HDAC inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma cells

摘要

Aim: To investigate the anticancer effect of histone deacetylase inhibitors (HDACIs) in combination with sorafenib in wild-type and mutant von Hippel-Lindau (VHL)-expressing renal cell carcinomas (RCCs). Materials and Methods: We exposed clear cell RCC cells to HDACIs (vorinostat or belinostat) or sorafenib. We performed 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays, western blotting, flow cytometry and enzyme-linked immunosorbent assays (ELISA) to evaluate mechanisms of cell death, and used CalcuSyn to analyze the potential synergism. Results: HDACIs alone inhibited the growth of clear cell RCC cell lines, increased acetylation of histone 3 and of tubulin, activated caspases-8, -9, and -3, and augmented the sub-G1 population, independently of VHL and permeability glycoprotein (P-gp). Moreover, pre-treatment of Caki-1 (wild-type VHL) and 786-O (mutant VHL) with HDACIs followed by sorafenib reduced cell viability synergistically via activation of caspases and downregulation of the levels of myeloid leukemia cell differentiation protein (MCL1), phospho-extracellular signal-regulated kinase (ERK), and secreted vascular endothelial growth factor (VEGF). Conclusion: Sorafenib is more effective in combination with HDACIs even for clear cell RCCs harboring mutant VHL.