title: Combination of suberoylanilide hydroxamic acid and ritonavir is effective against renal cancer cells.
abstract: OBJECTIVE
  To investigate the combined effect of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) and the protease inhibitor ritonavir on renal cancer cells.
  
  
  METHODS
  Renal cancer cells (769P, 786O, A498, ACHN, Caki-1) and renal proximal tubule epithelial cells were treated with SAHA (0-5 μM) with or without ritonavir (0-50 μM). Cell viability, clonogenecity, and changes in cell cycle were evaluated. The expression of acetylated histone, retinoblastoma protein (Rb), phosphorylated Rb, histone deacetylases, X-linked inhibitor of apoptosis, survivin, and active caspase 3 was assessed using Western blot analysis.
  
  
  RESULTS
  SAHA induced histone acetylation and Rb dephosphorylation and inhibited cell growth in a time- and dose-dependent manner. SAHA and ritonavir combined inhibited cell proliferation effectively and promoted histone acetylation and Rb dephosphorylation but only slightly affected renal proximal tubule epithelial cell survival. The combination induced the accumulation of the sub-G(1) fraction, decreased the expression of X-linked inhibitor of apoptosis and survivin, and increased active caspase 3, thus inducing apoptosis. It also inhibited the expression of histone deacetylases.
  
  
  CONCLUSIONS
  Combination therapy using SAHA and ritonavir inhibited the proliferation of renal cancer cells effectively, perhaps by inhibiting both histone deacetylase function and expression. It might be a useful new regimen for treating renal cancer.
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan. zenpaku@ndmc.ac.jp
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.forename: Takako
authors.initials: T
authors.lastname: Asano
authors.forename: Akio
authors.initials: A
authors.lastname: Horiguchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.forename: Makoto
authors.initials: M
authors.lastname: Sumitomo
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Asano
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019438:Ritonavir / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D019438:Ritonavir