Abstract 2151: Thiostrepton synergizes with paclitaxel and cisplatinum in ovarian cancer cell lines.

Abstract

Abstract Objective: Drug-resistance is a common problem in the up-front treatment of certain subtypes of epithelial ovarian cancer (clear-cell) and also for recurrent disease, resulting in high-mortality rates for these patients. Identification of new cytotoxic drugs and drugs that improve the efficacy of current chemotherapeutics is vital to overcoming this issue. Thiostrepton is a thiazole antibiotic that targets cancer cells by inactivating the oncogenic transcription factor, forkhead box M1 (FOXM1). Aberrantly activated FOXM1 leads to uncontrolled cell proliferation and dysregulation in the FOXM1 transcription network occurs in 87% of ovarian cancer cases. We seek to determine the combinatory effects of adding thiostrepton to treatment with paclitaxel and cisplatinum. Methods: Three human ovarian cancer cell lines (SKOV3, 429, and ES-2) were inoculated into 96-well plates at 5,000-10,000 cells/well. After incubation for 24 hours, cells were treated with single drug or in combination with thiostrepton. Cells were then incubated for 48 hours after which the sulforhodamine B assay was used to assess cytotoxicity. Drug combination effects were determined by calculating the combination index (CI) values using the Chou and Talalay method; CI <0.9 = synergy, CI 0.9-1.10 = additive effects and CI >1.10 = antagonism. Quantitative RT-PCR and western blot assays were performed to determine changes in FOXM1 expression. Results: FOXM1 mRNA expression was increased 11-, 28-, and 42-fold compared to normal ovarian tissue in the cell lines 429, SKOV3, and ES-2, respectively. RT-PCR and western blots in the SKOV3 cell line confirmed decrease in FOXM1 expression and protein levels upon thiostrepton treatment. Dose-response curves were generated for each drug and for combination therapy and all curves conformed to the principle of mass-action, r-values >0.92. Based on these curves, synergy between paclitaxel and thiostrepton was seen in all three cell lines, CI 0.33-0.87. Cisplatinum and thiostrepton showed synergistic effects in SKOV3, CI 0.34-0.77, and additive effects in ES-2 and 429, CI 0.92-1.09. Conclusion: The addition of thiostrepton improves the cytotoxic effects of both paclitaxel and cisplatinum in ovarian cancer cells. The ES-2 cell line is of the clear-cell histology and our data suggests thiostrepton may improve the efficacy of the current treatment regimen for these patients. Synergistic effects seen in the serous ovarian cancer cell lines SKOV3 and 429 predict that thiostrepton may also be used to reduce drug-resistance for patients with recurrent disease. Thiostrepton may also be used to decrease the dose of the taxane or platinum agent in up-front treatment to minimize toxicity yet still achieve clinical efficacy. Continued research on thiostrepton activity in vivo is an important next step in the development of this drug into a novel ovarian cancer treatment. Citation Format: Gina Westhoff, Yi Chen, Marcia Bieber, Nelson Teng. Thiostrepton synergizes with paclitaxel and cisplatinum in ovarian cancer cell lines. [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 2151. doi:10.1158/1538-7445.AM2013-2151