Vitamin C as a Modulator of the Response to Cancer Therapy – PMC

l-gluconolactone oxidase gene (GULO), which codes for the enzyme that catalyzes the final step in the biosynthesis of vitamin CnHighlight:Gulo−/− knockout mouse strain represents a more faithful biological model for studies of human vitamin C metabolismnHighlight:Vitamin C is present in the bloodstream at approximately 50–100 μM concentration in plasma of healthy subjectsnHighlight:sodium-dependent vitamin C transporters (SVCT 1 and 2) for AA transport or GLUT1, 3, and 4 for DHA entrynHighlight:Dietary consumption of vitamin C results in lower plasma levels of ascorbate than intravenous injectionnHighlight:AA in the blood is transientnHighlight:brain and heart were found to accumulate higher levels of AA than other organsnHighlight:At physiological concentrations, AA is known for its antioxidant properties (by scavenging free radicals) and its importance in collagen synthesisnHighlight:cofactor in the enzymatic hydroxylation of lysine and proline residuesnHighlight:cofactor for approximately 150 human enzymesnHighlight:neither the U.S. Food and Drug Administration nor European Medicines Agency has approved the use of intravenous high-dose vitamin C as a treatment for cancer.nSticky notes:Do we need their stamp of approval?nHighlight:Vitamin C has been shown to diminish the effects of chemotherapy due to its antioxidant properties when applied in low/physiological concentrationsnHighlight:data indicate that combining high-dose vitamin C with anticancer therapies inhibits tumor growth in models of pancreatic [36,37], liver [38], prostate [39], ovarian cancer [40], sarcoma [41] and malignant mesotheliomanHighlight:intravenous administration of vitamin C was well tolerated even at doses up to 1.5 g/kg of body weight or 70–80 g/m² [38]. ItnHighlight:Pires et al. found that simultaneous administration of ascorbate with oxaliplatin or irinotecan inhibited tumor growth in vivo, and the effect was significantly higher compared to that of these compounds alonenHighlight:potent chemosensitizernHighlight:high AA dosage on ovarian cancer cells observed induction of DNA damage, depletion of cellular ATP, and activation of the corresponding stress signaling kinases, ATM (ataxia telangiectasia mutated) and AMPK (AMP-activated protein kinase). The resulting repression of mTOR led to death of cancer cellsnHighlight:combination of parenteral AA with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancernHighlight:reduced chemotherapy-associated toxicitynHighlight:In vitro studies with a different cell model also detected synergistic effects of AA cotreatment with carboplatin and paclitaxelnHighlight:Physiological levels of vitamin C efficiently detoxify reactive oxygen species (ROS) and reactive nitrogen speciesnHighlight:metabolic remodeling is a heightened aggressiveness of the disease, which is manifested by resistance to therapy and decreased patient survivalnHighlight:A crucial mediator of the hypoxic response is the transcription factors HIF-1 and HIF-2nHighlight:these factors upregulate the expression of hundreds of genes that upregulate angiogenesis, glucose uptake, anaerobic metabolism, and cell motility [nHighlight:intracellular ascorbate suppresses the transcriptional activity of HIF-1 and HIF-2.nHighlight:AA at physiological concentrations significantly suppressed HIF-1α levels and expression of HIF-1 transcriptional targets in cancer cell lines [52]. However, the intracellular ascorbate content in many aggressive cancers may be suboptimal for the effective HIF-1 control [52,53,54], which can potentially be remediated by administration of pharmacological doses of vitamin CnHighlight:Metabolic reprogramming of all transformed cells is associated with overexpression of glucose transporters such as GLUT-1, GLUT-3 or GLUT-4nHighlight:GLUT and glycolysis genes are also positively regulated by HIF-1 as a part of the cellular adaptation to the low-nutrient conditions and high growth conditionsnHighlight:glucose uptake and glycolytic metabolism are enhanced in cancer compared to normal cellsnHighlight:In normal cells, GLUTs are unlikely to play a major role in the uptake of vitamin C due to competition from much higher concentrations of glucosenHighlight:The overabundance of GLUT transporters in cancer cells diminishes the inhibitory effects of glucose, permitting a higher accumulation of cellular vitamin C through uptake of DHAnHighlight:the heightened ability of GLUT-overexpressing cancer cells offers the opportunity to selectively overload them with ascorbatenHighlight:high doses of vitamin C selectively killed colon cancer cells harboring mutated BRAF or KRAS through hyperaccumulation of its oxidized form, DHA, via GLUT-1nHighlight:High DHA uptake caused a severe oxidative stress as a result of reduction of DHA to AA and the associated depletion of glutathione. The rise in ROS caused inactivation of the essential glycolytic enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase), resulting in the energy crisis and cell death.nHighlight:cells with high GLUT1 (glucose transporter) expression were more sensitive to AA treatment than cells with low GLUT1 expressionnHighlight:consistent with a contribution of GLUTs to vitamin C transport into the cellsnHighlight:A higher sensitivity of GLUT1-overexpressing cancer cells may not entirely be due to a higher cellular accumulation of vitamin C, as a greater glycolysis dependence or a modulation of enzymatic activities associated with the GLUT1-high phenotype could play a significant role in AA sensitivity.nHighlight:At high concentrations, AA can act as a pro-oxidant which in part results from its ability to effectively reduce Fe³⁺ and Cu²⁺ leading to elevated hydroxyl radical production in the Fenton reaction between Fe²⁺/Cu⁺ and H₂O₂nSticky notes:Through fenton reaction which produces OH-nHighlight:use of AA was considered as a part of strategy to exploit cancer vulnerabilitiesnHighlight:In light of its metal-reducing and antioxidant properties, AA may significantly contribute to the biological effects of bleomycinn]]>