab (0,4 μM) and vitamin C (5mM) abolished cell growth in the three lines tested.
ROS↓, Interestingly, we detected that vitamin C treatment dramatically reduced intracellular ROS levels in SW480 and LoVo cells (Figure 2D),
cMyc↓, strong inhibition of c-Myc oncogene in colonospheres treated at concentrations of vitamin C as low as 100 μM


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Results for Effect on Cancer/Diseased Cells:
AMPK↑,1,   ATP↓,1,   CD4+↑,1,   CD8+↑,1,   cMyc↓,1,   eff↑,2,   ERK↓,1,   GlucoseCon↓,1,   GLUT1↓,3,   Glycolysis↓,2,   HK2↓,1,   lactateProd↓,1,   LDHA↓,2,   mTOR↓,1,   NF-kB↓,1,   PD-L1↓,1,   PKM2↓,2,   p‑PKM2↓,1,   ROS↓,1,   selectivity↑,1,   TumCD↑,1,   TumCG↓,1,   tumCV↓,1,   Warburg↓,3,  
Total Targets: 24

Results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: PKM2, Pyruvate Kinase, Muscle 2
3 Vitamin C (Ascorbic Acid)
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:166  Target#:772  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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