ANTICARCINOGENIC EFFECTS AND MECHANISMS OF GENISTEIN

染料木黄酮的抗癌作用及机制

• 批准号: 2102537
• 负责人: HUACHEN WEI
• 金额: $ 7.99万
• 依托单位: MOUNT SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-15 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2102537
• 关键词: DNA damage; adduct; benzanthracenes; cancer prevention; carcinogenesis inhibitor; chemical carcinogenesis; chemoprevention; diet; flavonoids; gene expression; high performance liquid chromatography; histopathology; laboratory mouse; messenger RNA; neoplastic process; northern blottings; nutrition aspect of cancer; nutrition related tag; oral administration; oxidative stress; phorbols; skin neoplasms; soybeans; topical drug application; tumor promoters

Epidemiological studies suggest an inverse correlation between soyfood consumption and human cancer mortality. Laboratory studies indicate that soy diets also inhibit experimentally induced animal tumors. Although most studies attribute the anticarcinogenic effect of soybeans to the protease inhibitors, increasing evidence suggests that isoflavones, non- protein components richly present in soybeans, may also play important roles. Genistein, one of the major soybean isoflavones, has been shown to inhibit tyrosine protein kinase (TPK), DNA topoisomerase II (Topo Il), and ribosomal S6 kinase (RS6K), suppress tumor cell growth, and induce differentiation of several malignant cell lines. Our preliminary studies have shown that genistein suppresses 7,12-dimethylbenz[a]anthracene (DMBA)-induced DNA adduct formation and DNA oxidation, and inhibits 12-O- tetradecanoyl phorbol-13-acetate (TPA)-induced H2O2 formation, inflammatory responses, and proto-oncogene expression in vivo. However, whether genistein modifies chemical carcinogenesis in vivo remains unclear. This proposal is designed to test the hypothesis that genistein inhibits oxidative DNA damage induced by carcinogenic agents and further modifies the initiational, promotional, and progressional processes of chemical carcinogenesis. The overall objective is to determine if genistein modifies the initiation- and promotion-related biochemical events and subsequently inhibits skin tumor formation in vivo. The initial aim of the project is to determine if topical application of genistein modifies the initiation- and promotion-related events with an emphasis on oxidative DNA damage. The second aim is to determine if topical application of genistein affects initiation, promotion and/or progression of multistage skin carcinogenesis. Finally, we will determine if dietary administration of genistein modulates these carcinogenic processes in the multistage carcinogenesis model. If, in fact, genistein has anticarcinogenic effects, an elucidation of the mechanisms of genistein's action will contribute to application of this soybean isoflavone in prevention and/or therapy of human cancers.

流行病学研究表明，大豆食品与 消费和人类癌症死亡率。实验室研究表明 大豆饮食还能抑制实验诱发的动物肿瘤。 虽然 大多数研究将大豆的抗癌作用归因于 蛋白酶抑制剂，越来越多的证据表明异黄酮，非 大豆中富含的蛋白质成分也可能发挥重要作用 角色。金雀异黄酮是主要的大豆异黄酮之一，已被证明可以 抑制酪氨酸蛋白激酶 (TPK)、DNA 拓扑异构酶 II (Topo II) 和 核糖体 S6 激酶 (RS6K)，抑制肿瘤细胞生长，并诱导 几种恶性细胞系的分化。我们的初步研究 已表明金雀异黄酮可抑制 7,12-二甲基苯并[a]蒽 (DMBA) 诱导 DNA 加合物形成和 DNA 氧化，并抑制 12-O- 十四烷酰佛波醇 13 乙酸酯 (TPA) 诱导 H2O2 形成， 炎症反应和体内原癌基因表达。 然而， 金雀异黄素是否会改变体内化学致癌作用仍然存在 不清楚。该提案旨在检验染料木黄酮的假设 抑制致癌物质诱导的氧化 DNA 损伤，并进一步 修改启动、促进和进展过程 化学致癌作用。 总体目标是确定是否 金雀异黄素修饰启动和促进相关的生化 事件并随后抑制体内皮肤肿瘤的形成。最初的 该项目的目的是确定金雀异黄素的局部应用是否有效 修改启动和促销相关的事件，重点是 DNA 氧化损伤。第二个目标是确定是否具有话题性 金雀异黄素的应用影响起始、促进和/或进展 多阶段皮肤癌的发生。最后，我们将确定是否饮食 金雀异黄素的施用可调节这些致癌过程 多阶段致癌模型。事实上，如果金雀花素具有 抗癌作用，阐明金雀异黄酮的机制 行动将有助于该大豆异黄酮在 人类癌症的预防和/或治疗。