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

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dc.contributor.authorByrne, Frances L.en
dc.contributor.authorOlzomer, Ellen M.en
dc.contributor.authorMarriott, Gabriella R.en
dc.contributor.authorQuek, Lake-Eeen
dc.contributor.authorKaten, Aliceen
dc.contributor.authorSu, Jackyen
dc.contributor.authorNelson, Marin E.en
dc.contributor.authorHart-Smith, Geneen
dc.contributor.authorLarance, Marken
dc.contributor.authorSebesfi, Veronica F.en
dc.contributor.authorCuff, Jeffen
dc.contributor.authorMartyn, Gabriella E.en
dc.contributor.authorChildress, Elizabethen
dc.contributor.authorAlexopoulos, Stephanie J.en
dc.contributor.authorPoon, Ivan K.en
dc.contributor.authorFaux, Maree C.en
dc.contributor.authorBurgess, Antony W.en
dc.contributor.authorReid, Glenen
dc.contributor.authorMcCarroll, Joshua A.en
dc.contributor.authorSantos, Webster L.en
dc.contributor.authorQuinlan, Kate G. R.en
dc.contributor.authorTurner, Nigelen
dc.contributor.authorFazakerley, Daniel J.en
dc.contributor.authorKumar, Nareshen
dc.contributor.authorHoehn, Kyle L.en
dc.contributor.departmentChemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2020-01-14T18:37:55Zen
dc.date.available2020-01-14T18:37:55Zen
dc.date.issued2020-01en
dc.description.abstractA 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.en
dc.description.notesFLB 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.en
dc.description.sponsorshipHope Funds for Cancer Research [HFCR-14-06-04]; Cancer Institute NSW ECF [2018/ECF003]; UNSW; Cancer Institute NSW CDF; Australian Postgraduate AwardAustralian Government; UNSW Sydneyen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.redox.2019.101374en
dc.identifier.issn2213-2317en
dc.identifier.otherUNSP 101374en
dc.identifier.pmid31743887en
dc.identifier.urihttp://hdl.handle.net/10919/96431en
dc.identifier.volume28en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCancer metabolismen
dc.subjectQuinoneen
dc.subjectPeroxiredoxinen
dc.subjectMitochondriaen
dc.titlePhenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stressen
dc.title.serialRedox Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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