Fig. 5.

Consequences of AFR-mediated “destructive mode” of action of high dose vitamin C therapy in cancer.

(a) Induction of reverse electron transport in the respiratory chain and acceleration of superoxide production at Complex-I and Complex-III [34,60]. Degradation of Complex-I when CoQ “pool” is unbalanced, and Complex-III is dysfunctional [60]. In hypoxic conditions (common to many types of cancer cells), these redox reactions occur even faster, exponentially increasing superoxide production [34,60,61]. Superoxide can be converted to hydrogen peroxide, which is considered as a cytotoxic and onco-suppressive reactive oxygen species [15,24,31,35].

(b) Superoxide-mediated destruction of Fe/S clusters from the mitochondrial complexes and induction of Fenton's reactions [62,63], in the presence of AFR and/or ascorbate.

(c) Increase of NADH/NAD⁺ ratio when Cyb5R3 is inhibited. NADH reduces conduction of VDAC1 by partial channel block and/or modulation of its activity [64]. As ATP and many other vital substances pass from the mitochondria into the cytosol through VDAC1 [65], partial inhibition of the VDAC1 would also contribute to the impairment of mitochondrial respiration and decrease of cell viability.

(d) The conversion of AFR to dehydroascorbate (DHA) and subsequent reduction of DHA to ascorbate by glutathione- and NADPH-dependent pathways will promote a depletion of glutathione and other reducing equivalents in the cancer cells leading to severe oxidative stress [31].

(e) The reduction of cytochrome c by AFR leads to the transfer of electrons from cytoplasmic NADH to Complex-IV, which is accompanied by production of 1 mol ATP per 1 mol NADH, suggesting the likelihood of thermogenesis [66]. Cancer cells often express heat shock proteins and are very sensitive to elevated temperature of their environment [67]. This may also contribute to converting “cold” tumors into “hot” tumors, an important cell death-facilitating factor potentially from combining high dose vitamin C therapy with applications in immunotherapy [68].

(f) Competitive intracellular delivery of vitamin C via glucose transport proteins decreases the glycolytic rate, leading to further decrease of energy supply (by glycolytic ATP) and increased oxidative stress in the cytosol [69].

RET – reverse electron transport; VDAC1 – voltage-dependent anion channel 1.