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


Hif1a, HIF1α/HIF1a: Click to Expand ⟱
Source:
Type:
Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.
Scientific Papers found: Click to Expand⟱
3114- VitC,    Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
- in-vitro, AML, NA
TET2↑, Treatment with vitamin C, a cofactor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs
eff↑, enhances the efficacy of PARP inhibition in suppressing leukemia progression.
ROS↑, High levels of vitamin C can lead to reactive oxygen species (ROS) production via the Fenton reaction
Fenton↑,
Hif1a↓, One study suggested that vitamin C decreases viability of human leukemia cell lines by promoting downregulation of HIF1α and the anti-apoptotic genes, BCL2, BCL2L1, and MCL1

3115- VitC,    The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer
- in-vitro, BC, NA
NF-kB↓, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli.
Hif1a↓, Vitamin C activates enzymes that are able to inhibit NF-κB and HIF-1α as well as their target genes.
P53↑, vitamin C was reported to decrease NF-κB function and increase p53 overexpression and stability

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

3146- VitC,    Vitamin C protects against hypoxia, inflammation, and ER stress in primary human preadipocytes and adipocytes
- in-vivo, Nor, NA
*Obesity↓, These findings indicate that Vitamin C can reduce obesity-associated cellular stress and thus provide a rationale for future investigations.
*ER Stress↓, Vitamin C prevented the increase in hypoxia (Fig. 1A–B), significantly reduced the induction of ER stress
*Inflam↓, nd ameliorated the increased expression of inflammatory genes
Hif1a↓, Vitamin C treatment for 24 and 48 h significantly reducing induction of HIF1α protein by 30–40% and VEGFA and GLUT1 mRNA by 40–80%
VEGF↓,
GLUT1↓,
GRP78/BiP↓, significantly reversing the effects of TNFα+PA pre-treatment only on GRP78 induction, by 30–40%

596- VitC,    High-Dose Vitamin C in Advanced-Stage Cancer Patients
- Review, NA, NA
ChemoSideEff↓, reducing cancer-related symptoms, such as fatigue and bone pain
ROS↑, is able to reduce catalytic metals such as Fe3+ to Fe2+ and Cu2+ to Cu+, increasing the pro-oxidant chemistry of these metals and facilitating the generation of reactive oxygen species
H2O2↑, Reactions of ascorbate with oxygen or with free transition metal ions lead to the generation of superoxide, H2O2 and highly reactive oxidants, such as the hydroxyl radical by promoting the Fenton chemistry
Fenton↑,
Hif1a↝, Ascorbate regulates the transcription of hypoxia inducible factor-1α (HIF-1α)
Dose↑, Results obtained from in vitro studies revealed that millimolar ascorbate plasma concentrations, achievable only after intravenous vitamin C administration, are cytotoxic to fast-growing malignant cells.
BioAv↓, For this reason, ascorbate concentration in plasma does not exceed 100 μmol/L when it is supplied orally with food; even with oral supplementation approaching maximum tolerated doses, it is always <250 μmol/L
Dose↝, 100 mg, the concentration of ascorbate in daily fasting plasma reaches a plateau between 50–60 µmol/L [24]. Whereas increasing the daily dose ten times to 1000 mg gives only a slight increase in plasma concentration to 70–85 μmol/L
Half-Life↝, high concentrations are relatively transient due to the rapid clearance by the kidneys resulting in a half-life of about 2 h in circulation
IL1β↓, IVC (15–50 g up to three times a week) resulted in reduced CRP levels (in 76 ± 13% of study participants) and reduced concentration of pro-inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-8, tumor necrosis factor TNF-α)
IL2↓,
IL8↓,
TNF-α↓,

1219- VitC,    Ascorbic acid and ascorbate-2-phosphate decrease HIF activity and malignant properties of human melanoma cells
- in-vitro, Melanoma, NA
Hif1a↓,

1067- VitC,    Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer
- in-vivo, CRC, NA
PDK1↓,
Hif1a↓,
GLUT1↓,
ATP↓, Vitamin C induced remarkable ATP depletion
MMP↓,

632- VitC,    High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients
- Review, NA, NA
SVCT-2∅, vitamin C entry into cells is tightly regulated by SVCT
ROS↑, well-recognized pro-oxidant effects
Hif1a↓, HIF-1α proteasomal degradation
PARP∅, Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents.
TET2↑, However, the ability of vitamin C to restore TET2 activity seems to depend on N- and C-terminal lysine acetylation and type of TET2 mutations


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Results for Effect on Cancer/Diseased Cells:
ATP↓,1,   BioAv↓,1,   ChemoSideEff↓,1,   CHOP↑,1,   COX2↓,1,   Dose↑,1,   Dose↝,1,   eff↑,3,   ER Stress↑,1,   Fenton↑,2,   GLUT1↓,2,   Glycolysis↓,1,   GRP78/BiP↓,1,   H2O2↑,1,   Half-Life↝,1,   Hif1a↓,7,   Hif1a↝,1,   IL1β↓,1,   IL2↓,1,   IL8↓,1,   IRE1↑,1,   JNK↑,1,   MMP↓,1,   MMPs↓,1,   NF-kB↓,1,   P53↑,1,   PARP∅,1,   PDK1↓,1,   Risk↓,1,   ROS↑,4,   SVCT-2∅,1,   TET1↑,1,   TET2↑,2,   TNF-α↓,1,   TumMeta↓,1,   VEGF↓,2,   YAP/TEAD↓,1,  
Total Targets: 37

Results for Effect on Normal Cells:
ER Stress↓,1,   Inflam↓,1,   Obesity↓,1,   ROS↓,1,  
Total Targets: 4

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a
8 Vitamin C (Ascorbic Acid)
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:166  Target#:143  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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