Rerouting Chlorambucil to Mitochondria Combats Drug Deactivation and Resistance in Cancer Cells
Rerouting Chlorambucil to Mitochondria Combats Drug Deactivation and Resistance in Cancer Cells
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DOI：
10.1016/j.chembiol.2011.02.010
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发表时间：
2011-04-22
影响因子：
--
通讯作者：
Kelley, Shana O.
中科院分区：
文献类型：
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作者：
Fonseca, Sonali B.;Pereira, Mark P.;Kelley, Shana O.
进入线粒体基质的困难限制了针对该细胞器的治疗。在此，据我们所知，我们报告了首次成功地将活性 DNA 烷化剂苯丁酸氮芥递送至线粒体，并描述了这种药物在细胞内重新路由所产生的意想不到的特征。该药物的线粒体靶向显着增强其活性，并促进多种癌细胞系和患者样本中的细胞凋亡。即使在对苯丁酸氮芥具有抗性或细胞凋亡触发失效的细胞中也能观察到这种活性的保留。
The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent-chlorambucil-to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.