Abstract
Abstract We synthesized a novel hydroxamate-based HDACi, CG0005 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]}. Like other inhibitors, for example SAHA and PXD 101, CG0005 has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. The aliphatic chain of CG0005, which is presumed to be positioned at the narrow channel of pocket, is less flexible than that of SAHA and less rigid than that of PXD101. Of the other moieties, the tertiary amine was adopted to improve water solubility. Firstly, we analyzed its activity in hormone-dependent LNCaP cells and hormone-refractory DU145 and PC3 cells. CG0005 inhibited deacetylation of histone3 and tubulin as much as vorinostat and belinostat. CG0005 also inhibited growth of prostate cancer cells and increased sub-G1 population and activated caspase-9, -3 and -8. These results indicated that CG0005 induced apoptosis in prostate cancer cell lines. Next, we examined the effect of CG0005 on cell death induced by docetaxel in DU145 cells in vitro and in vivo. Pre-treatment of DU145 cells with docetaxel followed by CG0005 showed synergistic cytotoxicity, and increased the apoptotic sub-G1 population, caspase activation, and tubulin acetylation, compared with docetaxel alone. Moreover, the combination treatment decreased Mcl-1, Bcl-xl and cyclin D1. Docetaxel and CG0005 combination reduced tumor size in the DU145 xenograft model. These preclinical results show that post-treatment with CG0005 potentiated anti-tumor effect of docetaxel in hormone-refractory prostate cancer (HRPC) cells via intrinsic and extrinsic apoptotic pathway in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 179. doi:10.1158/1538-7445.AM2011-179
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