Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275
Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275
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DOI：
10.1158/1535-7163.mct-05-0533
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Blümcke, I
中科院分区：
文献类型：
--
作者：
Eyüpoglu, LY;Hahnen, E;Blümcke, I
组蛋白去乙酰化酶抑制剂是治疗癌症的有前途的化合物，但尚未在恶性脑肿瘤中进行系统研究。在这里，我们的特点是苯甲酰胺MS-275，I类组蛋白去乙酰化酶抑制剂，作为实验性治疗胶质母细胞瘤的有效药物。用MS-275处理四种胶质瘤细胞系（U87 MG、C6、F98和SMA-560）以浓度依赖性方式显著降低细胞生长（IC 90，3.75 μ mol/L）。其抗增殖作用使用溴脱氧尿苷增殖测定法证实，并由GO-G、细胞周期停滞（即，p21/WAF的上调）和凋亡性细胞死亡。将增强型绿色荧光蛋白转染的F98神经胶质瘤细胞植入大鼠脑切片培养物中，证实了MS-275在剂量递增至20 μ mol/L时对器官型神经元环境无神经毒性损伤的细胞抑制作用。在同系大鼠中原位植入胶质瘤细胞后7天，单次尿内注射MS-275证实了MS-275在体内的化疗功效。此外，其通过血脑屏障和增加脑组织中乙酰化组蛋白H3的蛋白水平的倾向将MS-275鉴定为治疗恶性神经胶质瘤的有希望的候选药物。
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 mu mol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by GO-G, 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 mu mol/L. A single intraturnoral 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.