Abstract
Background: We are developing organo-osmium complex 1 as an alternative to platinum-anticancer drugs in the clinic for the treatment of epithelial ovarian cancer (EOC).1,23,4 Method: We used time series RNA-sequencing to determine differential gene expression in A2780 EOC cells in response to treatment of complex 1. This was complemented with reverse-phase protein microarrays to study cellular levels of key proteins involved in DNA-damage repair, and flow cytometry and high-content imaging to investigate activation of oxidative stress and apoptosis. Results: Complex 1 was screened in 809 cancer cell lines as part of the Sanger Institute’s Cancer Genome Project with promising results. Whole transcriptome sequencing identified three missense mutations in the mitochondrial genome of A2780 cells, in the electron transport chain. 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. The MOA of 1 is appears to involve redox-mediation. Conclusion: Transcriptomic and proteomic studies suggest an attack on glycolysis which switches energy production towards OXPHOS in A2780 EOC cells. This pathway may already be stressed by the 3 mutations we detected in CI of the ETC.
Published Version
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