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Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275

Eyupoglu, I. Y., Hahnen, E., Tränkle, C., Savaskan, N. E., Siebzehnrubl, Florian, Buslei, R., Lemke, D., Wick, W., Fahlbusch, R. and Blümcke, I. 2006. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Molecular Cancer Therapeutics 5 (5) , p. 1248. 10.1158/1535-7163.MCT-05-0533

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Abstract

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC90, 3.75 μmol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G0-G1 cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein–transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 μmol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: American Association for Cancer Research
ISSN: 1535-7163
Last Modified: 04 Jun 2017 06:40
URI: http://orca.cf.ac.uk/id/eprint/63482

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