Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL.
Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL.
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Navitoclax（ABT-263）通过拮抗BCL-XL在药物诱导的有丝分裂停滞期间加速凋亡。
DOI：
10.1158/0008-5472.can-10-4336
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Mitchison TJ
中科院分区：
文献类型：
--
作者：
Shi J;Zhou Y;Huang HC;Mitchison TJ
将微管靶向抗有丝分裂药物与靶向凋亡增强剂相结合是一种有前景的癌症治疗新化疗策略。在这项研究中，我们研究了 Bcl-2 家族抑制剂 Navitoclax（以前称为 ABT-263）在一组上皮癌细胞系中增强紫杉醇和 Kinesin-5 (KSP) 抑制剂引发的细胞凋亡的细胞机制。使用延时显微镜，我们发现Navitoclax对间期细胞死亡几乎没有影响，但在有丝分裂停滞期间强烈加速细胞凋亡，并大大增加死亡的抗凋亡细胞的比例。通过系统地敲低单个 Bcl-2 蛋白，我们确定 Mcl-1 和 Bcl-xL 是长期有丝分裂停滞期间细胞凋亡的主要负调节因子。由于合成和周转之间的不平衡，Mcl-1 水平在有丝分裂停滞期间降低，而周转部分取决于 MULE/HUWE1 E3 连接酶。 Mcl-1 缺失与 Navitoclax 对 Bcl-xL 的抑制相结合，导致所有测试细胞系快速凋亡。 Mcl-1 和 Bcl-xL 表达水平的变化在很大程度上决定了我们小组对单独抗有丝分裂药物以及抗有丝分裂药物与 Navitoclax 联合反应的变化。我们的结论是，Bcl-xL 是 Bcl-2 家族抑制剂增强上皮癌抗有丝分裂药物致死率的关键靶点，Navitoclax 和纺锤体特异性抗有丝分裂药物（如 Kinesin-5 抑制剂）联合治疗可能比单独使用紫杉醇更有效。
Combining microtubule-targeting anti-mitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study we investigate the cellular mechanism by which Navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of Kinesin-5 (KSP), across a panel of epithelial cancer lines. Using time-lapse microscopy, we show that Navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest due to an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by Navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determine variation in response to anti-mitotics alone, and anti-mitotics combined with Navitoclax, across our panel. We conclude that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of anti-mitotic drugs in epithelial cancers, and combination treatment with Navitoclax and a spindle specific anti-mitotic, such as a Kinesin-5 inhibitor, might be more effective than paclitaxel alone.