Inhibition of thioredoxin reductase by mansonone F analogues: Implications for anticancer activity
Inhibition of thioredoxin reductase by mansonone F analogues: Implications for anticancer activity
复制标题
曼索酮 F 类似物对硫氧还蛋白还原酶的抑制：抗癌活性的影响
DOI：
10.1016/j.cbi.2008.09.002
复制
发表时间：
2009-01-15
影响因子：
5.1
通讯作者：
Gu, Lian-Quan
中科院分区：
文献类型：
--
作者：
Liu, Zhong;Huang, Shi-Liang;Gu, Lian-Quan
哺乳动物硫氧还蛋白还原酶（TixR）是一种普遍存在的含硒半胱氨酸的氧化还原酶，催化氧化硫氧还蛋白（Trx）的NADPH依赖性还原。TrxR在肿瘤细胞中的高表达及其在细胞内氧化还原调控、细胞生长和凋亡中的多种功能使其成为开发抗肿瘤药物的潜在靶点。Mansonone F（MF）化合物已显示出抗增殖作用，但其复杂的机制是未知的。在本研究中，我们研究了一些合成的MF类似物对TrxR和HeLa细胞的影响。对MF类似物IG 3的抑制作用及其与TrxR的相互作用的研究表明，MF化合物可被其C-末端硒硫醇活性中心部分还原。并且可能同时被TrxR的N-末端二硫醇基序和/或FAD结构域所修饰，伴随着氧化还原循环，产生超氧阴离子自由基。此外，MF类似物表现出抑制HeLa细胞生长和降低细胞裂解物中TrxR活性的潜力。细胞周期阻滞于G2/M期，并呈剂量依赖性诱导细胞凋亡。此外，我们的研究结果表明，IG 3处理的HeLa细胞诱导细胞内ROS的变化。两者合计，这里报道的结果表明，MF类似物对TrxR的抑制提供了一种可能的复杂机制，用于解释MF化合物的抗癌活性。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Mammalian thioredoxin reductase (TixR), a ubiquitous selenocysteine containing oxidoreductase, catalyzes the NADPH-dependent reduction of oxidized thioredoxin (Trx). TrxR has been suggested as a potential target for anticancer drugs development for its overexpression in human tumors and its diverse functions in intracellular redox control, cell growth and apoptosis. Mansonone F (MF) compounds have been shown to exhibit antiproliferative effects, but their complex mechanisms are unknown. In the present Study, we have investigated the effects of some synthesized MF analogues on TrxR and HeLa cells. The Studies of the mode of inhibition and the interactions of IG3, one of the most potent MF analogues, with TrxR showed MF compounds could be partly reduced by the C-terminal selenothiol active site. and possibly by the N-terminal dithiol motif and/or FAD domain of TrxR simultaneously, accompanied by redox cycling with the generation of superoxide anion radicals. In addition, MF analogues exhibited the potential to inhibit the growth of HeLa cells and reduce TrxR activity in cell lysates. The cell cycle was arrested in G2/M phase and apoptosis was induced in a dose-dependent manner. Furthermore, Our results showed that IG3-treated HeLa cells induced the change of intracellular ROS. Taken together, the reported results here suggest that inhibition of TrxR by MF analogues provides a possible complex mechanism for explaining the anticancer activity of MF compounds. (C) 2008 Elsevier Ireland Ltd. All rights reserved.