Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Research output: Contribution to journalArticle

Authors

  • Jessica M. Hearn
  • Alison F. Munro
  • Ying Fu
  • Ana M. Pizarro
  • Mathew J. Garnett
  • Ultan Mcdermott
  • Neil O. Carragher
  • Peter J. Sadler

Colleges, School and Institutes

External organisations

  • University of Warwick
  • University of Edinburgh
  • IMDEA Nanoscience Institute
  • Wellcome Trust Sanger Institute

Abstract

The organometallic “half-sandwich” compound [Os(η6-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-osmium compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.

Details

Original languageEnglish
Pages (from-to)E3800-E3805
JournalNational Academy of Sciences. Proceedings
Volume112
Issue number29
Early online date10 Jul 2015
Publication statusPublished - 21 Jul 2015

Keywords

  • organometallic anticancer compound, cancer metabolism, mitochondria, transcriptome, sequencing, protein microarrays