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

Abstract

Abstract. Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use. In this study, we tested using in vitro and in vivo models the differential biological effects of a novel HDAC inhibitor [belinostat (PXD101)], in a wide panel of androgensensitive and androgen-independent tumor cells. Belinostat significantly increased acetylation of histones H3 and H4. Belinostat potently inhibited the growth of prostate cancer cell lines (IC 50 range from 0.5 to 2.5 µM) with cytotoxic activity preferentially against tumor cells. This agent induced G 2 /M arrest and increased significantly the percentage of apoptosis mainly in androgen-sensitive tumor cells confirming its growthinhibitory effects. The cell death mechanisms were studied in three different prostate cancer cell lines with different androgen dependence and expression of androgen receptor; LAPC-4 and 22rv1 (androgen-dependent and expressing androgen receptor) and PC3 (androgen-independent not expressing androgen receptor). Belinostat induced the expression of p21 and p27, acetylation of p53 and G 2 /M arrest associated with Bcl2 and Bcl-Xl downmodulation and significant reduction of survivin, IAPs and Akt/pAkt and increased caspase-8 and -9 expression/activity. Belinostat effectiveness was dependent on the androgen receptor (AR), since the stable transfection of AR greatly increased the efficacy of this HDAC inhibitor. These observations were correlated using in vivo models. We demonstrated that belinostat preferentially resulted in antitumor effect in androgen-dependent tumor cells expressing AR. Our findings provide evidence that belinostat may be a promising anticancer drug for prostate cancer expressing AR, supporting its clinical role in prostate cancer.

Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer

“…Apoptosis induced by HDAC inhibition has been demonstrated to be dependent on AR expression [40]. Our study also demonstrates that PAN mediated apoptosis is AR dependent.…”

Antitumor Effects of Saffron-Derived Carotenoids in Prostate Cancer Cell Models

“…Morphological controls were performed every day with an inverted phase-contrast photomicroscope (Nikon Diaphot, Tokyo, Japan) before cell trypsinization and counting. Cells were trypsinized and resuspended in 1.0 mL of saline and counted using the NucleoCounter NC-100 (Chemotec, Cydevang, DK) as previously described [30]. NucleoCounter NC-100 also allows determination of the number of dead cells present in a cell sample and, therefore, we considered viable and dead cells to be separated entities.…”

Exploiting Epigenetic Alterations in Prostate Cancer

“…Their efficacy was evidenced in several prostate tumor models. In vivo activity was, for instance, reported for the pan-HDAC inhibitors panobinostat and belinostat [70,71], and for the more selective inhibitors entinostat and mocetinostat [72,73]. Panobinostat was also shown to block growth of castration-resistant models [74].…”