Thioredoxin reductase inhibition by antitumor quinols: a quinol pharmacophore effect correlating to antiproliferative activity
Thioredoxin reductase inhibition by antitumor quinols: a quinol pharmacophore effect correlating to antiproliferative activity
复制标题
DOI：
10.1096/fj.07-101477
复制
发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Holmgren, Arne
中科院分区：
文献类型：
--
作者：
Chew, Eng-Hui;Lu, Jun;Holmgren, Arne
新型杂芳族取代的 4-羟基环六2,5-二烯酮（醌醇）在肿瘤异种移植物中表现出有效的体外抗增殖活性和体内抗肿瘤活性。然而，这些有前途的新型抗癌药物的作用机制仍有待充分阐明。硫氧还蛋白 (Trx) 系统由 Trx、硫氧还蛋白还原酶 (TrxR) 和 NADPH 组成，参与细胞存活和增殖的广泛细胞功能。越来越多的证据表明，含硒代半胱氨酸的哺乳动物 TrxR 是开发新型癌症疗法的有效分子靶标。在这项研究中，我们证明含有对苯二酚药效基团的结构类似物可抑制 TrxR，其效力与其抗增殖和细胞毒性功效相关。与重组大鼠 TrxR 孵育 1 小时后，苯磺酰基-6F-吲哚取代的对苯二酚（化合物 6）不可逆地抑制 TrxR，其半最大抑制浓度为 2.7 μM。该抑制作用与浓度、时间和 NADPH 相关，并通过对倒数第二个 C 末端硒代半胱氨酸残基的直接对苯二酚攻击来介导。此外，用诱导凋亡剂量的对苯二酚处理的 HCT 116 细胞裂解物中的 TrxR 活性显着降低。根据获得的结果，我们认为 TrxR 抑制是一个关键的细胞事件，有助于对苯二酚的促凋亡作用。
Novel heteroaromatic-substituted 4-hydroxycyclohexa2,5-dienones (quinols) demonstrate potent in vitro antiproliferative activity and in vivo antitumor activity in tumor xenografts. The mechanism of action of these promising novel anticancer agents, however, remains to be fully elucidated. The thioredoxin (Trx) system comprising Trx, thioredoxin reductase (TrxR), and NADPH participates in a broad range of cellular functions involved in cell survival and proliferation. Accumulating evidence has indicated that the selenocysteine-containing mammalian TrxR is a valid molecular target for development of novel cancer therapeutics. In this study, we demonstrate that structural analogs containing a quinol pharmacophore inhibited TrxR with potencies correlated with their antiproliferative and cytotoxic efficacies. Benzenesulfonyl-6F-indole-substituted quinol (compound 6) irreversibly inhibited TrxR most strongly with a half-maximal inhibitory concentration of 2.7 mu M after 1 h of incubation with recombinant rat TrxR. The inhibition was shown to be concentration-, time-, and NADPH-dependent and mediated through a direct quinol attack on the penultimate C-terminal selenocysteine residue. Moreover, TrxR activity in lysates of HCT 116 cells treated with apoptosis-inducing doses of quinols was significantly reduced. From the results obtained, we propose that TrxR inhibition is a critical cellular event that contributes to the proapoptotic effects of quinols.