Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models

BACKGROUND. Histone deacetylase (HDAC) inhibitors represent a novel class of therapeutic agents with antitumor activity currently in clinical development. In this study, we tested the biological effects of the HDAC inhibitor MS-275 in various pre-clinical prostate cancer models both in vitro and in vivo. METHODS. In vitro cell proliferation XTT assay and protein expression analysis by Western blot were performed. In vivo tumor growth assessment in subcutaneous, orthotopic, and transgenic mouse models were conducted. RESULTS. MS-275 significantly upregulated histone H3 acetylation and p2l gene expression in human prostate cancer cell lines. MS-275 exerted growth arrest in PC-3 and LNCaP cells, and induced cell death in DU-145 cells. Prostate specific antigen protein levels were increased by MS-275 in LAPC4 cell line. In vivo, MS-275 inhibited the growth of DU-145, LNCaP, and PC-3 in subcutaneous xenografts. MS-275 had also a significant inhibition of PC-3 cells growth in a mouse intratibial model. Molecular analysis showed increased histone acetylation and p2l expression in tumor samples from MS-275-treated mice. In transgenic adenocarcinoma of mouse prostate (TRAMP) mice, long-term treatment of MS-275 slowed the progression of prostate carcinomas with significant reduction in cell proliferation. CONCLUSIONS. Taken together, these data support the clinical testing of MS-275 for the treatment of prostate cancer. Prostate 67:1182-1193,2007. (c) 2007 Wiley- Liss, Inc.