Anti-cancer effects of vitamin C revisited

Abstract

Vitamin C was first suggested to have cancer-fighting properties in the 1930s and has been the subject of controversy ever since. Despite repeated reports of selective cancer cell toxicity induced by high-dose vitamin C treatment in vitro and in mouse models, the mechanism of action has remained elusive.

Figure 1

Mechanistic overview of proposed vitamin C toxicity in CRCs driven by KRAS and BRAF mutations. KRAS and BRAF mutations induce metabolic reprogramming by upregulating GLUT1, glucose uptake, and glycolytic flux. Upon vitamin C treatment and its extracellular oxidation, DHA (the oxidized form of vitamin C) is taken up through GLUT1 and is reduced back to vitamin C in the cells, depleting GSH and NADPH. Consequently, an increase in ROS leads to GAPDH oxidation, and with it, to a decrease in glycolytic flux. In parallel, ROS-mediated oxidative DNA damage induces PARP activation and subsequently, NAD⁺ levels fall and cause additional inhibition of GAPDH and glycolysis, resulting in energy crisis and cell death.