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

Platinum-based metallodrugs are the most widely used anticancer agents. Their reduced effectiveness after repeat dosing (resistance) constitutes a major clinical problem. We study a potent organo-osmium compound with improved activity over cisplatin and no cross-resistance in platinum-resistant cancers. This compound disrupts metabolism in A2780 human ovarian cancer cells, generating reactive oxygen species and damaging DNA. We identified mutations in complex I of the electron transport chain in A2780 cells and suggest that the osmium compound may exploit these mutations to exert a potent mechanism of action. Such activity increases selectivity toward cancer cells, given that normal-functioning cells can better adapt to drug-induced metabolic perturbations. Therefore, this report highlights a promising strategy to drive the future development of organometallic anticancer compounds. The organometallic “half-sandwich” compound [Os(η ⁶- p -cymene)(4-(2-pyridylazo)- N,N -dimethylaniline)I]PF ₆ 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 relat