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

Akinori Sato, Takako Asano, Keiichi Ito, Makoto Sumitomo, Tomohiko Asano

研究成果: Article査読

26 被引用数 (Scopus)

抄録

OBJECTIVE: • 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. MATERIALS AND METHODS: • The effectiveness of the combination of bortezomib (10-20 nM) and SAHA (1-5 μM) on renal cancer cells (Caki-1, ACHN, A-498, 786-0, 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. RESULTS: • 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. CONCLUSION: • 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.

本文言語English
ページ(範囲)1258-1268
ページ数11
ジャーナルBJU International
109
8
DOI
出版ステータスPublished - 04-2012
外部発表はい

All Science Journal Classification (ASJC) codes

  • Urology

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