Abstract

Significance: Vitamin C (ascorbate), in regard to its effectiveness against malignancies, has had a controversial history in cancer treatment. It has been shown that in vitro and in vivo anticancer efficacy of ascorbate relies on its pro-oxidant effect mainly from an increased generation of reactive oxygen species (ROS). A growing understanding of its anticancer activities and pharmacokinetic properties has prompted scientists to re-evaluate the significance of ascorbate in cancer treatment. Recent Advances: A recent resurge in ascorbate research emerged after discovering that, at high doses, ascorbate preferentially kills Kirsten-Ras (K-ras)- and B-raf oncogene (BRAF)-mutant cancer cells. In addition, some of the main hallmarks of cancer cells, such as redox homeostasis and oxygen-sensing regulation (through inhibition of hypoxia-inducible factor-1 alpha [HIF-1 alpha] activity), are affected by vitamin C. Critical Issues: Currently, there is no clear consensus from the literature in regard to the beneficial effects of antioxidants. Results from both human and animal studies provide no clear evidence about the benefit of antioxidant treatment in preventing or suppressing cancer development. Since pro-oxidants may affect both normal and tumor cells, the extremely low toxicity of ascorbate represents a main advantage. This guarantees the safe inclusion of ascorbate in clinical protocols to treat cancer patients. Future Directions: Current research could focus on elucidating the wide array of reactions between ascorbate and reactive species, namely ROS, reactive nitrogen species as well as reactive sulfide species, and their intracellular molecular targets. Unraveling these mechanisms could allow researchers to assess what could be the optimal combination of ascorbate with standard treatments.