Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.
Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.
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通过 5-脂氧合酶抑制剂 Garcinol 对 7,12-二甲基苯并[a]蒽 (DMBA) 诱导的仓鼠颊囊癌发生进行化学预防。
DOI：
10.1080/01635581.2012.718032
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Chen X;Zhang X;Lu Y;Shim JY;Sang S;Sun Z;Chen X
我们以前的研究表明，花生四烯酸代谢异常，特别是5-脂氧合酶(5-Lox)途径参与了口腔癌的发生，可以作为预防癌症的靶点。为了开发有效的口腔癌化学预防外用药物，对5种已知的来自饮食和合成来源的5-Lox抑制剂齐留通、ABT-761、利可酮、姜黄素和藤黄酚进行了硅胶疗效评估。藤黄酚是从藤黄果皮中提取的一种聚异戊二烯基二苯甲酮，通过理论活性指数的计算，发现它是一种很有前途的试剂。计算机模拟表明，藤黄酚很好地符合5-Lox的活性部位，并可能通过酚羟基与非血红素催化铁之间的相互作用而抑制酶的活性。在对7，12-二甲基苯并[a]蒽(DMBA)处理的仓鼠颊囊进行的一项短期研究中，外用石桂酚抑制了口腔上皮中白三烯B4(LTB4)的生物合成，并抑制了炎症和细胞增殖。在一项长期的致癌研究中，外用石桂酚显著减少了可见肿瘤的大小、癌症病变的数量、细胞增殖和LTB4的生物合成。这些结果表明，外用5-Lox抑制剂藤黄酚对DMBA诱导的仓鼠颊囊癌具有化学预防作用。
Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources, Zileuton, ABT-761, Licofelone, Curcumin and Garcinol, were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.