Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention
Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention
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DOI：
10.1016/j.freeradbiomed.2009.10.028
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发表时间：
2010-01-01
影响因子：
7.4
通讯作者：
Westwell, Andrew D.
中科院分区：
文献类型：
--
作者：
Chew, Eng-Hui;Nagle, Amrita A.;Westwell, Andrew D.
反式肉桂醛(CA)及其类似物2-羟基肉桂醛和2-苯甲酰氧基肉桂醛已被报道具有抗肿瘤活性。CA也是已知的Nrf2激活剂。本研究合成了一系列邻位取代的肉桂醛类似物，并对其抗增殖活性和硫氧还蛋白还原酶(TrxR)抑制活性进行了筛选。虽然CA具有弱的细胞毒性和TrxR抑制作用，但羟基和苯甲氧基取代导致类似物具有增强的抗增殖活性，同时增强了TrxR失活的效力。5-氟-2-羟基肉桂醛是一种新的类似物，具有最强的抗肿瘤作用(对HCT 116细胞的GI(50)1.6mU M)和TrxR抑制(IC50 7mU M，与重组TrxR孵育1h)。CA及其2-羟基和2-苯甲酰氧基类似物具有TrxR抑制和Nrf2诱导双重作用，两者都归因于活跃的Michael受体药效团。以致命的浓度。TrxR抑制活性与化合物的抗增殖活性相关。倒数第二个C末端的硒半胱氨酸残基被证明是一个可能的目标。相反，在亚致死浓度下，这些药物通过Nrf2介导的II相酶上调，包括TrxR诱导，诱导适应性抗氧化反应。根据研究结果，我们得出结论，TrxR失活至少部分是肉桂醛细胞毒性的原因。这些迈克尔受体分子有可能被用于不同浓度的化疗和化学预防策略。(C)2009 Elsevier Inc.保留所有权利。
Trans-cinnamaldehyde (CA) and its analogs 2-hydroxycinnamaldehyde and 2-benzoyloxycinnamaldehyde have been reported to possess antitumor activity. CA is also a known Nrf2 activator. In this study a series of, ortho-substituted cinnamaldehyde analogs was synthesized and screened for antiproliferative and thioredoxin reductase (TrxR)-inhibitory activities. Whereas CA was weakly cytotoxic and TrxR inhibiting, hydroxy and benzoyloxy substitutions resulted in analogs with enhanced antiproliferative activity paralleling increased potency in TrxR inactivation. A novel analog, 5-fluoro-2-hydroxycinnamaldehyde, was identified as exhibiting the strongest antitumor effect (GI(50) 1.6 mu M in HCT 116 cells) and TrxR inhibition (IC50 7 mu M, 1 h incubation with recombinant TrxR). CA and its 2-hydroxy- and 2-benzoyloxy-substituted analogs possessed dual TrxR-inhibitory and Nrf2-inducing effects, both attributed to an active Michael acceptor pharmacophore. At lethal concentrations. TrxR-inhibitory potencies correlated with the compounds antiproliferative activities. The penultimate C-terminal selenocysteine residue was shown to be a possible target. Conversely, at sublethal concentrations, these agents induced an adaptive antioxidant response through Nrf2-mediated upregulation of phase II enzymes, including TrxR induction. We conclude from the results obtained that TrxR inactivation contributes at least partly to cinnamaldehyde cytotoxicity. These Michael acceptor molecules can potentially be exploited for use in different concentrations in chemotherapeutic and chemopreventive strategies. (C) 2009 Elsevier Inc. All rights reserved.