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

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.

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 [86]. 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 [89]. 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.

https://pubmed.ncbi.nlm.nih.gov/32411317

External mitochondrial NADH-dependent reductase of redox cyclers: VDAC1 or Cyb5R3?

Abstract

It was reported that VDAC1 possesses an NADH oxidoreductase activity and plays an important role in the activation of xenobiotics in the outer mitochondrial membrane. In the present work, we evaluated the participation of VDAC1 and Cyb5R3 in the NADH-dependent activation of various redox cyclers in mitochondria. We show that external NADH oxidoreductase caused the redox cycling of menadione ≫ lucigenin>nitrofurantoin. Paraquat was predominantly activated by internal mitochondria oxidoreductases. An increase in the ionic strength stimulated and suppressed the redox cycling of negatively and positively charged acceptors, as was expected for the Cyb5R3-mediated reduction. Antibodies against Cyb5R3 but not VDAC substantially inhibited the NADH-related oxidoreductase activities. The specific VDAC blockers G3139 and erastin, separately or in combination, in concentrations sufficient for the inhibition of substrate transport, exhibited minimal effects on the redox cycler-dependent NADH oxidation, ROS generation, and reduction of exogenous cytochrome c. In contrast, Cyb5R3 inhibitors (6-propyl-2-thiouracil, p-chloromercuriobenzoate, quercetin, mersalyl, and ebselen) showed similar patterns of inhibition of ROS generation and cytochrome c reduction. The analysis of the spectra of the endogenous cytochromes b5 and c in the presence of nitrofurantoin and the inhibitors of VDAC and Cyb5R3 demonstrated that the redox cycler can transfer electrons from Cyb5R3 to endogenous cytochrome c. This caused the oxidation of outer membrane-bound cytochrome b5, which is in redox balance with Cyb5R3. The data obtained argue against VDAC1 and in favor of Cyb5R3 involvement in the activation of redox cyclers in the outer mitochondrial membrane.

 

https://pubmed.ncbi.nlm.nih.gov/24945955