Cytotoxicity of vitamin C in cancer may be enhanced by Cyb5R3/VDAC1 inhibitors
Recent studies show that Cyb5R3/VDAC1 can activate bioreductive antitumor drugs, which in combination with vitamin C may affect mitochondrial activity, exhibiting additive or synergistic anticancer effects [17, 79, 80]. For example, vitamin C can sensitize cancer cells to redox-responsive chemotherapeutics (e.g., furanonaphtoquinones) after their bioreductive activation via Cyb5R3/VDAC1 [81, 82]. In this case, the “therapeutic” intravenous dose of vitamin C could be decreased to more tolerant values. It has been reported that high doses of vitamin C exhibit selective antitumor effects in combination with menadione—an analogue of 1,4-naphoquinone [83–85]. A recent study demonstrates that high/tolerable concentrations of menadione inhibit Cyb5R3 . It can be assumed that menadione-mediated inhibition of Cyb5R3 is involved in potentiation of the anticancer effect of high-dose vitamin C via overproduction of AFR and subsequent impairment of mitochondrial respiration (as we assume with our “model”). Moreover, vitamin C/menadione could achieve a selective cytotoxicity against cancer cells due to the rapid UBIAD1-mediated conversion of menadione to vitamin K2 in normal cells and downregulation of UBIAD1 in the majority of cancers leading to strong inhibition of this conversion [87, 88]. These assumptions could be a prerequisite/basis for the design of future studies aimed to elucidate the molecular mechanisms of the synergistic anticancer effects of vitamin C and vitamin C/menadione with conventional chemotherapeutics, described in the literature . Clarifying the effects of conventional anticancer drugs and high-dose vitamin C on Cyb5R3 may also be a prerequisite for predicting the effectiveness of vitamin C in adjuvant settings and stratification of patients with good/poor prognosis.
External mitochondrial NADH-dependent reductase of redox cyclers: VDAC1 or Cyb5R3?
"Clarifying the effects of conventional anticancer drugs and high-dose vitamin C on Cyb5R3 may also be a prerequisite for predicting the effectiveness of vitamin C in adjuvant settings and stratification of patients with good/poor prognosis."
Indeed, today's treatments are pretty much hit-or-miss yet the knowledge is available to do better.
I remember reading quite a few very positive testimonials about a therapy called apatone (IV C and K3). Identifying effective synergies is really the holy grail in cancer treatment IMO.