title: HDAC inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma cells.
abstract: OBJECTIVE
  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).
  
  
  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).
  
  
  CONCLUSIONS
  Sorafenib is more effective in combination with HDACIs even for clear cell RCCs harboring mutant VHL.
authors: Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Mi Joung
authors: MJ
authors: Kim
authors: Dong Eun
authors: DE
authors: Kim
authors: In Gab
authors: IG
authors: Jeong
authors: Jene
authors: J
authors: Choi
authors: Sejin
authors: S
authors: Jang
authors: Je-Hwan
authors: JH
authors: Lee
authors: Seonggu
authors: S
authors: Ro
authors: Jung Jin
authors: JJ
authors: Hwang
authors: Choung-Soo
authors: CS
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D013449:Sulfonamides; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010671:Phenylurea Compounds; D011725:Pyridines; D013449:Sulfonamides; D009536:Niacinamide; D000077337:Vorinostat; D000077157:Sorafenib; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C487081:belinostat