Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor
Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor
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DOI：
10.4161/cc.2.3.357
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发表时间：
2003-01-01
期刊：
影响因子：
4.3
通讯作者：
Zagzag, David
中科院分区：
文献类型：
--
作者：
Newcomb, Elizabeth W.;Tamasdan, Cristina;Zagzag, David
胶质母细胞瘤（GBM）由于其高度增殖性、血管生成性和侵袭性的性质而仍然是治疗最具挑战性的实体癌之一。小分子CDK抑制剂flavopiridol已在人类异种移植模型中显示出抗肿瘤活性，目前正在临床试验中显示对晚期疾病患者的疗效。我们已经开发了一种实验动物模型，使用鼠胶质瘤GL 261细胞作为一种新的体内系统来筛选潜在的治疗药物GBM。体外试验的结果表明，夫拉普利醇具有几个相关的临床特征，如它的能力：1。抑制细胞生长;2.抑制细胞迁移;3.降低cyclin D1、CDK 4和p21的表达;4.在具有高水平p27表达的细胞中诱导凋亡;和5.降低抗凋亡蛋白Bcl-2的表达。我们证明，通过电子显微镜和免疫组化，药物治疗诱导线粒体损伤，伴随着细胞色素c释放到细胞质中，与易位的凋亡诱导因子（AIF）到细胞核。小鼠神经胶质瘤细胞中的这一发现与我们报道的人类神经胶质瘤细胞黄吡醇诱导细胞死亡的机制不同（Alonso等人，Mol Cancer Ther 2003; 2：139），其中药物治疗在不存在对线粒体的可检测损伤的情况下诱导半胱天冬酶和细胞色素c非依赖性途径。在凋亡的人脑胶质瘤细胞中，只有AIF易位到细胞核中发生。因此，同一种药物通过不同的神经胶质瘤依赖途径杀死不同类型的神经胶质瘤细胞。
Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to:1. inhibit cell growth;2. inhibit cell migration;3. decrease expression of cyclin D1, CDK4 and p21;4. induce apoptosis in cells with high levels of p27 expression; and5. decrease the expression of the anti-apoptotic protein Bcl-2.The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridol-induced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2: 139) where drug treatment induced a caspase-and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways.