Abstract
Abstract Resistance to chemotherapy is a major hurdle in the treatment of cutaneous T cell lymphoma. Histone deacetylase (HDAC) inhibitors are known to display antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor ≤ (RARα). Some HDAC inhibitors have begun to be used for cutaneous T cell lymphoma patients in Japan. In this study, we tested the antitumor effect of the HDAC inhibitor MS-275 in combination with retinoic acid Am80 on two human cutaneous T cell lymphoma cell lines in vitro. Treatment of MS-275 showed a dose-dependent inhibitory effect on SeAx and MJ cell lines in a MTT assay. These cell lines were relatively resistant to Am80. A greater inhibitory effect (up to 80%) was achieved with a combination of MS-275 and Am80 compared with each agent alone. The lack of RARα2 gene expression was associated with histone deacetylation and gene methylation at the promoter level. Treatment with the combination of MS-275 and Am80 restored retinoid sensitivity by reversing RARα2 epigenetic silencing, which was verified by ChIP assay using histone H4. P21 was induced in both cell lines but the biological effect of MS-275 was G1cell cycle arrest in MJ and apoptosis in the SeAx cell line. These results suggest that the HDAC inhibitor MS-275 has a greater antitumor activity in combination with Am80 in cutaneous T cell lymphomas but that the degree of induced cell death may vary. The combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for cutaneous T cell lymphoma that warrants clinical testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4078. doi:1538-7445.AM2012-4078
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