Targeted Delivery of Doxorubicin to Mitochondria
Targeted Delivery of Doxorubicin to Mitochondria
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DOI：
10.1021/cb400095v
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Kelley, Shana O.
中科院分区：
文献类型：
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作者：
Chamberlain, Graham R.;Tulumello, David V.;Kelley, Shana O.
几种高效抗癌药物对癌细胞具有选择性毒性，因为它们扰乱了细胞核内的核酸合成。然而，关于干扰线粒体中的核酸合成是否会对细胞产生重大影响，我们知道的要少得多。在这项研究中，我们通过线粒体靶向形式的抗癌药物阿霉素来探索这一点，阿霉素可以抑制DNA拓扑异构酶II，DNA拓扑异构酶II是一种同时存在于人类细胞线粒体和细胞核中的酶。当阿霉素结合到以线粒体为靶标的多肽上时，它表现出显著的毒性。然而，当用过度表达普通外排泵的细胞系挑战时，它不会表现出核定位母药的活性降低，并抵制从细胞中移除。这些结果表明，靶向线粒体的药物提供了一种限制药物外流的手段，并提供了线粒体靶向DNA拓扑异构酶毒物在细胞器内活跃的证据。
Several families of highly effective anticancer drugs are selectively toxic to cancer cells because they disrupt nucleic acid synthesis in the nucleus. Much less is known, however, about whether interfering with nucleic acid synthesis in the mitochondria would have significant cellular effects. In this study, we explore this with a mitochondrially targeted form of the anticancer drug doxorubicin, which inhibits DNA topoisomerase II, an enzyme that is both in mitochondria and nuclei of human cells. When doxorubicin is attached to a peptide that targets mitochondria, it exhibits significant toxicity. However, when challenged with a cell line that overexpresses a common efflux pump, it does not exhibit the reduced activity of the nuclear-localized parent drug and resists being removed from the cell. These results indicate that targeting drugs to the mitochondria provides a means to limit drug efflux and provide evidence that a mitochondrially targeted DNA topoisomerase poison is active within the organelle.