Combination of Suberoylanilide Hydroxamic Acid and Ritonavir is Effective Against Renal Cancer Cells
Received 26 November 2009; accepted 21 April 2010. published online 13 July 2010. Corrected Proof
Objectives
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-G1 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.
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan
Reprint requests: Akinori Sato, M.D., Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513 Japan
ABSTRACT