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

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. Santos; Kate GR. Quinlan; Nigel Turner; Daniel J. Fazakerley; Naresh Kumar; Kyle L. Hoehn

Redox Biology (Jan 2020)

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

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. Santos,
Kate GR. Quinlan,
Nigel Turner,
Daniel J. Fazakerley,
Naresh Kumar,
Kyle L. Hoehn

Affiliations

Frances L. Byrne: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia; Corresponding author.School of Biotechnology and Biomolecular Sciences, Level 4 D26 Biological Sciences Building, University of New South Wales, Sydney, 2052, Australia.
Ellen M. Olzomer: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Gabriella R. Marriott: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Lake-Ee Quek: School of Mathematics and Statistics, The University of Sydney, Sydney, Australia
Alice Katen: School of Chemistry, University of New South Wales, Sydney, NSW, Australia
Jacky Su: School of Chemistry, University of New South Wales, Sydney, NSW, Australia
Marin E. Nelson: Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Australia
Gene Hart-Smith: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Mark Larance: Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Australia
Veronica F. Sebesfi: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Jeff Cuff: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Gabriella E. Martyn: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Elizabeth Childress: Department of Chemistry and VT Center for Drug Discovery, Virginia Tech, Blacksburg, VA, USA
Stephanie J. Alexopoulos: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Ivan K. Poon: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
Maree C. Faux: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Antony W. Burgess: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Glen Reid: Concord Medical School, Asbestos Disease Research Institute, University of Sydney, Australia
Joshua A. McCarroll: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia
Webster L. Santos: Department of Chemistry and VT Center for Drug Discovery, Virginia Tech, Blacksburg, VA, USA
Kate GR. Quinlan: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
Nigel Turner: School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
Daniel J. Fazakerley: Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Australia
Naresh Kumar: School of Chemistry, University of New South Wales, Sydney, NSW, Australia
Kyle L. Hoehn: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia; Corresponding author.

Journal volume & issue: Vol. 28

Abstract

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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. Keywords: Cancer metabolism, Quinone, Peroxiredoxin, Mitochondria

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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