Department of Neuro-Oncology, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA.
J Neurooncol. 2011 Nov;105(2):241-51. doi: 10.1007/s11060-011-0604-7. Epub 2011 May 20.
Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time-dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas.
组蛋白去乙酰化酶抑制作用通过改变染色质已被证实对恶性肿瘤有疗效。这些药物的作用机制具有多效性，并且可能具有肿瘤特异性。在这项研究中，我们研究了伏立诺他诱导胶质瘤细胞效应的机制。在体外（D54、U87 和 U373 神经胶质瘤细胞系）研究了伏立诺他对增殖、诱导细胞凋亡和细胞周期效应的影响。为了进一步了解其对人神经胶质瘤的影响，使用新型器官型人神经胶质瘤切片模型研究了伏立诺他诱导的变化。伏立诺他治疗导致所有测试的神经胶质瘤细胞中 p21 水平增加，这与 p53 无关。此外，cyclin B1 水平转录下调，导致 cyclin B1/cdk1 复合物激酶活性降低，导致 G2 期阻滞。这些效应与细胞增殖和锚定独立生长的剂量和时间依赖性抑制相关，与核心组蛋白的乙酰化增加和细胞凋亡诱导有关。特别重要的是，我们证明了在作为器官型切片培养物保存的新鲜切除的人神经胶质瘤标本中存在组蛋白乙酰化增加和 p21 水平升高，类似于细胞系，表明这种药物可以靶向人神经胶质瘤。我们的数据表明，伏立诺他的作用与细胞周期相关蛋白的调节以及 G2 检查点的激活以及细胞凋亡的诱导有关。这些效应是通过转录和翻译后机制介导的，为开发针对神经胶质瘤的新治疗方法提供了潜在的选择。
