Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress
AuthorByrne, FL; Olzomer, EM; Marriott, GR; Quek, L-E; Katen, A; Su, J; Nelson, ME; Hart-Smith, G; Larance, M; Sebesfi, VF; ...
Source TitleRedox Biology
University of Melbourne Author/sBurgess, Antony
Document TypeJournal Article
CitationsByrne, F. L., Olzomer, E. M., Marriott, G. R., Quek, L. -E., Katen, A., Su, J., Nelson, M. E., Hart-Smith, G., Larance, M., Sebesfi, V. F., Cuff, J., Martyn, G. E., Childress, E., Alexopoulos, S. J., Poon, I. K., Faux, M. C., Burgess, A. W., Reid, G., McCarroll, J. A. ,... Hoehn, K. L. (2020). Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress. REDOX BIOLOGY, 28, https://doi.org/10.1016/j.redox.2019.101374.
Access StatusOpen Access
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.
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