Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells
Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells
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DOI：
10.1016/j.bbrc.2008.12.091
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发表时间：
2009-02-06
影响因子：
3.1
通讯作者：
Cattaneo, Elena
中科院分区：
文献类型：
--
作者：
Papait, Roberto;Magrassi, Lorenzo;Cattaneo, Elena
替莫唑胺（TMZ）和卡莫司汀（BCNU）是一种DNA甲基化剂，产生O 6-甲基鸟嘌呤，常用于治疗胶质瘤。已经表明，06-甲基鸟嘌呤触发DNA错配修复，并进而分别在4天和6天的时间内诱导细胞凋亡和衰老[Y. Hirose，M.S. Berger，R.O. Pieper，p53影响替莫唑胺处理的人胶质母细胞瘤细胞的G2/M停滞持续时间和命运，Cancer Res.61（2001）1957 - 1963; W.鲁什，M.鲍姆加特纳，B。Kaina，Apoptosis triggered by DNA damage 06-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1，Oncogene 23（2004）359 - 367]。在这里，我们表明，TMZ和BCNU有较早的影响，核组织和染色质结构。特别是，我们报告TMZ和BCNU诱导着丝粒周围异染色质区域聚集，并增加与染色质结合的异染色质蛋白MeCP 2和HP 1 α的量。这些药物还降低了组蛋白H3乙酰化的总体水平，并增加了组蛋白H3在赖氨酸9上三甲基化（H3-triMeK9）的水平。这些事件先于衰老状态。我们的结论是TMZ和BCNU治疗胶质瘤的疗效可能涉及的第一个事件，其特征在于异染色质组织的变化和沉默，然后是细胞凋亡和衰老。(C)2008年爱思唯尔公司All rights reserved.
Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage 06-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1 alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We Conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence. (C) 2008 Elsevier Inc. All rights reserved.