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

Publication date: Available online 5 November 2019Source: Redox BiologyAuthor(s): Frances L. Byrne, Ellen M. Olzomer, Gabriella R. Marriott, Lake-Ee Quek, Alice Katen, Jacky Su, Marin E. Nelson, Gene Hart-Smith, Mark Larance, Veronica F. Sebesfi, Jeff Cuff, Gabriella E. Martyn, Elizabeth Childress, Stephanie J. Alexopoulos, Ivan K. Poon, Maree C. Faux, Antony W. Burgess, Glen Reid, Joshua A. McCarroll, Webster L. SantosAbstractA 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-targete...
Source: Redox Biology - Category: Biology Source Type: research