Biological and Pharmaceutical Bulletin

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42 巻 (2019) 3 号 p. 448-452

Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer

Mari Ishigami-Yuasa, Hisao Ekimoto, Hiroyuki Kagechika

Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/β agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2′-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.

編集者のコメント

The growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/β agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA) on androgen receptor positive or negative prostate cancer cell lines were investigated. Ishigami-Yuasa et al. found that the combination therapy of Am80 and SAHA showed an enhanced growth-inhibitory effect on LNCaP cells. Studies with various HDAC isotype-selective inhibitors indicated that the Class IIb HDACs, especially HDAC6, had significant roles in the enhanced effect of the combination. Thus, dual targeting of Class IIb HDAC and RARα would be useful therapeutic strategy for prostate cancer.

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