Prevention of colon cancer with the de novo suppressants of iNOS and COX-2 expressions

诱导型一氧化氮合酶（inducible nitric oxide synthase，iNOS）和环氧合酶-2（cyclooxygenase-2，考克斯-2）的表达增强和持续参与了许多肿瘤的发生、发展过程，包括在实验动物和人类的结肠中。因此，最近的实验室研究已经证明了iNOS/考克斯-2的选择性抑制剂在减少大鼠和小鼠中致癌物诱导的腺癌发展方面的有效性。重要的是，人类干预试验表明，塞来昔布，一种考克斯-2选择性抑制剂，减少了家族性腺瘤性息肉病患者群体的息肉形成。当cox-2抑制剂阻断催化活性时，抑制或延迟iNOS/考克斯-2从头合成的其它类型的化学物质可被认为是新一代的抗iNOS/考克斯-2调节剂。在目前的研究中，我们已经确定了两种食物因素，玉米黄酮（ZER）和诺贝尔奖（NOB），显着抑制考克斯-2的表达，从而减少形成的压力。 ...更多信息 氧化偶氮甲烷处理的大鼠结肠粘膜中的ostagliptin E2。相反，这些植物化学物质显着抑制氧化偶氮甲烷诱导的大鼠结肠异常隐窝病灶（ACF）的穿孔。此外，我们观察到升高的诱导阶段2异生素酶的活性，如谷胱甘肽S-转移酶和醌还原酶在结肠和肝脏相比，基础饮食组。ZER是一种含有α，β-不饱和羰基的倍半萜烯，广泛分布于东南亚国家，是紫茎泽兰的主要成分，也是一种传统的抗炎药和民间药物。另一方面，NOB是一种多甲基化的黄酮类化合物，存在于柑橘类水果中，包括温州蜜柑。我们的机制研究提供了一些数据，这些化合物抑制RAW小鼠巨噬细胞中脂多糖和干扰素-γ诱导的IκBα（NF-κB的抑制因子）的降解。由于NF-κB是iNOS/COX-2基因的主要转录因子之一，ZER和NO B均通过抑制IκB降解来减弱这些基因的表达。总之，我们提出了一个实验原理，即除了COX-2抑制剂之外，还使用iNOS/考克斯-2从头合成抑制剂来预防和治疗大肠疾病，如溃疡性结肠炎和结直肠癌。少

Enhanced and sustained expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in many oncogenic processes, including that in the colon of experimental rodents and human as well. Accordingly, recent laboratory studies have demonstrated the effectiveness of selective inhibitors of iNOS/COX-2 in terms of reduction of the carcinogen-induced development of adenocarcinoma in rats and mice. Of importance, human intervention trials revealed that celecoxib, a cox-2 selective inhibitor, diminished polyp formation of a population of the familial adenomatous polyposis patients. While the cox-2 inhibitors block the catalytic activity, other types of chemicals that suppress or delay the de novo synthesis of iNOS/COX-2 may be considered as a new generation of the anti-iNOS/COX-2 regulators. In the present study, we have identified two food factors, zerumbone (ZER) and nobiletin (NOB), markedly suppressed expression of COX-2 and thereby reducing formation of pr … More ostaglandin E2 in the colonic mucosa of the azoxymethane treated rats. Conversely, these phytochemicals markedly inhibited azoxymethane-induced foramtoin of aberrant crypt foci (ACF) in rat colon. In addition, we observed elevated induction of phase 2 xenobiotic enzyme activities such as glutathione S-transferase and quinone reductase in the colon and liver as compared with the basal diet group. ZER, a sesquiterpene carrying an α,β-unsaturated carbonyl group, a major constituent of Zingiber zerumbet Smith that occurs widely in southea st Asian countries and used as a ingredient of traditional cousins and folk medicine for anti-inflammation as well. On the other hand, NOB, a polymethylated flavonoid, is found in citrus fruits including satsuma mandarin. Our mechanistic studies provided some data that these compounds suppress degradation of the combined lipopolysaccharide and interferon-γ-induced IκBα, a suppressive factor of NF-κB, in RAW murine macrophages. Because NF-κB is one of the major transcription factor for iNOS/COX-2 genes, both ZER and NOB attenuate these gene expressions through suppression of IκB degradation.In conclusion, we have presented an experimental rationale for the used of the iNOS/COX-2 de novo synthesis suppressants, in addition of the cox-2 inhibitors, for preventing and treating large bowel disease such as ulcerative colitis and colorectal cancer. Less