Overcoming Platinum Resistance in Ovarian Cancer Cells by Epigenetic Reprogramming Strategies

Abstract

Ovarian cancer causes over 200,000 deaths annually, with platinum resistance limiting five-year survival to less than 30%. Chemoresistance emerges through complex molecular mechanisms, including aberrant epigenetic regulation via DNA methylation and histone modifications. Elevated epigenetic regulators (DNMT1, EZH2, etc.) in resistant cells silence pro-apoptotic genes and enhance DNA repair capacity. This dissertation research investigated the use of RG-7388, an MDM2 inhibitor, and CM-272, a dual G9a/DNMT inhibitor, as a strategy to overcome platinum resistance through comprehensive epigenetic reprogramming. Cisplatin-resistant cell lines (A2780Cis, SKOV3) and sensitive A2780 cells were characterized for epigenetic profiles and CM-272 sensitivity using cytotoxicity assays, Western blotting, and RT² Profiler PCR arrays. Pathway enrichment analysis elucidated mechanisms of action. CM-272 demonstrated superior efficacy over Cisplatin and RG-7388 in resistant cells, with baseline DNMT1 expression inversely correlating with therapeutic sensitivity, establishing it as a predictive biomarker. In addition, CM-272 induced comprehensive transcriptional reprogramming affecting multiple resistance mechanisms. Pathway analysis revealed significant enrichment in DNA replication, cell cycle regulation, p53 signaling, and platinum resistance pathways.