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-G(1) 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.
Written by:
Kim MJ, Kim DE, Jeong IG, Choi J, Jang S, Lee JH, Ro S, Hwang JJ, Kim CS. Are you the author?
Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Reference: Anticancer Res. 2012 Aug;32(8):3161-8.
PubMed Abstract
PMID: 22843888
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