Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction
Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction
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DOI：
10.1158/0008-5472.can-05-1724
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
De Maria, R
中科院分区：
文献类型：
--
作者：
Eramo, A;Pallini, R;De Maria, R
多形性胶质母细胞瘤患者的预期寿命极低。肿瘤坏死因子相关凋亡诱导配体（TRAIL）的治疗用途已被提出来治疗这种疾病的基础上，它的能力，杀死胶质瘤细胞系在体外和体内。在这里，我们表明，不同的神经胶质瘤细胞系多形性胶质母细胞瘤肿瘤是耐TRAIL刺激，因为它们表达低水平的caspase-8和高水平的死亡受体抑制剂PED/PEA-15。地西他滨对甲基转移酶的抑制导致TRAIL受体-1和caspase-8的显著上调，PED/ PEA-15的下调，细胞生长的抑制，以及原代胶质母细胞瘤细胞对TRAIL诱导的凋亡的敏感性。外源性caspase-8表达是能够恢复原发性胶质母细胞瘤细胞中TRAIL敏感性的主要事件。地西他滨和TRAIL的抗肿瘤活性在多形性胶质母细胞瘤小鼠模型中得到体内证实。在裸鼠多形性胶质母细胞瘤异种移植瘤中对肿瘤大小、细胞凋亡和半胱天冬酶激活的评估显示，地西他滨和TRAIL在胶质母细胞瘤治疗中具有显著的协同作用，而单药在肿瘤质量减少、细胞凋亡诱导和半胱天冬酶激活方面几乎无效。因此，TRAIL和去甲基化剂的组合可以提供克服胶质母细胞瘤对治疗性治疗的抗性的关键工具。
Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/ PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenotis caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma, cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma, multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma, resistance to therapeutic treatments.