Updated: Jun 16
Long known as the anti-scurvy substance, vitamin C is an essential dietary supplement commonly found in fruits and vegetables.(1) Although previous research has established its importance in several physiological processes (e.g., collagen production), considerable controversy still surrounds the role of vitamin C in cancer therapy. In the mid-20th century, Toronto physician William McCormick postulated that vitamin C conferred a protective effect against cancer after observing that patients with malignancies were deficient in the key nutrient.(2) Capitalizing on this correlation, Cameron and Pauling conducted a pair of studies whose results decisively validated McCormick’s hypothesis.(3,4) Soon after though, in the 1980s, researchers from the Mayo Clinic failed to replicate such positive findings and published them in the New England Journal of Medicine.(5) The more rigorous design and high-profile publication of the follow-up trials extinguished enthusiasm for vitamin C as a cancer therapy, despite the data from the Cameron-Pauling trials.(2) Interest subsided further as findings from subsequent investigations suggested that vitamin C had little clinical value as an anticancer mono-therapy.(6)
Since the mid-1980s, scientific understanding of vitamin C and its effects in the human body has advanced considerably. With time, researchers have also been able to explain the discordant results collected from 20th century trials of vitamin C in cancer patients. Perhaps the most consequential difference between trials was the route of administration. Scientists understand now that a millimolar concentration of ascorbate is necessary to induce cytotoxicity in cancer cells, but patients can only achieve such levels of vitamin C through intravenous administration.(7) Many mechanisms acting together, like intestinal absorption, tissue accumulation, and renal reabsorption, prevent orally-administered vitamin C from reaching such high concentrations.(1) In an analysis by Levine et al., the oral vitamin C doses used in the Mayo Clinic studies would have resulted in a peak plasma concentration of less than 200 μM. The same dose given intravenously, as done in the Cameron-Pauling studies, produces peak plasma concentrations that are around twenty-five times greater (6 mM)!(8)
Although accumulating evidence indicates that vitamin C has value in cancer therapy, several challenges remain in validating results from preclinical studies. Because vitamin C is not patentable, pharmaceutical companies lack financial incentives to fund large-scale, randomized controlled trials of the nutrient in cancer therapy. Clinician prejudices against vitamin C also remain intact, largely because of the Mayo studies conducted in the 1980s.(1) Further complicating matters, biomarkers for predicting patients’ responses to therapy have not yet been conclusively identified, nor do clinicians have an idea of the optimal dose to administer to patients.(7) While work continues to elucidate the biochemical processes regulated by vitamin C, some explanations have already emerged that explain its potent anticancer activity.(9)
Compared with normal cells, cancerous cells exhibit a high rate of glycolysis even in oxygen-rich environments. This phenomenon, known as the Warburg effect, occurs in part because of oncogenic mutations in KRAS or BRAF, which result in up-regulation of the glucose transporter GLUT1.(10) When ascorbate is oxidized to Dehydroascorbic Acid (DHA), it can readily pass through GLUT1 because of its structural similarity to glucose.(11) Unconverted ascorbate can also enter tumor cells via separate SVCT2 transporters. In the intracellular environment, enzymes convert DHA back to ascorbate, which reduces Fe3+ to Fe2+ through the Fenton reaction (Figure 1).(7) Cancer cells additionally have abnormally high concentrations of Fe2+, which can react with H2O2 to produce hydroxyl radicals (OH-) that can compromise the cell membrane.(12) Concurrent with damage to phospholipid bilayer is an energy crisis precipitated by the reduction of DHA to ascorbate. Because this reduction reaction occurs at the expense of GSH and NADPH, intracellular antioxidant concentrations fall and levels of reactive oxygen species rise further.9 Over time, the accumulation of reactive oxygen species leads to the depletion of ATP stores, disruption of the Tricarboxylic Acid cycle, DNA damage, and cancer cell death.(7)
Figure 1: The Fenton reaction results in the generation and accumulation of reactive oxygen species that eventually precipitate cell death through ATP and NAD+ depletion, GAPDH inhibition, glycolysis blockade, and DNA damage. Figure courtesy of Giansanti et al. (2021)
Beyond acting as a pro-oxidant agent, vitamin C also functions as an epigenetic modulator of the Ten Eleven Translocation (TET) enzymes. The TET enzymes (TET1, TET2, TET3) belong to the αKGDD enzyme family and participate in DNA Demethylation; they catalyze the oxidation of 5-Methylcytosine (5mC) to 5-Hydroxymethycytsoine.(9) Insufficient activity from TET enzymes, most often a product of loss of function mutations, results in cancer. Hypermethylation of DNA on CpG island promoter sites leads to the silencing of tumor suppressors and unchecked cell proliferation.(13) Investigators have also observed that the TET enzymes have a varying tissue distribution, with a loss of function in TET2 being associated with myeloid and lymphoid hematological malignancies.(14,15) In patient-derived tumor xenograft models, investigators have demonstrated that treatment with vitamin C increases TET activity, which then prevents the progression of leukemia.(16) Mechanistically, vitamin C acts as a co-factor for TET enzymes, and it is required for optimal activity.(9) Consequently, prolonged treatment with vitamin C at sufficient concentrations may induce anticancer, epigenetic modifications.(7)
In addition to modulating the TET enzymes, vitamin C may counteract cancer growth through regulation of HIF1.(9) HIF1 is a Heterodimeric transcription factor that cancer cells activate to thrive in hypoxic environments created by solid tumor masses.(17) Growing amounts of evidence illustrate a clear inverse correlation between ascorbate concentrations and activity of H1F1α – one of the two subunits comprising HIF1.(9) In an in vitro study of thyroid cells, researchers observed that ascorbate treatment induced a dose-dependent decrease in H1F1α, as well as in GLUT1.(18) Findings from a separate study appear to corroborate this association, with researchers noting that tumors with the highest H1F1 activity having the least amount of ascorbate.(19) Although these studies do not establish causality, the robust relationship warrants continued investigation and further supports the use of vitamin C in select cancer patients.
Table 1: High-Dose Intravenous Ascorbate + Standard Therapies – Phase I & II Trials. Adapted from Nauman et al., 2018.
Table 2: Ongoing Phase 1 & Phase 2 Clinical Trials Evaluating Ascorbic Acid in Cancer
Because vitamin C appears to act through several mechanisms, it may have therapeutic value in a broad range of cancer patients. Results from preclinical studies already suggest it has utility in patients harboring mutations in KRAS, BRAF, TET2, IDH1, IDH2, VHL, SH, and FDH.(9) Notably, over half of colorectal cancers harbor KRAS or BRAF mutations, and patients with these variants tend to have the highest likelihood of being refractory to treatment.(1) As such, high-dose, intravenously administered vitamin C could represent a breakthrough approach and may address the unmet needs of this patient population. Its affordability, coupled with its tolerability at high doses, makes it an attractive alternative to existing treatments with poorer tolerability profiles.(9)
Alternatively, because of its effects on DNA, vitamin C may also prove useful when paired with PARP inhibitors and Hypomethylating agents used in hematological malignancies.(7) If validated in large-scale, randomized clinical trials, vitamin C may revolutionize cancer treatments by lending greater credence to the idea of targeting glucose metabolism specifically to counter several kinds of cancers.
Cantley L, Yun J. Intravenous high-dose vitamin C in cancer therapy. National Cancer Institute. https://www.cancer.gov/research/key-initiatives/ras/ras-central/blog/2020/yun-cantley-vitamin-c. Published January 24, 2020. Accessed May 7, 2021.
Roa FJ, Pena E, Gatica M, et al. Therapeutic use of vitamin C in cancer: physiological considerations. Front Pharm. 2020;11:211.
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. 1976;73:3685-3689.
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. 1978;75:4538-4542.
Moertel CG, Fleming TR, Creagan ET, 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. 1985;312:137-141.
Carr AC, Cook J. Intravenous vitamin C for cancer therapy – identifying the current gaps in our knowledge. Front Physiol. 2018;9:1182.
Giansanti M, Karimi T, Faraoni I, et al. High-dose vitamin C: preclinical evidence for tailoring treatment in cancer patients. Cancer (Basel). 2021;13(6):1428.
Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537.
Ngo B, Van Piper JM, Cantley LC, et al. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019;19(5):271-282.
Yun J, Rago C, Cheong I, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555-1559.
Yun J, Mullarky E, Lu C, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350(6266):1391-1396.
Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA. 2007;104:8749-8754.
Yun J, Johnson JL, Hanigan CL, et al. Interactions between epigenetics and metabolism in cancers. Front Oncol. 2012;2:163.
Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancers. Genes Dev. 2016;30:733-750.
Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009; 360:2289-2301.
Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170(6):1079-1095.e20.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721-732.
Jozwiak P, Ciesielski P, Zaczek A, et al. Expression of hypoxia inducible factor 1a and 2a and its association with vitamin C level in thyroid lesions. J Biomed Sci. 2017;24:83.
Kuiper C, Dachs GU, Munn D, 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. 2014;4:10.