Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence

Abstract

Whether vitamin C (ascorbate) has a role to play as an anti-cancer agent has been debated for decades. Ascorbate has been used by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion, with numerous reports of clinical benefit, but in the absence of rigorous clinical trial data. The design of appropriate clinical trials has been hindered by a lack of understanding of the mechanism(s) of action that would inform the choice of effective dose, timing of administration and likely responsive cancer models. More recently, expanded understanding of the biological activities of ascorbate has led to a number of plausible hypotheses for mechanisms of anti-cancer activity. Prominent among these are the generation of significant quantities of hydrogen peroxide by the autoxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells. The 2-OGDDs include the hydroxylases that regulate the hypoxic response, a major driver of tumor survival, angiogenesis, stem cell phenotype and metastasis, and the epigenetic histone and DNA demethylases. The latter are of particular interest, with recent studies suggesting a promising role for ascorbate in the regulation of the ten-eleven translocase (TET) DNA demethylases in hematological cancers. Support for these proposed mechanisms has come from many in vitro studies, and xenograft animal models have consistently shown an anti-cancer effect of ascorbate administration. However, decisive evidence for any particular mechanism(s) of action is not yet available from an in vivo setting. With a number of early phase clinical trials currently underway, evidence for potential mechanism(s) of action is required to inform the most appropriate study design and choice of cancer model. Hopefully such information will result in sound clinical data that will avert adding any further controversy to this already contentious debate.

Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations

“…Guarnieri et al compared the influence of a single portion of natural vs. synthetic vitamin C on DNA damage induced by hydrogen peroxide [62]. They observed similar plasma concentrations of this vitamin in 7 volunteers, but only natural vitamin, consumed from orange juice, decreased the extent of H 2 O 2 -induced DNA damage in peripheral 4 Oxidative Medicine and Cellular Longevity blood mononuclear cells. The authors concluded that this might not be vitamin C itself that was directly responsible for the protective effects against DNA damage, but rather other compounds, like phytochemicals that might synergize the action of the vitamin or act independently of it.…”

“…Vitamin C is also reported to exert beneficial effects in the immune system and inflammation, which is crucial in fighting precancerous and cancer cells by the host (reviewed in [3]). Anticancer potential of vitamin C is suggested by the results of many other laboratory studies on experimental animals and cell cultures (reviewed in [4]).…”

“…Anticancer properties of vitamin C have been reviewed in several recent papers (e.g., [4,[6][7][8][9][10]). These studies suggest several potential targets of anticancer action of vitamin C-some of them will be described and referenced in the next sections.…”

The benefits of ascorbate to protect healthy cells in the prevention and treatment of oncological diseases

“…Potential mechanisms of action of P-AscHin cancer and clinical studies in this field were reviewed in a third 2018 paper (Vissers and Das, 2018). The authors state that there is a substantial body of literature that documents potential anti-tumor effects of ascorbate in in vitro and in vivo settings, with many reporting cytotoxicity toward cancer cells and a slowing of tumor growth in animal models.…”

Vitamin C administration by intravenous infusion increases tumour ascorbate content in patients with colon cancer: a clinical intervention study

“…Current research is focussed on the identi cation and veri cation of several proposed mechanisms whereby ascorbate could affect tumour progression. These include: (i) the localised generation of cytotoxic quantities of H 2 O 2 as a consequence of ascorbate oxidation (15,18,19); (ii) ascorbatedependent activation of the 2-oxoglutarate-dependent dioxygenases that down-regulate the hypoxiainducible factors (HIFs) (20)(21)(22) and that are responsible for the demethylation of DNA and histones (11,17,(23)(24)(25) and (iii) increased oxidative stress induced by dehydroascorbic acid taken up into tumour cells via the glucose transporters (26). These mechanisms all require effective delivery of ascorbate to the tumour.…”