Abstract
Vitamin C as a cancer therapy has a controversial history. Much of the controversy arises from the lack of predictive biomarkers for stratification of patients, as well as a clear understanding of the mechanism of action and its multiple targets underlying the anticancer effect. Our review expands the analysis of cancer vulnerabilities for high-dose vitamin C, based on several facts, illustrating the cytotoxic potential of the ascorbyl free radical (AFR) via impairment of mitochondrial respiration and the mechanisms of its elimination in mammals by the membrane-bound NADH:cytochrome b5 oxidoreductase 3 (Cyb5R3). This enzyme catalyzes rapid conversion of AFR to ascorbate, as well as reduction of other redox-active compounds, using NADH as an electron donor. We propose that vitamin C can function in “protective mode” or “destructive mode” affecting cellular homeostasis, depending on the intracellular “steady-state” concentration of AFR and differential expression/activity of Cyb5R3 in cancerous and normal cells. Thus, a specific anticancer effect can be achieved at high doses of vitamin C therapy. The review is intended for a wide audience of readers—from students to specialists in the field.
Highlights
In the April 2019 issue of Nature Reviews Cancer, Ngo et al have described cancer vulnerabilities for high-dose vitamin C therapy [1]
(vi) We propose that the accumulation of high concentrations of ascorbyl free radical (AFR) in cells during oxidative stress and/or some specific metabolic activity is responsible for the impairment of mitochondrial respiration in the absence or downregulation of cytochrome b5 oxidoreductase 3 (Cyb5R3), the enzyme located on the outer mitochondrial membrane (OMM Cyb5R3)
Our hypothesis is focused on the intracellular generation of AFR at low and high doses of vitamin C, together with its effect on mitochondrial respiration, intracellular redox balance, and energy metabolism mediated by the Outer mitochondrial membrane recessive hereditary methemoglobinemia (RHM) (OMM) Cyb5R3/voltagedependent anion channel 1 (VDAC1)
Summary
In the April 2019 issue of Nature Reviews Cancer, Ngo et al have described cancer vulnerabilities for high-dose vitamin C therapy [1]. In vitro studies on isolated mitochondria indicate that the OMM Cyb5R3/VDAC1 complex is responsible for the transfer of electrons from cytosolic NADH into mitochondria and that the process is dependent to Complex IV [24, 25] This is accompanied by oxygen uptake, proton pumping, and generation of mitochondrial potential, supported by small catalytic amounts of external (mitochondrial) cytochrome c. Studies discussed above suggest that OMM Cyb5R3/VDAC1 is vital for mitochondrial homeostasis, protection against oxidative stress, prevention of cell senescence, and cellular longevity These events clearly relate to AFR elimination and maintenance of the cytosolic NAD+/NADH ratio—crucial factors for cell survival. It is interesting to note that Cyb5R3-siRNA-silenced cancer cells stop proliferation and metastasis, but they continue to survive [34]
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