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首页> 外文期刊>Oncogene >Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins
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Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins

机译：新型Bcl-2家族小分子抑制剂ABT-737基于凋亡的胶质母细胞瘤治疗

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Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.
机译：凋亡信号级联反应中的缺陷导致恶性神经胶质瘤的不良治疗反应。由于胶质母细胞瘤的特征在于高水平的抗凋亡Bcl-2家族蛋白，我们研究了新型Bcl-2抑制剂ABT-737对恶性神经胶质瘤细胞的作用。 ABT-737处理从其结合伴侣Bcl-2释放促凋亡的Bax蛋白，并在体外和体内有效诱导胶质母细胞瘤细胞凋亡。在颅内神经胶质瘤异种移植模型中，ABT-737的局部给药可延长生存期。 Mcl-1的下调和Bcl-2的过表达使细胞对ABT-737介导的细胞凋亡敏感。此外，ABT-737增强了化学治疗药物长春新碱和依托泊苷以及死亡配体TRAIL的细胞毒性。由于神经胶质瘤干细胞可能在胶质母细胞瘤的肿瘤进展和抗药性中起关键作用，因此我们研究了ABT-737对具有干细胞特征的神经胶质瘤细胞亚群的影响。与非干细胞样神经胶质瘤细胞相比，ABT-737在神经胶质瘤干细胞中抑制增殖和诱导凋亡的效率较低。由于神经胶质瘤干细胞的耐药性与高的Mcl-1表达水平相关，因此ABT-737治疗与Mcl-1的下调结合可能代表胶质母细胞瘤治疗中的一种有前途的新方法。

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