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


Glycolysis, Glycolysis: Click to Expand ⟱
Source:
Type:
Glycolysis is a metabolic pathway that converts glucose into pyruvate, producing a small amount of ATP (energy) in the process. It is a fundamental process for cellular energy production and occurs in the cytoplasm of cells. In normal cells, glycolysis is tightly regulated and is followed by aerobic respiration in the presence of oxygen, which allows for the efficient production of ATP.
In cancer cells, however, glycolysis is often upregulated, even in the presence of oxygen. This phenomenon is known as the Warburg Mutations in oncogenes (like MYC) and tumor suppressor genes (like TP53) can alter metabolic pathways, promoting glycolysis and other anabolic processes that support cell growth.effect.
Acidosis: The increased production of lactate from glycolysis can lead to an acidic microenvironment, which may promote tumor invasion and suppress immune responses.

Glycolysis is a hallmark of malignancy transformation in solid tumor, and LDH is the key enzyme involved in glycolysis.

Pathways:
-GLUTs, HK2, PFK, PK, PKM2, LDH, LDHA, PI3K/AKT/mTOR, AMPK, HIF-1a, c-MYC, p53, SIRT6, HSP90α, GAPDH, HBT, PPP, Lactate Metabolism, ALDO

Natural products targeting glycolytic signaling pathways https://pmc.ncbi.nlm.nih.gov/articles/PMC9631946/
Alkaloids:
-Berberine, Worenine, Sinomenine, NK007, Tetrandrine, N-methylhermeanthidine chloride, Dauricine, Oxymatrine, Matrine, Cryptolepine

Flavonoids: -Oroxyline A, Apigenin, Kaempferol, Quercetin, Wogonin, Baicalein, Chrysin, Genistein, Cardamonin, Phloretin, Morusin, Bavachinin, 4-O-methylalpinumisofavone, Glabridin, Icaritin, LicA, Naringin, IVT, Proanthocyanidin B2, Scutellarin, Hesperidin, Silibinin, Catechin, EGCG, EGC, Xanthohumol.

Non-flavonoid phenolic compounds:
Curcumin, Resveratrol, Gossypol, Tannic acid.

Terpenoids:
-Cantharidin, Dihydroartemisinin, Oleanolic acid, Jolkinolide B, Cynaropicrin, Ursolic Acid, Triptolie, Oridonin, Micheliolide, Betulinic Acid, Beta-escin, Limonin, Bruceine D, Prosapogenin A (PSA), Oleuropein, Dioscin.

Quinones:
-Thymoquinone, Lapachoi, Tan IIA, Emodine, Rhein, Shikonin, Hypericin

Others:
-Perillyl alcohol, HCA, Melatonin, Sulforaphane, Vitamin D3, Mycoepoxydiene, Methyl jasmonate, CK, Phsyciosporin, Gliotoxin, Graviola, Ginsenoside, Beta-Carotene.
Scientific Papers found: Click to Expand⟱
3107- VitC,    Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment
- Review, Var, NA
Risk↓, VitC supplementation resulted in dose-dependent reductions in all-cause mortality and the risk of various cancers
*ROS↓, Vitamin C (VitC) at the physiological dose (μM) is known to exhibit antioxidant properties.
ROS↑, However, it functions as a prooxidant at the pharmacological dose (mM) achieved by intravenous administration.
VEGF↓, VitC suppressed tumor angiogenesis in colon cancer-bearing mice by downregulating the expression and secretion of VEGF-A and VEGF-D
COX2↓, VitC impairs COX-2 activity and inhibits VEGF mRNA expression in melanoma cells in a time-dependent manner
ER Stress↑, VitC increases the ER stress-mediated breast cancer apoptosis via activation of the IRE-JNK-CHOP signaling pathway, an effect independent of ROS
IRE1↑,
JNK↑,
CHOP↑,
Hif1a↓, On the one hand, VitC directly inhibits HIF-1α-mediated glycolysis-related genes expression and the downstream acidic metabolites
eff↑, ROS generated by VitC treatment exerts a synergistic effect with other glycolysis inhibitors, providing a combined therapeutic strategy
Glycolysis↓,
MMPs↓, VitC inhibits a variety of metalloproteinases (MMPs) mRNA, which degrade ECM and release growth factors that drive tumor metastasis
TumMeta↓,
YAP/TEAD↓, VitC treatment reduces YAP1 expression while upregulating SYNPO-2; therefore, inhibiting metastasis of TNBC
eff↑, VitC enhances the killing efficiency of Hep G2 cells by low-dose sorafenib in vitro.
TET1↑, VitC stimulation of TET2 activity in the renal cell carcinoma

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↓,

3143- VitC,  ATO,    Vitamin C enhances the sensitivity of osteosarcoma to arsenic trioxide via inhibiting aerobic glycolysis
- in-vitro, OS, NA
TumCP↓, synthetic application of vitamin C (VitC, 800 μM) and ATO (1 μM) significantly further inhibited the proliferation, migration, and invasion of OS cells and promoted cell apoptosis in vitro.
TumCMig↓,
TumCI↓,
eff↑, synthetic application of vitamin C (VitC, 800 μM) and ATO (1 μM) significantly further inhibited the proliferation,
Glycolysis↓, VitC and ATO directly suppresses the aerobic glycolysis of OS cells with the decreased production of pyruvate, lactate, and ATP via inhibiting the expression of the critical glycolytic genes (PGK1, PGM1, and LDHA).
lactateProd↓,
ATP↓,
PGK1↓,
PGM1↓,
LDHA↓,

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+↑,

3140- VitC,    Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest
- in-vitro, PC, MIA PaCa-2 - in-vitro, Nor, HEK293
citrate↓, pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels
FASN↓, Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression.
ACLY↓,
LDH↓, correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism.
Glycolysis↓,
Warburg↓, Dismissed citrate metabolism correlated with reduced Warburg effectors such as the pyruvate dehydrogenase kinase 1 (PDK1) and the glucose transporter 1 (GLUT1),
PDK1↓,
GLUT1↓,
LDHA↓, Reduced LDHA expression was also observed after vitamin C exposure, leading to a vast extracellular acidification rate (ECAR) reduction.
ECAR↓,
PDH↑, enhancing PDH activity
eff↑, Surprisingly, an impressive 85% of tumor growth inhibition is described in the combinatory treatment of vitamin C and gemcitabine in our preclinical PDAC PDX model


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Results for Effect on Cancer/Diseased Cells:
ACLY↓,1,   AMPK↑,1,   ATP↓,2,   CD4+↑,1,   CD8+↑,1,   CHOP↑,1,   citrate↓,1,   COX2↓,1,   ECAR↓,1,   eff↑,5,   ER Stress↑,1,   FASN↓,1,   GlucoseCon↓,1,   GLUT1↓,3,   Glycolysis↓,5,   Hif1a↓,1,   HK2↓,1,   IRE1↑,1,   JNK↑,1,   lactateProd↓,2,   LDH↓,1,   LDHA↓,4,   MMPs↓,1,   mTOR↓,1,   NF-kB↓,1,   PD-L1↓,1,   PDH↑,1,   PDK1↓,1,   PGK1↓,1,   PGM1↓,1,   PKM2↓,2,   Risk↓,1,   ROS↑,1,   selectivity↑,1,   TET1↑,1,   TumCG↓,1,   TumCI↓,1,   TumCMig↓,1,   TumCP↓,1,   tumCV↓,1,   TumMeta↓,1,   VEGF↓,1,   Warburg↓,3,   YAP/TEAD↓,1,  
Total Targets: 44

Results for Effect on Normal Cells:
ROS↓,1,  
Total Targets: 1

Scientific Paper Hit Count for: Glycolysis, Glycolysis
5 Vitamin C (Ascorbic Acid)
1 Arsenic trioxide
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:166  Target#:129  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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