Abstract 3277: Pifithrin-α and veliparib synergize in the sensitization of p53 wild-type ovarian cells to cisplatin therapy.

Abstract

Objectives. Veliparib (ABT), a PARP1/2 inhibitor, has been studied in ovarian adenocarcinoma treatment, particularly in conjunction with platinum therapy, and sensitizes cells to cisplatin (Cis). Pifithrin-α (PFT), a transcriptional inhibitor of p53, sensitizes p53 wild-type ovarian cancer cells to antimicrotubule agent-induced apoptosis. No studies have evaluated the interaction of PFT with platinum drugs or PARP inhibitors. We evaluated the potential synergistic interactions between PFT and ABT/Cis in p53 intact ovarian cancer cells. Methods. We conducted clonogenic assays using BG-1, a human ovarian adenocarcinoma cell line with WT p53 activity. Cells were seeded in 6-well plates and, after 24 hours, treated with combinations of 5μM PFT and multiple doses of ABT and Cis. After 8 days, colony counts were obtained with automated GelDoc software. To identify synergistic interactions, Combination Indices (CI) were calculated with Calcusyn software. Results. At the lowest dose of Cis (0.625μM), relative cell survival is 60.4% with Cis-PFT, 64.9% with Cis-ABT, and 24.5% with Cis-ABT-PFT. At the highest dose (10μM), relative cell survival is 34.3% with Cis-PFT, 5.25% with Cis-ABT, and 0.85% with Cis-ABT-PFT. At low concentrations of Cis, Cis-PFT showed mild to moderate antagonism. At Cis concentrations >2.5μM, moderate synergism developed. At all concentrations, PFT-ABT showed moderate to strong antagonism. Cis-ABT-PFT showed moderate to strong synergism at all concentrations. Conclusions. PFT sensitizes BG-1 cells to Cis in a dose dependent pattern, improving synergism at increasing doses of both Cis and PFT. In contrast, PFT shows marked antagonism to the cytotoxic effects of ABT, independent of ABT dose. The combination of ABT+PFT shows strong, dose-independent synergism in the sensitization of BG-1 cells to Cis and significantly reduces relative survival, suggesting the potential for improved tumor control at reduced doses of cisplatin in p53 WT ovarian cancer. Pifithrin-α and veliparib synergize in the sensitization of BG-1 cells to cisplatin therapy Cis (μM) ABT (μM) PFT (μM) CI Synergy Cisplatin + Pifithrin-α 0.625 − 5 1.729 −−− 1.25 − 5 1.342 −− 2.5 − 5 0.865 + 5 − 5 0.469 +++ 10 − 5 0.390 +++ Veliparib + Pifithrin-α − 0.625 5 1.803 −−− − 1.25 5 3.325 −−−− − 2.5 5 1.647 −−− − 5 5 2.657 −−− − 10 5 1.503 −−− Cisplatin + Veliparib 0.625 1.25 − 0.566 +++ 1.25 2.5 − 0.794 ++ 2.5 5 − 0.863 + 5 10 − 0.656 +++ 10 20 − 0.823 ++ Cisplatin + Veliparib + Pifithrin-α 0.625 1.25 5 0.293 ++++ 1.25 2.5 5 0.418 +++ 2.5 5 5 0.392 +++ 5 10 5 0.291 ++++ 10 20 5 0.262 ++++ Synergism: CI<1, “+” Antagonism: CI>1, “−” Citation Format: Margaret Whicker, Brian Liang, Z. Ping Lin, Alan Sartorelli, Elena Ratner. Pifithrin-α and veliparib synergize in the sensitization of p53 wild-type ovarian cells to cisplatin therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3277. doi:10.1158/1538-7445.AM2013-3277