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Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeuticsrapidly approaching clinical use. In this study, we tested using in vitro andin vivo models the differential biological effects of a novel HDAC inhibitor [belinostat(PXD101)], in a wide panel of androgen-sensitive and androgen-independent tumorcells. Belinostat significantly increased acetylation of histones H3 and H4. Belinostatpotently inhibited the growth of prostate cancer cell lines (IC50 range from 0.5to 2.5 µM) with cytotoxic activity preferentially against tumor cells. This agentinduced G2/M arrest and increased significantly the percentage of apoptosis mainlyin androgen-sensitive tumor cells confirming its growth-inhibitory effects. Thecell death mechanisms were studied in three different prostate cancer cell lineswith different androgen dependence and expression of androgen receptor; LAPC-4and 22rv1 (androgen-dependent and expressing androgen receptor) and PC3 (androgen-independentnot expressing androgen receptor). Belinostat induced the expression of p21 andp27, acetylation of p53 and G2/M arrest associated with Bcl2 and Bcl-Xl downmodulationand significant reduction of survivin, IAPs and Akt/pAkt and increased caspase-8and -9 expression/activity. Belinostat effectiveness was dependent on the androgenreceptor (AR), since the stable transfection of AR greatly increased the efficacyof this HDAC inhibitor. These observations were correlated using in vivo models.We demonstrated that belinostat preferentially resulted in antitumor effect inandrogen-dependent tumor cells expressing AR. Our findings provide evidence thatbelinostat may be a promising anticancer drug for prostate cancer expressing AR,supporting its clinical role in prostate cancer.

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models