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

abstract

  • 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.

authors

  • Byrne, FL
  • Olzomer, EM
  • Marriott, GR
  • Quek, LE
  • Katen, A
  • Su, J
  • Nelson, ME
  • Hart-Smith, G
  • Larance, M
  • Sebesfi, VF
  • Cuff, J
  • Martyn, GE
  • Childress, E
  • Alexopoulos, SJ
  • Poon, Ivan K
  • Faux, MC
  • Burgess, AW
  • Reid, G
  • McCarroll, JA
  • Santos, WL
  • Quinlan, KG
  • Turner, N
  • Fazakerley, DJ
  • Kumar, N
  • Hoehn, KL

publication date

  • 2020