2-Bromo-1,4-naphthoquinone: a potentially improved substitute of menadione in Apatone™ therapy

Abstract

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.

Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells

“…As naphthalene organic derivatives, 1,4-naphthoquinone compounds have been extensively investigated for their potential biological benefits, including their anti-inflammatory and anti-bacterial activities (24). In addition, the 1,4-naphthoquinone pharmacophore exhibits anti-cancer activity and has been the focus of previous studies (25,26). Among the 1,4-naphthoquinone compounds, plumbagin, mitomycin and shikonin have been used in the development of potent anti-cancer drugs (27).…”

The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process

“…Several studies have demonstrated the potential of VK 3 + VC combinations against several cancer cells [ 18 – 25 ], which induce pro-oxidative imbalance through the generation of reactive species [ 42 ]. It is well described that the non-enzymatic reduction of VK 3 by ascorbate leads to VK 3 semiquinone and ascorbyl free radicals.…”

“…From this ROS, others as H 2 O 2 and HO ● can be generated [ 26 ]. Thus, Apatone ® (one VK 3 + VC combination) was developed as a new therapeutic strategy for cancer treatment [ 42 , 43 ]. Previous studies have also reported that the VK 3 + VC combination has low systemic toxicity [ 20 , 44 ] and may have different biochemical targets, depending on the cellular type.…”

Understanding the Role of pH in Protein‐Haptenation Reaction: Kinetics and Mechanisms of the Protein‐Haptenation Reactions of Selected Quinones Present in the Environment

“…[28][29][30] They also have the ability to bring colour to food, and their biological properties are very broad, for example, antimicrobial, antiviral, antiparasitic, antitumor, antioxidant, chelatant, diuretic and laxative amongst others. [21] [16,[31][32][33][34][35] In addition, 1,2-naphthoquinone (1,2-NQ) has been found to be present in diesel exhaust as a by-product of incomplete combustion and it is an environmental pollutant found in polluted air. 9,10-Phenanthrenequinone is also one of the ubiquitous environmental pollutant found in diesel exhaust particles present in the air.…”