Targeting cancer vulnerabilities with high-dose vitamin C


Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.

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Fig. 1: Integrated pro-oxidant mechanism of vitamin C and cancer cell cytotoxicity.
Fig. 2: Regulation of TET enzymes by ascorbate.
Fig. 3: Ascorbate and HIF1α regulation.


  1. 1.

    Strebhardt, K. & Ullrich, A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat. Rev. Cancer 8, 473–480 (2008).

    CAS  Google Scholar 

  2. 2.

    Levine, M., Padayatty, S. J. & Espey, M. G. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv. Nutr. 2, 78–88 (2011).

    CAS  Google Scholar 

  3. 3.

    Nauman, G. et al. Systematic review of intravenous ascorbate in cancer clinical trials. Antioxidants 7, E89 (2018).

    Google Scholar 

  4. 4.

    Padayatty, S. J. & Levine, M. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 22, 463–493 (2016).

    CAS  Google Scholar 

  5. 5.

    Maeda, N. et al. Aortic wall damage in mice unable to synthesize ascorbic acid. Proc. Natl Acad. Sci. USA 97, 841–846 (2000).

    CAS  Google Scholar 

  6. 6.

    Corti, A., Casini, A. F. & Pompella, A. Cellular pathways for transport and efflux of ascorbate and dehydroascorbate. Arch. Biochem. Biophys. 500, 107–115 (2010).

    CAS  Google Scholar 

  7. 7.

    Vera, J. C. et al. Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid. Blood 84, 1628–1634 (1994).

    CAS  Google Scholar 

  8. 8.

    Wilson, J. X. The physiological role of dehydroascorbic acid. FEBS Lett. 527, 5–9 (2002).

    CAS  Google Scholar 

  9. 9.

    Buettner, G. R. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch. Biochem. Biophys. 300, 535–543 (1993).

    CAS  Google Scholar 

  10. 10.

    Lane, D. J. R. & Richardson, D. R. The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption! Free Radic. Biol. Med. 75, 69–83 (2014).

    CAS  Google Scholar 

  11. 11.

    Kuiper, C. & Vissers, M. C. M. Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front. Oncol. 4, 359 (2014).

    Google Scholar 

  12. 12.

    Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453–R462 (2014).

    CAS  Google Scholar 

  13. 13.

    Chio, I. I. C. & Tuveson, D. A. ROS in cancer: the burning question. Trends Mol. Med. 23, 411–429 (2017).

    CAS  Google Scholar 

  14. 14.

    Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl Med. 6, 221ra15 (2014). This study demonstrates that dietary supplementation of antioxidants ( N -acetylcysteine and vitamin E) markedly increases tumour progression and reduces survival in mouse models of KRAS-induced or BRAF-induced lung cancer.

    Google Scholar 

  15. 15.

    Le Gal, K. et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl Med. 7, 308re8 (2015).

    Google Scholar 

  16. 16.

    Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).

    CAS  Google Scholar 

  17. 17.

    Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 306, 1549–1556 (2011).

    CAS  Google Scholar 

  18. 18.

    Omenn, G. S. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155 (1996).

    CAS  Google Scholar 

  19. 19.

    Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029–1035 (1994).

    Google Scholar 

  20. 20.

    Wondrak, G. T. Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid. Redox Signal. 11, 3013–3069 (2009).

    CAS  Google Scholar 

  21. 21.

    Torti, S. V. & Torti, F. M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013).

    CAS  Google Scholar 

  22. 22.

    DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).

    Google Scholar 

  23. 23.

    Manz, D. H. et al. Iron and cancer: recent insights. Ann. NY Acad. Sci. 1368, 149–161 (2016).

    CAS  Google Scholar 

  24. 24.

    Hentze, M. W. et al. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24–38 (2010).

    CAS  Google Scholar 

  25. 25.

    Du, J., Cullen, J. J. & Buettner, G. R. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta 1826, 443–457 (2012).

    CAS  Google Scholar 

  26. 26.

    Chen, Q. et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl Acad. Sci. USA 102, 13604–13609 (2005).

    CAS  Google Scholar 

  27. 27.

    Du, J. et al. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin. Cancer Res. 16, 509–520 (2010).

    CAS  Google Scholar 

  28. 28.

    Rawal, M. et al. Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation. Cancer Res. 73, 5232–5241 (2013).

    CAS  Google Scholar 

  29. 29.

    Duarte, T. L., Almeida, G. M. & Jones, G. D. D. Investigation of the role of extracellular H2O2 and transition metal ions in the genotoxic action of ascorbic acid in cell culture models. Toxicol. Lett. 170, 57–65 (2007).

    CAS  Google Scholar 

  30. 30.

    Sakagami, H. et al. Effect on an iron-chelator on ascorbate-induced cytotoxicity. Free Radic. Biol. Med. 23, 260–270 (1997).

    CAS  Google Scholar 

  31. 31.

    Buettner, G. R. & Jurkiewicz, B. A. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat. Res. 145, 532–541 (1996).

    CAS  Google Scholar 

  32. 32.

    Clément, M. V. et al. The in vitro cytotoxicity of ascorbate depends on the culture medium used to perform the assay and involves hydrogen peroxide. Antioxid. Redox Signal. 3, 157–163 (2001).

    Google Scholar 

  33. 33.

    Carr, A. & Frei, B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 13, 1007–1024 (1999).

    CAS  Google Scholar 

  34. 34.

    Halliwell, B. Vitamin C: antioxidant or pro-oxidant in vivo? Free Radic. Res. 25, 439–454 (1996).

    CAS  Google Scholar 

  35. 35.

    Chen, Q. et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl Acad. Sci. USA 104, 8749–8754 (2007). This study shows that pharmacological ascorbate is a prodrug for preferential steady-state formation of Asc •− and H2O2 in the extracellular space but not in the blood in vivo system.

    CAS  Google Scholar 

  36. 36.

    Ma, E. et al. Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis. Free Radic. Biol. Med. 113, 36–47 (2017).

    CAS  Google Scholar 

  37. 37.

    Rychtarcikova, Z. et al. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget 8, 6376–6398 (2017).

    Google Scholar 

  38. 38.

    Kiessling, M. K. et al. Inhibition of constitutively activated nuclear factor-kappaB induces reactive oxygen species- and iron-dependent cell death in cutaneous T cell lymphoma. Cancer Res. 69, 2365–2374 (2009).

    CAS  Google Scholar 

  39. 39.

    Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl Med. 2, 43ra56 (2010).

    Google Scholar 

  40. 40.

    Corna, G. et al. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 95, 1814–1822 (2010).

    CAS  Google Scholar 

  41. 41.

    Recalcati, S. et al. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur. J. Immunol. 40, 824–835 (2010).

    CAS  Google Scholar 

  42. 42.

    Panis, C. et al. Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer. Breast Cancer Res. Treat. 133, 881–888 (2012).

    CAS  Google Scholar 

  43. 43.

    Schoenfeld, J. D. et al. O2 •− and H2O2 mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 31, 487–500 (2017). This study shows that pharmacological ascorbate selectively sensitizes non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells by generating redox-active labile iron and H 2O2 using in vitro cell lines and mouse models. In addition, it shows the potential efficacy of ascorbate therapy combined with other chemotherapies in patients with GBM and NSCLC.

    CAS  Google Scholar 

  44. 44.

    Xia, J. et al. Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid. EBioMedicine 18, 41–49 (2017).

    Google Scholar 

  45. 45.

    Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    CAS  Google Scholar 

  46. 46.

    Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).

    CAS  Google Scholar 

  47. 47.

    Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells.

    CAS  Google Scholar 

  48. 48.

    Nualart, F. J. et al. Recycling of vitamin C by a bystander effect. J. Biol. Chem. 278, 10128–10133 (2003).

    CAS  Google Scholar 

  49. 49.

    May, J. M. et al. Ascorbate recycling in human erythrocytes: role of GSH in reducing dehydroascorbate. Free Radic. Biol. Med. 20, 543–551 (1996).

    CAS  Google Scholar 

  50. 50.

    Tu, H. et al. Chemical transport knockout for oxidized vitamin C, dehydroascorbic acid, reveals its functions in vivo. EBioMedicine 23, 125–135 (2017).

    Google Scholar 

  51. 51.

    Lu, Y.-X. et al. Pharmacological ascorbate suppresses growth of gastric cancer cells with GLUT1 overexpression and enhances the efficacy of oxaliplatin through redox modulation. Theranostics 8, 1312–1326 (2018).

    CAS  Google Scholar 

  52. 52.

    Tian, W. et al. The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity. J. Biol. Chem. 289, 3339–3351 (2014).

    CAS  Google Scholar 

  53. 53.

    Vera, J. C. et al. Resolution of the facilitated transport of dehydroascorbic acid from its intracellular accumulation as ascorbic acid. J. Biol. Chem. 270, 23706–23712 (1995).

    CAS  Google Scholar 

  54. 54.

    Szatrowski, T. P. & Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991).

    CAS  Google Scholar 

  55. 55.

    Policastro, L. L. et al. The tumor microenvironment: characterization, redox considerations, and novel approaches for reactive oxygen species-targeted gene therapy. Antioxid. Redox Signal. 19, 854–895 (2013).

    CAS  Google Scholar 

  56. 56.

    Rees, D. C., Kelsey, H. & Richards, J. D. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 306, 841–842 (1993).

    CAS  Google Scholar 

  57. 57.

    Quinn, J. et al. Effect of high-dose vitamin C infusion in a glucose-6-phosphate dehydrogenase-deficient patient. Case Rep. Med. 2017, 5202606 (2017).

    Google Scholar 

  58. 58.

    Rakitzis, E. T. & Papandreou, P. T. Ascorbate-induced generation of free radical species in normal and glucose-6-phosphate dehydrogenase-deficient erythrocytes. Biochem. Soc. Trans. 17, 371–372 (1989).

    CAS  Google Scholar 

  59. 59.

    Mehta, J., Singhal, S. & Mehta, B. Ascorbic-acid-induced haemolysis in G-6-PD deficiency. Lancet 336, 944 (1990).

    CAS  Google Scholar 

  60. 60.

    Gaetani, G. F. et al. Predominant role of catalase in the disposal of hydrogen peroxide within human erythrocytes. Blood 87, 1595–1599 (1996).

    CAS  Google Scholar 

  61. 61.

    May, J. M., Qu, Z. & Morrow, J. D. Mechanisms of ascorbic acid recycling in human erythrocytes. Biochim. Biophys. Acta 1528, 159–166 (2001).

    CAS  Google Scholar 

  62. 62.

    Yun, J. et al. Interactions between epigenetics and metabolism in cancers. Front. Oncol. 2, 163 (2012).

    Google Scholar 

  63. 63.

    Rasmussen, K. D. & Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30, 733–750 (2016).

    CAS  Google Scholar 

  64. 64.

    Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).

    Google Scholar 

  65. 65.

    Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  Google Scholar 

  66. 66.

    Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    CAS  Google Scholar 

  67. 67.

    Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095 (2017). Using genetic mouse models of leukaemia, vitamin C is shown to enhance TET2 activity, increase DNA demethylation and suppress leukaemia progression.

    CAS  Google Scholar 

  68. 68.

    Mingay, M. et al. Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 32, 11–20 (2018).

    CAS  Google Scholar 

  69. 69.

    Shenoy, N. et al. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 7, e587 (2017).

    CAS  Google Scholar 

  70. 70.

    Gustafson, C. B. et al. Epigenetic reprogramming of melanoma cells by vitamin C treatment. Clin. Epigenetics 7, 51 (2015).

    Google Scholar 

  71. 71.

    Peng, D. et al. Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer. Clin. Epigenetics 10, 94 (2018).

    Google Scholar 

  72. 72.

    Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476–481 (2017). Using various GEMMs, including GULO-knockout mice, this study reveals that vitamin C is necessary for normal haematopoietic stem cell development and the prevention of leukaemia in mice.

    Google Scholar 

  73. 73.

    Monfort, A. & Wutz, A. Breathing-in epigenetic change with vitamin C. EMBO Rep. 14, 337–346 (2013).

    CAS  Google Scholar 

  74. 74.

    Fedeles, B. I. et al. The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J. Biol. Chem. 290, 20734–20742 (2015).

    CAS  Google Scholar 

  75. 75.

    Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    CAS  Google Scholar 

  76. 76.

    Koivunen, P. et al. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279, 9899–9904 (2004).

    CAS  Google Scholar 

  77. 77.

    Vissers, M. C. M. & Das, A. B. Potential mechanisms of action for vitamin C in cancer: reviewing the evidence. Front. Physiol. 9, 809 (2018).

    Google Scholar 

  78. 78.

    Wilkes, J. G. et al. Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. Clin. Exp. Metastasis 35, 37–51 (2018).

    CAS  Google Scholar 

  79. 79.

    Gao, P. et al. HIF-dependent anti-tumorigenic effect of anti-oxidants in vivo. Cancer Cell 12, 230–238 (2007).

    CAS  Google Scholar 

  80. 80.

    Józwiak, P. et al. Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions. J. Biomed. Sci. 24, 83 (2017).

    Google Scholar 

  81. 81.

    Campbell, E. J. et al. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(−/−) mice. Cancer Med. 4, 303–314 (2015).

    CAS  Google Scholar 

  82. 82.

    Campbell, E. J., Vissers, M. C. & Dachs, G. U. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo−/− mice. Hypoxia 4, 41–52 (2016).

    Google Scholar 

  83. 83.

    Campbell, E. J. et al. Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice. Free Radic. Biol. Med. 99, 451–462 (2016).

    CAS  Google Scholar 

  84. 84.

    Kuiper, C. et al. Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4, 10 (2014).

    Google Scholar 

  85. 85.

    Wohlrab, C. et al. The association between ascorbate and the hypoxia-inducible factors in human renal cell carcinoma requires a functional Von Hippel-Lindau protein. Front. Oncol. 8, 574 (2018).

    Google Scholar 

  86. 86.

    Kuiper, C. et al. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 70, 5749–5758 (2010).

    CAS  Google Scholar 

  87. 87.

    King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006).

    CAS  Google Scholar 

  88. 88.

    Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).

    CAS  Google Scholar 

  89. 89.

    Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).

    CAS  Google Scholar 

  90. 90.

    Gill, A. J. et al. Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. N. Engl. J. Med. 364, 885–886 (2011).

    CAS  Google Scholar 

  91. 91.

    Pasini, B. & Stratakis, C. A. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J. Intern. Med. 266, 19–42 (2009).

    CAS  Google Scholar 

  92. 92.

    Clark, G. R. et al. Germline FH mutations presenting with pheochromocytoma. J. Clin. Endocrinol. Metab. 99, E2046–E2050 (2014).

    CAS  Google Scholar 

  93. 93.

    Cameron, E. & Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc. Natl Acad. Sci. USA 73, 3685–3689 (1976). This study is the first large-scale clinical trial designed to analyse the efficacy of high-dose ascorbate for the treatment of cancer.

    CAS  Google Scholar 

  94. 94.

    Cameron, E. & Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl Acad. Sci. USA 75, 4538–4542 (1978).

    CAS  Google Scholar 

  95. 95.

    Creagan, E. T. et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 301, 687–690 (1979). This large-scale clinical trial shows that daily oral intake of high-dose vitamin C had no therapeutic benefit in patients with cancer.

    CAS  Google Scholar 

  96. 96.

    Moertel, C. G. et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N. Engl. J. Med. 312, 137–141 (1985).

    CAS  Google Scholar 

  97. 97.

    Padayatty, S. J. et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Intern. Med. 140, 533–537 (2004). This paper emphasizes the importance of the route of administration of vitamin C and explains why two early clinical trials of vitamin C as an anticancer therapy had conflicting results.

    CAS  Google Scholar 

  98. 98.

    Hoffer, L. J. et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann. Oncol. 19, 1969–1974 (2008).

    CAS  Google Scholar 

  99. 99.

    Klimant, E. et al. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr. Oncol. 25, 139–148 (2018).

    CAS  Google Scholar 

  100. 100.

    Carr, A. C. & Cook, J. Intravenous vitamin C for cancer therapy — identifying the current gaps in our knowledge. Front. Physiol. 9, 1182 (2018).

    Google Scholar 

  101. 101.

    Kuiper, C., Vissers, M. C. M. & Hicks, K. O. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. Free Radic. Biol. Med. 77, 340–352 (2014).

    CAS  Google Scholar 

  102. 102.

    Cao, D. et al. Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 9, 432 (2009).

    Google Scholar 

  103. 103.

    Tian, Y. et al. Association of TET1 expression with colorectal cancer progression. Scand. J. Gastroenterol. 52, 312–320 (2017).

    CAS  Google Scholar 

  104. 104.

    Mustafi, S. et al. Vitamin C sensitizes melanoma to BET inhibitors. Cancer Res. 78, 572–583 (2018).

    CAS  Google Scholar 

  105. 105.

    Du, J. et al. Pharmacological ascorbate radiosensitizes pancreatic cancer. Cancer Res. 75, 3314–3326 (2015).

    CAS  Google Scholar 

  106. 106.

    Liu, M. et al. Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine. Proc. Natl Acad. Sci. USA 113, 10238–10244 (2016).

    CAS  Google Scholar 

  107. 107.

    Zhao, H. et al. The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk. Res. 66, 1–7 (2018).

    CAS  Google Scholar 

  108. 108.

    Gillberg, L. et al. Vitamin C — a new player in regulation of the cancer epigenome. Semin. Cancer Biol. 51, 59–67 (2017).

    Google Scholar 

  109. 109.

    Carr, A. C. & Maggini, S. Vitamin C and immune function. Nutrients 9, 1211 (2017).

    Google Scholar 

  110. 110.

    Sorice, A. et al. Ascorbic acid: its role in immune system and chronic inflammation diseases. Mini Rev. Med. Chem. 14, 444–452 (2014).

    CAS  Google Scholar 

  111. 111.

    Ang, A. et al. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans. 46, 1147–1159 (2018).

    CAS  Google Scholar 

  112. 112.

    Hausinger, R. P. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004).

    CAS  Google Scholar 

  113. 113.

    Kersten, K. et al. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 9, 137–153 (2017).

    CAS  Google Scholar 

  114. 114.

    Ma, Y. et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl Med. 6, 222ra18 (2014). This paper shows in its preclinical and clinical studies that high-dose vitamin C can potentially increase the efficacy and reduce the toxicities of certain conventional chemotherapies when used in combination to treat patients with ovarian cancer.

    Google Scholar 

  115. 115.

    May, J. M. The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C. Br. J. Pharmacol. 164, 1793–1801 (2011).

    CAS  Google Scholar 

  116. 116.

    Corpe, C. P. et al. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J. Clin. Invest. 120, 1069–1083 (2010).

    CAS  Google Scholar 

  117. 117.

    Sotiriou, S. et al. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat. Med. 8, 514–517 (2002).

    CAS  Google Scholar 

  118. 118.

    Vera, J. C. et al. Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364, 79–82 (1993).

    CAS  Google Scholar 

  119. 119.

    Spielholz, C. et al. Increased facilitated transport of dehydroascorbic acid without changes in sodium-dependent ascorbate transport in human melanoma cells. Cancer Res. 57, 2529–2537 (1997).

    CAS  Google Scholar 

  120. 120.

    Agus, D. B., Vera, J. C. & Golde, D. W. Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. Cancer Res. 59, 4555–4558 (1999).

    CAS  Google Scholar 

  121. 121.

    Mayland, C. R., Bennett, M. I. & Allan, K. Vitamin C deficiency in cancer patients. Palliat. Med. 19, 17–20 (2005).

    Google Scholar 

  122. 122.

    Anthony, H. M. & Schorah, C. J. Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br. J. Cancer 46, 354–367 (1982).

    CAS  Google Scholar 

  123. 123.

    Ullah, M. F. et al. Ascorbic acid in cancer chemoprevention: translational perspectives and efficacy. Curr. Drug Targets 13, 1757–1771 (2012).

    CAS  Google Scholar 

  124. 124.

    Lee, K. W. et al. Vitamin C and cancer chemoprevention: reappraisal. Am. J. Clin. Nutr. 78, 1074–1078 (2003).

    CAS  Google Scholar 

  125. 125.

    Khaw, K. T. et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet 357, 657–663 (2001).

    CAS  Google Scholar 

  126. 126.

    Luo, J., Shen, L. & Zheng, D. Association between vitamin C intake and lung cancer: a dose-response meta-analysis. Sci. Rep. 4, 6161 (2014).

    CAS  Google Scholar 

  127. 127.

    Harris, H. R., Orsini, N. & Wolk, A. Vitamin C and survival among women with breast cancer: a meta-analysis. Eur. J. Cancer 50, 1223–1231 (2014).

    CAS  Google Scholar 

  128. 128.

    Harris, H. R., Bergkvist, L. & Wolk, A. Vitamin C intake and breast cancer mortality in a cohort of Swedish women. Br. J. Cancer 109, 257–264 (2013).

    CAS  Google Scholar 

  129. 129.

    Wohlrab, C., Phillips, E. & Dachs, G. U. Vitamin C transporters in cancer: current understanding and gaps in knowledge. Front. Oncol. 7, 74 (2017).

    Google Scholar 

  130. 130.

    Michels, A. J., Hagen, T. M. & Frei, B. Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Annu. Rev. Nutr. 33, 45–70 (2013).

    CAS  Google Scholar 

  131. 131.

    Savini, I. et al. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34, 347–355 (2008).

    CAS  Google Scholar 

  132. 132.

    Wright, M. E. et al. Genetic variation in sodium-dependent ascorbic acid transporters and risk of gastric cancer in Poland. Eur. J. Cancer 45, 1824–1830 (2009).

    CAS  Google Scholar 

  133. 133.

    Casabonne, D. et al. Fruit and vegetable intake and vitamin C transporter gene (SLC23A2) polymorphisms in chronic lymphocytic leukaemia. Eur. J. Nutr. 56, 1123–1133 (2017).

    CAS  Google Scholar 

  134. 134.

    Duell, E. J. et al. Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort. Genes Nutr. 8, 549–560 (2013).

    CAS  Google Scholar 

  135. 135.

    Mastrangelo, D. et al. Mechanisms of anti-cancer effects of ascorbate: Cytotoxic activity and epigenetic modulation. Blood Cells. Mol. Dis. 69, 57–64 (2018).

    CAS  Google Scholar 

  136. 136.

    Bienert, G. P. & Chaumont, F. Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide. Biochim. Biophys. Acta 1840, 1596–1604 (2014).

    CAS  Google Scholar 

  137. 137.

    Uetaki, M. et al. Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress. Sci. Rep. 5, 13896 (2015).

    Google Scholar 

  138. 138.

    Li, R. Vitamin C, a multi-tasking molecule, finds a molecular target in killing cancer cells. React. Oxyg. Species 1, 141–156 (2016).

    Google Scholar 

  139. 139.

    Young, J. I., Züchner, S. & Wang, G. Regulation of the epigenome by vitamin C. Annu. Rev. Nutr. 35, 545–564 (2015).

    CAS  Google Scholar 

  140. 140.

    Camarena, V. & Wang, G. The epigenetic role of vitamin C in health and disease. Cell. Mol. Life Sci. 73, 1645–1658 (2016).

    CAS  Google Scholar 

  141. 141.

    Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8, 705–713 (2008).

    CAS  Google Scholar 

  142. 142.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01852890 (2018).

  143. 143.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01752491 (2018).

  144. 144.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03797443 (2019).

  145. 145.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03410030 (2019).

  146. 146.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02420314 (2019).

  147. 147.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03613727 (2018).

  148. 148.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02344355 (2018).

  149. 149.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03146962 (2018).

  150. 150.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02905591 (2018).

  151. 151.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02905578 (2018).

  152. 152.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02516670 (2019).

  153. 153.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03334409 (2019).

  154. 154.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03418038 (2018).

  155. 155.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03015675 (2017).

  156. 156.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02969681 (2019).

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The authors thank S. Wang in the Yun laboratory for helpful discussions and proofreading of the manuscript. The authors apologize for any references left uncited owing to space limitations. This work was supported by the US National Institutes of Health (NIH) grant R35 CA197588 (L.C.C.), Stand Up to Cancer–American Association for Cancer Research grant SU2C-AACR-DT22-17 (L.C.C.), the Cancer Prevention and Research Institute of Texas (CPRIT) grant RR170039 (J.Y.), the US National Cancer Institute (NCI) grant 1K22CA216036 (J.Y.), the US National Science Foundation Graduate Research Fellowship Program grant DGE1257284 (B.N.) and NCI grant 1F99CA234950-01 (B.N.). L.C.C. is a founder and member of the senior advisory boards of Agios Pharmaceuticals and Petra Pharmaceuticals, which are developing novel therapies for cancer. The L.C.C. laboratory also receives financial support from Petra Pharmaceuticals.

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Nature Reviews Cancer thanks J. Cullen, G. Dachs and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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L.C.C. and J.Y. contributed to the discussion of content of the article. J.Y. and B.N. researched data for the article. J.Y. and B.N. wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Lewis C. Cantley or Jihye Yun.

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2-Phosphate l-ascorbic acid

A derivative of ascorbate that is not oxidized in culture or serum but releases ascorbate once it is inside the cells via hydrolysis mediated by alkaline phosphatase on the plasma membrane.

5-Aza-CdR (decitabine)

A cytidine antimetabolite analogue that incorporates into DNA and inhibits DNA methyltransferase (DNMT) activity, which results in DNA demethylation (hypomethylation).


Any biological measurable indicators of the severity or presence of some disease state.

Fenton reaction

A chemical reaction that converts hydrogen peroxide into a highly toxic hydroxyl radical in the presence of labile iron.


A protein that contains iron and is the primary form of iron stored inside of cells.

Free radicals

Molecules possessing unpaired electrons and thus are reactive and short-lived in a biological setting.


An iron-containing group that gives myoglobin and haemoglobin the ability to bind oxygen.

Hydroxyl radical

(OH). A highly reactive and short-lived radical that attacks any molecule in its immediate vicinity, especially DNA, protein and lipids, eventually leading to cell death.


A BCR-ABL-selective tyrosine kinase inhibitor, also known as Gleevec. Imatinib has been used to treat chronic myelogenous leukaemia and acute lymphocytic leukaemia.

Intraperitoneal (IP) injection

Giving medicines or fluids into the peritoneum (body cavity), which is more often applied to animals than to humans.

Intravenous injection

Giving medicines or fluids through a needle or tube inserted into a vein, allowing them to enter the bloodstream immediately.

Michaelis constant

(Km). The substrate concentration at the half of the maximum velocity (Vmax). An enzyme with a high Km has a low affinity for its substrate and requires a greater concentration of substrate to achieve Vmax.

Parenteral injection

Giving medicine or fluids intravenously (into a vein), subcutaneously (under the skin) and intraperitoneally (into the peritoneum).


The study of the biochemical and physiological effects of drugs. Generally refers to the dose–response relationship for a particular drug.


The activity of drugs in the body over a period, including the processes by which drugs are absorbed, distributed in the body, localized in the tissues and excreted.

Pharmacological ascorbate

Intravenous or intraperitoneal delivery of vitamin C, which allows for plasma concentrations to reach the millimolar scale.

Physiological ascorbate

An oral dose of dietary vitamin C, usually resulting in a peak plasma concentration of 200 μM.

Predictive biomarkers

A biomarker that gives information about the effect of a therapeutic intervention.


A group that is a tightly bound, specific non-polypeptide unit required for the biological function of some proteins. It may be organic or inorganic (such as a metal ion), but not amino acids.

Randomized controlled trials

(RCTs). A study design that randomly assigns participants into an experimental group or a control group (or placebo group).

Reactive oxygen species

(ROS). Derivatives of oxygen that are more reactive than molecular oxygen.

Single-nucleotide polymorphisms

(SNPs). A variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some high degree within a population (for example, >1%).

Therapeutic window

The range of doses of a drug that can treat disease effectively without having toxic effects.


(Tf). The main protein in the blood that binds to iron and transports it throughout the body.


A selective V600E mutant BRAF kinase inhibitor, also known as PLX4032. It has been used to treat BRAF V600E mutant melanoma.

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Ngo, B., Van Riper, J.M., Cantley, L.C. et al. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer 19, 271–282 (2019). https://doi.org/10.1038/s41568-019-0135-7

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