Abstract 178: Pre-treatment with histone deacetylase inhibitor HDACI) synergizes the anti-cancer effect of sorafenib in renal cell carcinoma cells

Abstract

Abstract Background: Renal cell carcinoma (RCC), account for 3% of all adult malignances and 75% of RCCs are clear cell renal cell carcinoma (ccRCC), which are highly vascularised tumors. Although a multi-kinase inhibitor, sorafenib has been used for treatment of advanced renal cell carcinoma, it has limitation such as toxicity and long term resistance. Recently, it was reported that histone deacetylase (HDAC) activity is increased in cancer, which leads to suppression of the genes that are related to tumor suppressor and differentiation. Therefore, histone deacetylase inhibitors (HDACIs) are considered as a new anti-cancer drug. In this study, we evaluated the effect of HDACI on anti-tumor effect of sorafenib in ccRCC cells. Materials and Methods: We used various types of RCC cells including Caki-1(VHL+/+), ACHN (VHL+/+), 786-O (VHL−/−), A498 (VHL−/−), SN12C, TK-10, RXF393, and MDR-over-expressing UO31 cells. We calculated the viability of RCC cells treated with HDACIs (belinostat or vorinostat) alone or in combination with sorafenib using MTS Assay. Combination indexes were determined by CalcuSyn software. We analyzed activation of caspases, and the levels of Mcl-1, Bcl-xl, p-Erk by Western Bolt. Levels of secreted vascular endothelial growth factor (VEGF) were measured by ELISA kit. Results: Mono-treatment with HDACI (belinostat or vorinostat) induced apoptosis via activation of intrinsic and extrinsic pathways in all RCC cells. Moreover, pre-treatment with belinostat or vorinostat synergistically potentiated cell death induced by sorafenib in Caki-1 and 786-O ccRCC cells. The combination treatment activated caspase-8, -3 and -9 and down-regulated Mcl-1, Bcl-xl, phosphorylation of Erk (p-Erk) and secretion of VEGF in Caki-1 and 786-O cells. Conclusions: HDACI alone induced apoptotic cell death in various RCC cells. In addition, combination treatment with HDACIs and sorafenib represented synergistic anti-cancer effect in ccRCC cells, indicating that this combination may be a new therapeutic modality for RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 178. doi:10.1158/1538-7445.AM2011-178