Suberoylanilide hydroxamic acid (SAHA) combined with bortezomib inhibits renal cancer growth by enhancing histone acetylation and protein ubiquitination synergistically.

Abstract

To investigate the combined effect of two clinically feasible drugs, the proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), on human renal cancer cells in vitro and in vivo. The effectiveness of the combination of bortezomib (10-20 nm) and SAHA (1-5 µm) on renal cancer cells (Caki-1, ACHN, A-498, 786-O, 769-P) was assessed by MTS assay, colony formation assay, cell cycle analysis, and apoptosis assay. In vivo efficacy was evaluated using murine subcutaneous (s.c.) tumour models. Protein ubiquitination, unfolded protein response, histone acetylation, and changes in the expression of HDAC were evaluated by western blotting. The combination of SAHA and bortezomib induced apoptosis and inhibited cancer cell proliferation synergistically (combination indices <1) and colony formation significantly (P < 0.05). In s.c. tumour models a 10-day treatment with a combination of SAHA (50 mg/kg) and bortezomib (60 µg/kg) inhibited tumour growth significantly (P < 0.05). Mechanistically, SAHA combined with bortezomib enhanced protein ubiquitination synergistically and enhanced histone acetylation by inhibiting the expression of HDACs. SAHA combined with bortezomib inhibits the proliferation of renal cancer cells in vitro and in vivo, and the effectiveness of the combination is due to its synergistic enhancement of histone acetylation and protein ubiquitination.