Abstract
High-dose vitamin C therapy for cancer, originally advocated by Linus Pauling (Proc Natl Acad Sci, 1976, 73, 3685-3689), remains a subject of ongoing debate. In this study, we investigate why only pharmacological doses are effective and explore the reasons behind inconsistent therapeutic outcomes. Our data suggest that the bona fide cause of toxicity was oxidized vitamin C rather than hydrogen peroxide. We found that vitamin C at millimolar concentrations, directly inhibits hypochlorous acid generation by myeloperoxidase, through competition with chloride rather than by scavenging the hypochlorous acid that is formed. Products of vitamin C oxidation reacted with the thiols of peroxiredoxin 2 and GAPDH, but failed to react with the cysteine of p16ᴵᴺᴷ⁴ᵃ. The growth and viability of Jurkat cells were affected by oxidized vitamin C. These experiments were conducted in the presence of catalase, demonstrating that the biological effects were due to the products of vitamin C oxidation and not hydrogen peroxide. These findings may have practical implications for the treatment of cancer and diseases in which the deleterious effects of neutrophil activation are observed. For intravenous administration of pharmacological vitamin C to have a beneficial effect, its concentration in the blood must be maintained at millimolar levels and this can only be achieved via maintenance infusion. As a proof-of-concept, our data suggest that to enhance anticancer therapy interventions, it is crucial to implement treatments that facilitate the oxidation of vitamin C in the bloodstream.