权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

使用 iNOS 和 COX-2 表达的从头抑制剂预防结肠癌

基本信息

批准号：
12556018
负责人：
OHIGASHI Hajime
金额：
$ 7.68万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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

诱导型一氧化氮合酶（iNOS）和环氧化酶-2 （COX-2）的增强和持续表达参与了许多致癌过程，包括实验性啮齿动物和人类的结肠。因此，最近的实验室研究已经证明了iNOS/COX-2选择性抑制剂在减少致癌物诱导的大鼠和小鼠腺癌发展方面的有效性。重要的是，人类干预试验显示，塞来昔布，一种cox-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。虽然cox-2抑制剂阻断了催化活性，但其他类型的化学物质可以抑制或延迟iNOS/ cox-2的重新合成，可能被认为是新一代的抗iNOS/ cox-2调节剂。在本研究中，我们发现两种食物因子zerumbone （ZER）和nobiletin （NOB）可以显著抑制COX-2的表达，从而减少偶氮氧甲烷处理大鼠结肠黏膜中COX-2的形成。相反，这些植物化学物质明显抑制偶氮氧甲烷诱导的大鼠结肠异常隐窝灶（ACF）的foramtoin。此外，我们观察到，与基础饲粮组相比，结肠和肝脏中谷胱甘肽s转移酶和醌还原酶等2期异种酶活性的诱导升高。ZER，一种携带α，β-不饱和羰基的倍半萜，是生姜的主要成分，广泛分布在东南亚国家，是传统的亲缘植物和民间药物的抗炎成分。另一方面，NOB是一种多甲基化的类黄酮，在柑橘类水果中发现，包括蜜橘。我们的机制研究提供了一些数据，这些化合物抑制了脂多糖和干扰素-γ-诱导的NF-κB α （NF-κB的抑制因子）在RAW小鼠巨噬细胞中的降解。由于NF-κB是iNOS/COX-2基因的主要转录因子之一，ZER和NOB均通过抑制i -κB降解来减弱这些基因的表达。总之，我们提出了iNOS/COX-2从头合成抑制剂和COX-2抑制剂用于预防和治疗溃疡性结肠炎和结直肠癌等大肠疾病的实验原理。少