Abstract 5515: Combining FK228 and cisplatin synergistically induces cancer cell death and reduces clonogenic survival

Abstract

Abstract The purpose of this study was to investigate the effectiveness of FK228 (romidepsin) to increase cisplatin's ability to induce cell death and reduce clonogenic survival of human urinary bladder cancer cells. Human urinary bladder cancer is the fifth most common cancer in the United States, but long-term, disease-free survival in patients is still suboptimal. Therefore, it is crucial to develop effective chemotherapeutic regimens to decrease the morbidity and mortality of this cancer. FK228, a depsipeptide and histone deacetylase inhibitor, is approved by the U.S. Food and Drug Administration for treatment of T cell lymphoma. However, its therapeutic value in treatment of bladder cancer is yet to be determined. Cisplatin is a DNA-damaging agent for treating various human cancers, including bladder, brain, ovary, lung, and testis cancers. However, the efficacy of cisplatin is often dampened by cancer cell drug resistance, mostly associated with glutathione (GSH)-based detoxification. Our study revealed that FK228 combined with cisplatin synergistically induced cell death and reduced clonogenic survival of human urinary bladder cancer cells. The Erk-Nox pathway played an important role in mediating signals highly increased by this combined treatment to induce significantly-elevated levels of reactive oxygen species, leading to substantially-induced caspase activation and synergistically-increased death in cancer cells. Cisplatin was able to enhance the ability of FK228 to significantly reduce GSH, indicating a novel activity of combined FK228 and cisplatin in reducing drug resistance. The ability of combined FK228 and cisplatin to synergistically induce cell death and reduce clonogenic survival was also applicable to colon cancer cells. Hence, combined use of FK228 with cisplatin should be considered in development of therapeutic strategies to control urinary bladder cancer and other cancer development and recurrence. Citation Format: Shambhunath Choudhary, Shilpa Sood, Lenora A. Pluchino, Hwa-Chain R. Wang. Combining FK228 and cisplatin synergistically induces cancer cell death and reduces clonogenic survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2014-5515