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.
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
