High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients

2) (a Latin-derived word, meaning “without scurvy”)nHighlight:ascorbate anion (AscH),nHighlight:reduced dominant form of vitamin C at physiological pHnHighlight:AscH undergoes oxidation and this reaction is dependent on pH and is accelerated by catalytic metals (e.g., iron)nHighlight:In particular, AscH undergoes one-electron oxidation to form the ascorbate radical (Asc•−).nHighlight:Donation of the second electron gives rise to dehydroascorbic acid (DHA), the fully oxidized form of vitamin CnHighlight:The ascorbate radical is relatively unreactivenHighlight:These oxidation reactions are coupled with reactive oxygen species (ROS) formation and metals reduction.nHighlight:After transporter-mediated entry into the cell, the DHA form is reduced back to ascorbate. This reaction involves glutathione (GSH) and enzymatic activities like glutaredoxin or other dehydroascorbate reductases with generation of the oxidized glutathione disulfide form (GSSG). The subsequent reduction in GSSG is mediated by the NADPH-dependent glutathione reductasenHighlight:GLUT transportersnHighlight:Ascorbate also donates electrons to metals such as copper and ironnHighlight:SVCT1 is expressed at the apical level in the epithelial intestinal and renal proximal tubules cells in addition to liver and lungnHighlight:SVCT1 is involved in the intestinal absorption of vitamin C and in its renal re-absorption back to the bloodnHighlight:SVCT2 is expressed throughout the body tissues (with the exception of red blood cells)nHighlight:this uptake-pathway maintains the homeostatic physiological concentration of vitamin C in the blood nHighlight:When Ca2+ and Mg2+ are absent, the SVCT2 transport system is in an inactive conformation, despite the presence of Na+ nSticky notes:Reason to add Ca and MgnHighlight:Another possibility for vitamin C entry into the cells is in its DHA form that is transported through a facilitated diffusion mechanism by glucose transporters (GLUT)nHighlight:a diet rich in free sugars inhibits DHA gut absorptionnHighlight:DHA competes with glucose to be transported via GLUT1 and GLUT3nHighlight:GLUTs affinity for DHA (Km ~1–3 mM) is lower than SVCTs affinity for ascorbatenHighlight:In normal conditions, the glucose concentration (2–5 mM) in the blood is much higher than DHA (˂2 μM); therefore, cell uptake of ascorbate through SVCT2 is preferrednHighlight:Interestingly, the rate of DHA uptake via GLUT1 and GLUT3 in cancer cells is faster than the uptake of ascorbate through SVCT2, even in the presence of glucosenHighlight:In tumor microenvironment oxidizing conditions, the prominent extracellular form of vitamin C is likely DHA that is taken up by the cells and rapidly reduced back to ascorbate, creating a steep gradient across the cell membrane. Furthermore, due to the high requirement of glucose by cancer cells for their metabolism, the GLUT transporters are up-regulated, contributing to DHA intake [,,,].nSticky notes:KeynHighlight:Studies in humans have revealed that oral doses exceeding 250 mg/day produce plateau plasma concentrations that never exceed 100 µMnSticky notes:Key point—fixednHighlight:Phase 1 studies identified 3 g of vitamin C orally administered every 4 h (12 g/day) as the maximum tolerated dose, with maximum plasma concentrations of 220 µMnHighlight:In contrast, when the plasma ascorbate levels are higher than 70–80 µM (oral doses >100 g/d), renal excretion increases because of saturated tubular re-absorption at the kidney level and the ascorbate plasma half-life is very short (~30 min)nHighlight:studies performed in cancer patient have demonstrated that after I.V. administration, the tight control mechanisms of intestinal absorption are by-passed and the observed vitamin C plasma concentrations are in the millimolar rangenHighlight:100-fold higher than those detected after oral dosesnHighlight:vitamin C reaches a plasma peak higher than 20 mM and shows a half-life of 2 hnHighlight:the elevated inflammation and oxidative stress presents in cancer patients results in increased vitamin C utilization and lower plasma levels comparing to healthy peoplenHighlight:vitamin C pharmacokinetic properties depend on the route of administration used, the results of studies with oral or intravenous doses are not directly comparablenSticky notes:KeynHighlight:weekly I.V. administration of high-dose vitamin C to prostate cancer patients did not induce tumor regressionnHighlight:it has been suggested that in patients with an intact kidney function, a bolus loading dose followed by a maintenance continuous infusion is likely required to achieve a steady-state plasma concentration of vitamin C in the millimolar rangenHighlight:many of the first studies testing vitamin C as single agent were done in terminal patients without tumors stratification and a clear definition of efficacy endpointsnHighlight:future randomized clinical trials should be designed to evaluate vitamin C activity in specific tumor molecular subtypes, such as those characterized by HIF-1α over-expression and TET2, L2HGDH, IDH1/2, or WT1 altered pathwaysnHighlight:intravenous treatment with ascorbate induced clinical remission in a patient with AML carrying TET2 and WT1 mutations in separate clones, after failure of induction chemotherapynHighlight:induction of DNA demethylationnHighlight:conversion of 5mC to 5hmC deriving from vitamin C-mediated activation of TETs may synergize with passive DNA demethylation (i.e., absence of methylation of newly synthesized DNA strands) obtained by azacytidine or decitabine that are inhibitors of DNMT1nHighlight:I.V. administration of low-dose vitamin C in combination with decitabine to elderly AML patients resulted in enhanced TET2 activity and improved clinical responsenHighlight:role in modulating the BER pathwaynHighlight:enhance the activity of PARP inhibitors reducing the viability of human AML and promyelocytic leukemia cell linesnHighlight:a case study on eight cancer patients with advanced stage malignancies characterized by defects in the homologous recombination repair system showed that I.V. vitamin C in combination with PARP inhibitors (niraparib or olaparib or talazoparib) induced 37.5% complete remissions (3 patients out of 8)nHighlight:oxalate nephropathy in patients with renal impairment due to increased urinary excretion of oxalate as end-product of vitamin C metabolismnHighlight:severe hemolysis in patients with paroxysmal nocturnal hemoglobinuria or with glucose-6-phosphate dehydrogenase deficiency due to erythrocyte inability to maintain glutathione in its reduced formnHighlight:increased risk of thrombosis in cancer patients due to procoagulant activation of erythrocytesn]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.

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