Abstract 5812: Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin

Abstract

Abstract Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States. Long-term survival of patients is still suboptimal with current therapeutic regimens failing to impede drug resistance and recurrence. Thus, it is urgent to develop therapeutic regimens that effectively control tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We investigated the efficacy of combination regimens to control various human urinary bladder cancer cells in vitro and cell-derived xenografts in vivo. Our studies revealed, for the first time, a combination of gemcitabine plus cisplatin and romidepsin effective in synergistically inducing cell death and reducing drug resistance in vitro. The enhanced Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species, leading to enhanced caspase activation, enhanced DNA damage and oxidation, and reduced glutathione, which synergistically increased cell death and reduced drug resistance in cells treated with combined gemcitabine, cisplatin, and romidepsin. The unfolded protein response also played a role in the modulation of cyto-protection and cell death through the combined regimen. In vivo studies verified the efficacy of gemcitabine plus cisplatin and romidepsin in control of xenograft tumor growth in immune-deficient mice. Hence, our results lead us to suggest that a combination of gemcitabine, cisplatin, and romidepsin should be seriously considered as an advanced regimen over the conventional gemcitabine plus cisplatin regimen for controlling the development and recurrence of human urinary bladder cancer. Citation Format: Hwa-Chain R. Wang, Pawat Pattarawat. Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5812.