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. To develop potent topical agents for oral cancer chemoprevention, 5 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.

译文

我们以前的研究表明,异常的花生四烯酸代谢,尤其是5-脂氧合酶 (5-Lox) 途径,与口腔癌的发生有关,可以作为预防癌症的靶标。为了开发用于口腔癌化学预防的有效局部药物,在计算机上评估了饮食和合成来源的5种已知的5-Lox抑制剂 (Zileuton,ABT-761,licofelone,姜黄素和藤黄酚) 的潜在功效。根据理论活性指数的计算,发现藤黄酚是一种来自藤黄属果皮的聚异戊二烯化二苯甲酮,是一种有前途的试剂。计算机建模表明,藤酚非常适合5-Lox的活性位点,并通过酚羟基和非血红素催化铁之间的相互作用潜在地抑制了酶活性。在对7,12-二甲基苯并 [a] 蒽 (DMBA) 处理的仓鼠颊袋进行的短期研究中,外用藤黄酚抑制了白三烯B4 (LTB4) 的生物合成并抑制了口腔上皮的炎症和细胞增殖。在一项长期的致癌研究中,外用藤黄酚可显着减少可见肿瘤的大小,癌症病变的数量,细胞增殖和LTB4生物合成。这些结果表明,局部应用5-Lox抑制剂藤黄酚对DMBA诱导的仓鼠颊袋致癌具有化学预防作用。

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