Elucidation of thioredoxin as a molecular target for antitumor quinols
Elucidation of thioredoxin as a molecular target for antitumor quinols
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DOI：
10.1158/0008-5472.can-04-4141
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Stevens, MFG
中科院分区：
文献类型：
--
作者：
Bradshaw, TD;Matthews, CS;Stevens, MFG
杂芳香喹啉4-（苯并噻唑-2-基）-4-羟基环己-2,5-二烯酮(1)和4-（1-苯磺酰基- 1h -吲哚-2-基）-4-羟基环己-2,5-二烯酮(2)在体外对结肠癌、肾癌和乳腺癌细胞系表现出有效的选择性抗肿瘤活性（GI(50) < 500 nmol/L）。已经观察到肾脏、结肠和乳房异种移植物的体内生长抑制。在生长抑制浓度为1或2的HCT 116细胞处理后，cdk1蛋白表达下降，证实了Profound G(2)-M细胞周期阻滞伴随cdk1基因转录下调。喹诺药效团4-（羟基环己-2,5-二烯酮）的化学结构表明，这些新型药物很容易与亲核试剂在双迈克尔（β -碳）加成中发生反应。事实上，美国国家癌症研究所数据库中的COMPARE分析显示，许多化学相关的醌衍生物可能以类似的方式与硫亲核试剂发生反应，并表明硫氧还蛋白/硫氧还蛋白还原酶信号转导可能是一个假定的目标。分子模型预测喹啉类似物与硫氧还蛋白的半胱氨酸残基32和35之间的共价不可逆结合，从而抑制酶的活性。通过质谱分析证实，还原的人硫氧还蛋白与1。对未处理的HCT 116细胞和暴露于1 （1 μ mol/L）或2 （500 nmol/L和1 μ mol/L）的HCT 116细胞进行微阵列分析发现，在>= 10,000个癌症相关基因中，硫氧还蛋白还原酶的表达上调> 3倍。此外，喹啉I和2抑制胰岛素还原，由硫氧还蛋白/硫氧还蛋白还原酶信号催化，呈剂量依赖性（IC50 < 6 μ mol/L）。结果与新型抗肿瘤喹啉的作用机制一致，其作用机制涉及抑制小氧化还原蛋白硫氧还蛋白。
Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI(50) < 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G(2)-M Cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (beta-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/ thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 mu mol/L) or 2 (500 nmol/L and 1 mu mol/L) determined that of >= 10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated > 3-fold. Furthermore, quinols I and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC50 < 6 mu mol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.