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  • Title: Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models.
    Author: Qian DZ, Wei YF, Wang X, Kato Y, Cheng L, Pili R.
    Journal: Prostate; 2007 Aug 01; 67(11):1182-93. PubMed ID: 17520666.
    Abstract:
    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 p21 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 p21 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.
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