Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress ; Redox Biology

Abstract

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD(+) ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity. ; Hope Funds for Cancer Research [HFCR-14-06-04]; Cancer Institute NSW ECF [2018/ECF003]; UNSW; Cancer Institute NSW CDF; Australian Postgraduate AwardAustralian Government; UNSW Sydney ; FLB was supported by a postdoctoral fellowship from the Hope Funds for Cancer Research (HFCR-14-06-04) and is currently supported by a Cancer Institute NSW ECF (2018/ECF003). Financial support was provided in part by a UNSW faculty collaboration grant to KLH and NK. JM is supported by a Cancer Institute NSW CDF. GEM was supported by an Australian Postgraduate Award. KGRQ is supported by a UNSW Sydney Scientia Fellowship.