Therapeutic Use of Vitamin C in Cancer: Physiological Considerations

Abstract

Since the early studies of William J. McCormick in the 1950s, vitamin C has been proposed as a candidate for the treatment of cancer. A number of reports have shown that pharmacological concentrations of vitamin C selectively kill cancer cells in vitro and decrease the growth rates of a number of human tumor xenografts in immunodeficient mice. However, up to the date there is still doubt regarding this possible therapeutic role of vitamin C in cancer, mainly because high dose administration in cancer patients has not showed a clear antitumor activity. These apparent controversial findings highlight the fact that we lack information on the interactions that occurs between cancer cells and vitamin C, and if these transformed cells can uptake, metabolize and compartmentalize vitamin C like normal human cells do. The role of SVCTs and GLUTs transporters, which uptake the reduced form and the oxidized form of vitamin C, respectively, has been recently highlighted in the context of cancer showing that the relationship between vitamin C and cancer might be more complex than previously thought. In this review, we analyze the state of art of the effect of vitamin C on cancer cells in vitro and in vivo, and relate it to the capacity of cancer cells in acquiring, metabolize and compartmentalize this nutrient, with its implications on the potential therapeutic role of vitamin C in cancer.

Keywords: GLUT; SVCT2; cancer; cancer therapy; vitamin C; vitamin C transporters.

FIGURE 1

Comparative diagram of vitamin C doses and its possible effects on cancer cells. (A) Physiological doses of ascorbic acid (AA) are oxidized with the help of activated leucocytes that are infiltrating the tumor, producing dehydroascorbic acid (DHA), which is the main form transported by cancer cells. Once inside the cell, DHA is rapidly reduced to AA where it can enter mitochondria via SVCT2 reducing oxidative stress at this level. (B) Pharmacological doses of AA may induce the production of ascorbate radical (AA*) and hydrogen peroxide (H₂O₂) inducing cell death. On the other hand, increased amounts of DHA entering cancer cells through GLUTs may participate in cell death due to an increase in oxidative stress. Role of mitochondrial GLUTs must be further studied in cancer. Finally, intracellular vitamin C could contribute to cell arrest. All these events are related to the cytotoxic effects of vitamin C in cancer cells. Created with BioRender.com.