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: Jessica M Hearn, Isolda Romero-Canelón, Alison F Munro, Ying Fu, Ana M Pizarro, Mathew J Garnett, Ultan McDermott, Neil O Carragher, Peter J Sadler
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 29 Pg. E3800-5 (Jul 21 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26162681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Organometallic Compounds
• Osmium Compounds
• Transcription Factor AP-1

Topics

• Apoptosis (drug effects)
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Chromosomes, Human (genetics)
• DNA Damage (genetics)
• DNA, Mitochondrial (genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mitochondria (genetics)
• Mutation (genetics)
• NF-E2-Related Factor 2 (metabolism)
• Neoplasms, Glandular and Epithelial (drug therapy, genetics, metabolism, pathology)
• Organometallic Compounds (chemistry, pharmacology, therapeutic use)
• Osmium Compounds (chemistry, pharmacology, therapeutic use)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Oxidative Stress (drug effects, genetics)
• Sequence Analysis, RNA
• Transcription Factor AP-1 (metabolism)