title: Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.
abstract: The organometallic "half-sandwich" compound [Os(η(6)-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.
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom; Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Hearn
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom;
authors.forename: Isolda
authors.initials: I
authors.lastname: Romero-Canelón
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom;
authors.forename: Alison F
authors.initials: AF
authors.lastname: Munro
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; Georgetown University Medical Centre, Washington, DC 20057;
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049 Madrid, Spain;
authors.forename: Ana M
authors.initials: AM
authors.lastname: Pizarro
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom;
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; p.j.sadler@warwick.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017892:Osmium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017423:Sequence Analysis, RNA; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009942:Organometallic Compounds; D017892:Osmium Compounds; D018808:Transcription Factor AP-1
keywords: cancer metabolism; mitochondria; organometallic anticancer compound; protein microarrays; transcriptome sequencing