Nanomedicine Assembled by Coordinated Selenium-Platinum Complexes Can Selectively Induce Cytotoxicity in Cancer Cells by Targeting the Glutathione Antioxidant Defense System
Nanomedicine Assembled by Coordinated Selenium-Platinum Complexes Can Selectively Induce Cytotoxicity in Cancer Cells by Targeting the Glutathione Antioxidant Defense System
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由协调的硒铂复合物组装的纳米药物可以通过靶向谷胱甘肽抗氧化防御系统选择性地诱导癌细胞的细胞毒性
DOI：
10.1021/acsbiomaterials.7b00362
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发表时间：
2018-06-01
影响因子：
5.8
通讯作者：
Xu, Huaping
中科院分区：
文献类型：
--
作者：
Li, Feng;Li, Tianyu;Xu, Huaping
硒是一种独特的必需微量元素，在生物过程的抗氧化防御和氧化还原调节中起着重要作用。我们已经报道了新型含硒铂基抗癌分子（EG-Se/Pt）对癌细胞具有选择性细胞毒性。在此，我们发现选择性细胞毒性的潜在机制与谷胱甘肽抗氧化防御系统密切相关。升高的活性氧（ROS）使癌细胞更容易受到ROS进一步升高的影响。EGSe/Pt可通过耗尽谷胱甘肽诱导ROS异常增加。因此，线粒体膜电位崩溃，细胞色素c释放，导致细胞凋亡。然而，EG-Se/Pt类似物，如EGSe/Cu和EG-Se/Ni，在我们的研究中没有表现出谷胱甘肽耗竭能力或选择性杀伤活性，尽管它们可以有效地杀死癌细胞。这些结果表明，谷胱甘肽抗氧化系统是一个有效的目标，使治疗的选择性。硒-铂配位分子的两亲性有助于它们组装成纳米颗粒并缩短药物在血流中的循环时间，这对于体内药物递送是重要的。体内抗肿瘤实验表明，EG-Se/Pt对肿瘤生长的抑制率可达69%（p < 0.05）。更令人鼓舞的是，与顺铂相比，EG-Se/Pt表现出最小的副作用。这项工作也为开发抗癌治疗策略提供了新的机会。
Selenium is a unique, essential trace element that plays an important role in the antioxidant defense and redox regulation of biological processes. We have reported that novel selenium-containing platinum-based anticancer molecules (EG-Se/Pt) had selective cytotoxicity toward cancer cells. Herein, we found the underlying mechanism of selective cytotoxicity to be closely related to the glutathione antioxidant defense system. Elevated reactive oxygen species (ROS) make cancer cells more vulnerable to further elevation of ROS. EGSe/Pt can induce abnormal increases in ROS by depletion of glutathione. Consequently, the mitochondrial membrane potential collapses and cytochrome c is released, resulting in cell apoptosis. However, EG-Se/Pt analogues, such as EGSe/Cu and EG-Se/Ni, did not exhibit glutathione depletion capacity or selective killing activity in our investigation, although they can effectively kill cancer cells. These results suggest that the glutathione antioxidant system is an effective target to enable therapeutic selectivity. The amphiphilic property of the selenium-platinum coordination molecules facilitates their assembly into nanoparticles and prolongs the circulation time of the drug in the bloodstream, which is important for in vivo drug delivery. Our in vivo anticancer study demonstrated that the tumor growth inhibition rate of EG-Se/Pt can reach 69% (p < 0.05). What is more encouraging is that EG-Se/Pt exhibited minimal side effects compared to cisplatin. This work also provides new opportunities for the development of therapeutic strategies against cancer.