SCREENING AND IDENTIFICATION OF NOVEL CHEMOTHERAPY AGENTS IN PLATINUM-RESISTANT OVARIAN CANCER

ObjectivesTo screen the efficacy of potential chemotherapeutics against platinum-sensitive & resistant ovarian cancer cell lines.MethodsWe performed in-vitro screening on mithramycin, an antineoplastic antibiotic; telaglenastat, a glutaminase inhibitor; savolitinib, a c-met tyrosine kinase inhibitor; and AMG-232, an MDM2 inhibitor. We tested all agents against a platinum-resistant cell line (OVCAR3) and a platinum-sensitive line (CAOV3). Additionally, we tested mithramycin against UWB1.289, a BRCA mutant, and an induced platinum-resistant UWB1.289 line. DMSO and cisplatin were the negative and positive controls, respectively, and we performed all experiments in triplicate. Cell viability was determined by measuring cellular ATP content.ResultsThe IC50 values of mithramycin ranged from 42.4 to 65.5 nM. Cisplatin IC50 values ranged from a median of 2067 to 7267nM. The IC50 values of telaglenastat, savolitinib, and AMG-232 did not reach a level of 10µm in any of the tested cell lines. Table 1. IC50 values of agents sorted by cell lines. N/A indicating value not achieved at threshold of 10um.ConclusionsPlatinum-resistant ovarian cancer has a poor prognosis highlighting the need for new therapeutic modalities. Neither telaglenastat, savolitinib, nor AMG-232 exhibit any appreciable cytotoxicity; however, mithramycin demonstrates cytotoxicity in the low nanomolar range in several representative ovarian cancer cell lines, including two platinum-resistant lines. The potential therapeutic benefit of mithramycin warrants further preclinical evaluation.