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

Figure 5

Vitamin C induces the ten-eleven translocation 2 (TET2) proteins to kill leukemic blasts. TETs are involved in active DNA demethylation that is achieved through TET2-mediated oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Oxidized 5mC is progressively lost in subsequent cellular divisions or converted to nonmethylated C by thymine DNA glycosylase (TDG). 5mC can undergo spontaneous or activation-induced deaminase- (AID-) mediated deamination converting it into thymine (T) that can be replaced by C by TDG or in mismatch repair (MMR). AID can convert 5hmC to 5-hydroxymethyluracil (5hmU) or T. If TET2 is deficient in leukemic stem cells, their self-renewal is disturbed leading to increased blast production and progression of the disease. Vitamin C exerts similar effects as restoration of TET2 that leads to increased differentiation and less aggressive disease. Vitamin C-induced oxidation of 5mC results in an increased sensitivity of the cells to inhibitors of poly(ADP-ribose) polymerase (PARPi) that can induce cell death and inhibit disease progression.