Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?

Figure 2

“Destructive mode” of action of ascorbyl free radical via the OMM Cyb5R3/VDAC1 at high (“therapeutic”) concentrations of vitamin C in cancer cells (at normoxia). High intracellular concentration of ascorbate may induce Cyb5R3 end-product inhibition, accompanied by elevated levels of ascorbyl free radical (AFR) in the mitochondrial intermembrane space and decrease of the NAD⁺/NADH ratio in the cytosol. AFR may transfer one electron to oxidized cytochrome c, causing a partial (or complete) arrest of electron flow between Complex III and Complex IV. Rapid reduction of cytochrome c by AFR effectively competes with and perturbs the proton pumping at Complex III, as well as the temporal electron transport provided by CoQ cycles of Complex III. When Complex III is blocked, succinate (from the citric acid cycle) builds up, mitochondrial membrane potential rises, and the CoQ “pool” becomes unbalanced. Reverse electron transport (RET) to Complex I is driven, which causes a superoxide “burst” [95, 96]. RET is also accompanied by synthesis of succinate and NADH. We propose that the “destructive mode” caused by high-dose vitamin C may contribute to RET not only during tissue reperfusion at angiogenesis but also during tumor hypoxia and normoxia in cancer cells. In addition, the reduction of cytochrome c by AFR results in production of DHA. DHA is converted to ascorbate by glutathione, which provokes a depletion of reducing equivalents in cancer cells—a crucial factor for their survival. VDAC1: voltage-dependent anion channel 1; Cyb5R3: NADH:cytochrome b5 oxidoreductase 3; OMM: outer mitochondrial membrane; Cyt. c: cytochrome c; RET: reverse electron transport; DHA: dehydroascorbate; AscH^-: ascorbate in anion form; Asc^⋅-: ascorbyl free radical.