Apatone™, a combination of
menadione (2-methyl-1,4-naphthoquinone, VK3) and
ascorbic acid (
vitamin C, VC) is a new strategy for
cancer treatment. Part of its effect on
tumor cells is related to the cellular pro-oxidative imbalance provoked by the generation of
hydrogen peroxide (H2O2) through
naphthoquinone redox cycling. In this study, we attempted to find new
naphthoquinone derivatives that would increase the efficiency of H2O2 production, thereby potentially increasing its efficacy for
cancer treatment. The presence of an electron-withdrawing group in the
naphthoquinone moiety had a direct effect on the efficiency of H2O2 production. The compound
2-bromo-1,4-naphthoquinone (BrQ), in which the
bromine atom substituted the methyl group in VK3, was approximately 10- and 19-fold more efficient than VK3 in terms of oxygen consumption and H2O2 production, respectively. The ratio [H2O2]produced / [
naphthoquinone]consumed was 68 ± 11 and 5.8 ± 0.2 (µM/µM) for BrQ and VK3, respectively, indicating a higher efficacy of BrQ as a catalyst for the autoxidation of
ascorbic acid. Both VK3 and BrQ reacted with
glutathione (GSH), but BrQ was the more effective substrate. Part of GSH was incorporated into the
naphthoquinone, producing a nucleophilic substitution product (Q-SG). The depletion of BrQ by GSH did not prevent its redox capacity since Q-SG was also able to catalyze the production of
reactive oxygen species. VK3/VC has already been submitted to clinical trials for the treatment of
prostate cancer and has demonstrated promising results. However, replacement of VK3 with BrQ will open new lines of investigation regarding this approach to
cancer treatment.