Abstract 5878: Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway

Abstract

Abstract Trichostatin A (TSA), a potent histone deacetylase (HDAC) inhibitor, has been reported to elicit anti-proliferative response in various tumors. Here, we investigated antitumor effect of TSA alone or in combination with conventional chemotherapeutic agents on urothelial carcinoma (UC) cells. We use one high-grade UC cell line (T24) and another UC cells (NTUUC) obtained by primary culture from the surgical specimen of a women with high-grade and metastatic bladder UC. The cytotoxicity and apoptosis induced by TSA alone , chemotherapeutic agents (cisplatin, gemcitabine and doxorubicin) and combined treatment were assessed by MTT assay and fluorescence-activated cell sorting and flow cytometry. The expression of phosphor c-Raf, phosphor-MEK1/2, and phosphor-ERK1/2 were measured by Western blot. urther elucidation on the role of Raf/MEK/ERK pathoway on the TSA-enhanced cytoxicity were exmained by using ERK1 siRNA knockdown and the specific MEK inhibitor (PD98059). Our results showed TSA markedly enhances the cytotoxicity and apoptosis of three chemotherapeutic agents in UC cells with concurrent suppression of Raf/MEK/ERK signaling pathway. Consistently, inhibition of Down-regulation of ERK by MEK inhibitor or by ERK 1 siRNA knockdown potentiated the chemotherapeutic agnet-induced cytotoxicity of TSA in UC cells. We concluded that TSA potentiates the therapeutic efficacy of cisplatin, gemcitabine and doxorubicin in human UC cells through Raf/MEK/ERK signaling pathway. These findings provide a new treatment strategy against UC. Note: This abstract was not presented at the meeting. Citation Format: Kuan-Lin Kuo, Chung-Sheng shi, Ju-Tong Hsieh, Shiang-Peng Chen, Wei-Chou Lin, Shih-Ming Liao, Shing-Hwa Liu, Kuo-How Huang. Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5878. doi:10.1158/1538-7445.AM2017-5878