Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells
Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells
复制标题
硫氧还蛋白还原酶选择性激活前药，提供靶向癌细胞的策略
DOI：
10.1002/anie.201801058
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发表时间：
2018-05-22
影响因子：
16.6
通讯作者：
Fang, Jianguo
中科院分区：
文献类型：
--
作者：
Li, Xinming;Hou, Yanan;Fang, Jianguo
活性氧和抗氧化防御系统的升高已被认为是癌细胞的标志之一。硒蛋白硫氧还蛋白还原酶（TrxR）作为细胞氧化还原稳态的主要调节因子，越来越被认为是抗癌药物开发的一个有前途的靶点。目前抑制TrxR的方法主要依赖于修饰该酶C-末端活性位点的硒代半胱氨酸残基，其中难以避免脱靶效应。通过将抗癌药物吉西他滨与1，2-二硫戊环骨架缀合，公开了一种前所未有的前药策略，其通过TrxR在细胞中实现吉西他滨的特异性释放。由于在不同类型的肿瘤中经常发现TrxR的过表达，因此TrxR依赖性前药有希望作为癌症化疗剂进一步开发。
Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.