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| 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 Selenium supplementation may protect cells against iron-dependent cell death by supporting increased expression of selenoproteins, including GPX4, which defend against oxidative stress. Meaning it may decrease effectiveness of high dose VitC.(#4468) |
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| Citrate is a key metabolite involved in cellular energy metabolism, and its levels are often elevated cancer cells. -Citrate is a key substrate for the citric acid cycle (also known as the Krebs cycle or tricarboxylic acid cycle), which is involved in cellular energy metabolism. -Citrate is also involved in the regulation of glycolysis, which is the primary source of energy for many cancer cells. -Citrate has been shown to promote cancer cell growth and survival by regulating various signaling pathways, including the PI3K/AKT pathway. High citrate levels are often associated with poor prognosis in various cancers, including breast, lung, colorectal, prostate, pancreatic, ovarian, and glioblastoma. – Several studies have reported that in certain aggressive tumors, intracellular citrate levels tend to be lower relative to adjacent normal tissues. This is thought to be due to increased utilization of citrate for anabolic processes (e.g., fatty acid synthesis). It was found that the citrate levels of normal human prostate tissue are uniquely much higher than those in malignant prostate tissue (43.1 versus 19.9 mmol/kg). Furthermore, the drastic decrease of citrate level (up to 40-fold in early and 80-fold in advanced stages) in prostate cancer tissues in comparison to normal prostatic tissues is a key characteristic utilized to distinguish between normal and hyperplastic glands. In addition to prostate cancer, citrate levels are significantly decreased in blood of patients with lung, bladder, pancreas and esophagus cancers compared with healthy persons. As a consequence, normal prostate has high concentrations of citrate whereas prostate cancer has low concentrations of citrate. It was widely believed that cancer cells did not take up citrate from the circulation (blood levels of citrate, ~200 μM) and that they met their increased demands for this metabolite via de no synthesis from glutamine (Metallo et al., 2011). This requires a novel reprogramming of the metabolism involving the reversal of the Krebs cycle in which α-ketoglutarate arising from glutamine gets converted into citrate by a process known as “reductive carboxylation.” Indeed, uptake of glutamine resulting from increased expression of multiple glutamine transporters has been associated with cancer cells. Citrate is not only a metabolic intermediate but also a critical signaling node that affects epigenetic regulation (via acetyl-CoA), lipogenesis, and cellular survival pathways. The expression levels of ACLY, SLC25A1, IDH1/2, FASN, and SREBF1 have emerged as important prognostic biomarkers or therapeutic targets in various cancers. -Lower plasma citrate levels have been observed in some cancer patients, suggesting that the tumor’s high metabolic demand may deplete circulating citrate. While many tumors show reduced tissue citrate due to its rapid utilization in anabolic pathways, circulating citrate levels can also be altered, potentially serving as noninvasive biomarkers. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Citrate is a gauge of nutrients available for biosynthesis and ATP production generated via oxidative phosphorylation (OXPHOS). In addition, citrate is a key regulatory molecule, which targets (directly or indirectly) catabolic and anabolic pathways (fatty acid β-oxidation (FAO) and FAS, glycolysis, and gluconeogenesis) in a manner such that when one pathway is activated, the other is inhibited. For example, citrate directly inhibits the main regulators of glycolysis, phosphofructokinase-1 (PFK1) and phosphofructokinase-2 (PFK2) [2,3], while it enhances gluconeogenesis by promoting fructose-1,6-biphosphatase (FBPase). Hypothesis that a low citrate level promotes the Warburg effect. |
| 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 |
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
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