Byrne, Frances L.Olzomer, Ellen M.Marriott, Gabriella R.Quek, Lake-EeKaten, AliceSu, JackyNelson, Marin E.Hart-Smith, GeneLarance, MarkSebesfi, Veronica F.Cuff, JeffMartyn, Gabriella E.Childress, ElizabethAlexopoulos, Stephanie J.Poon, Ivan K.Faux, Maree C.Burgess, Antony W.Reid, GlenMcCarroll, Joshua A.Santos, Webster L.Quinlan, Kate G. R.Turner, NigelFazakerley, Daniel J.Kumar, NareshHoehn, Kyle L.2020-01-142020-01-142020-012213-2317UNSP 101374http://hdl.handle.net/10919/96431A 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.application/pdfenCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalCancer metabolismQuinonePeroxiredoxinMitochondriaArticle - Refereedhttps://doi.org/10.1016/j.redox.2019.1013742831743887