Chemoprevention of Familial Adenomatous Polyposis by a Combination of 3,3?-Diind

3,3?-Diind 组合化学预防家族性腺瘤性息肉病

• 批准号: 7545704
• 负责人: BIN GUO
• 金额: $ 7.15万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-02 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545704
• 关键词: Adenomatous Polyposis Coli; American Cancer Society; Apoptosis; Apoptotic; Butyrates; Cancer Etiology; Cancer Patient; Cessation of life; Chemoprevention; Clinical; Clinical Trials; Colon; Colon Carcinoma; Data; Dietary Fiber; Down-Regulation; Failure; Fermentation; Future; Genus Cola; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Knowledge; Mediating; Methods; Mus; Mutate; Mutation; Prevention; Prevention strategy; Proteins; Research; Resistance; Second Primary Cancers; Testing; United States; Work; anticancer research; base; butyrate; cancer cell; cancer diagnosis; cancer prevention; colon carcinogenesis; concept; diindolylmethane; improved; mouse model; mutant; novel; novel strategies; prevent; response; statistics; success; survivin; tumor

DESCRIPTION (provided by applicant): Colon cancer is the third most commonly diagnosed cancer and the second most common cause of cancer death in the United States. Butyrate, an inhibitor of histone deacetylase (HDAC) and naturally produced by anaerobic bacterial fermentation of dietary fibers in the colon, has been extensively tested as a chemoprevention agent for colon cancer. However, the lack of knowledge on the mechanism of action of butyrate prevents its success in clinical prevention trials. We recently discovered that colon cancers expressing wild-type adenomatous polyposis coli (APC) are sensitive to HDAC inhibitor- induced apoptosis, while colon cancers expressing mutant APC are resistant (Huang and Guo, Cancer Research, 2006). Since APC is frequently mutated in colon cancers and is one the earliest mutations that are responsible for colon carcinogenesis, our data predict failure of response for most colon cancers to butyrate as a prevention agent. Our preliminary data have demonstrated that resistance to butyrate-induced apoptosis in colon cancer cells with mutant APC was a result of failure to down-regulate the anti-apoptotic protein survivin. To overcome such resistance to butyrate, we have identified 3, 3'-Diindolylmethane as a candidate agent to be used to down-regulate survivin and enhance butyrate- induced apoptosis in colon cancer cells expressing mutant APC. Our long-term goal is to develop more effective prevention strategies for colon cancer. The objective of this project is to test our central hypothesis that 3, 3'- Diindolylmethane can down-regulate survivin and enhance the effects of butyrate in prevention of familial adenomatous polyposis in APCmin/+ mice, a mouse model wildly used in colon cancer prevention studies. To test our hypothesis, we propose the following specific aims: 1) To determine the effects of butyrate and 3, 3'-Diindolylmethane combination in cancer prevention using APCmin/+ mice; 2) To determine the key apoptosis-regulatory mechanisms underlying the combination of butyrate and 3, 3'-Diindolylmethane. At the completion of this project, we expect to have developed a novel strategy of using butyrate in the prevention of colon cancer, which can be tested in future clinical trials. Relevance: A novel and effective method to use butyrate in colon cancer prevention will be established and the new knowledge will be useful to improve clinical response to butyrate in prevention trials. Since APC is frequently mutated in colon cancer patients, the results from this research have clear clinical implications.

描述（由申请人提供）：结肠癌是美国第三大最常见的诊断癌症和第二大最常见的癌症死亡原因。丁酸盐是组蛋白脱乙酰基酶（HDAC）的抑制剂，并且由结肠中的膳食纤维的厌氧细菌发酵天然产生，已被广泛测试为结肠癌的化学预防剂。然而，对丁酸盐的作用机制缺乏了解，阻碍了其在临床预防试验中的成功。我们最近发现，表达野生型腺瘤性结肠息肉病（APC）的结肠癌对HDAC抑制剂诱导的细胞凋亡敏感，而表达突变APC的结肠癌具有抗性（Huang和Guo，Cancer Research，2006）。由于APC在结肠癌中经常发生突变，并且是导致结肠癌发生的最早突变之一，因此我们的数据预测大多数结肠癌对丁酸盐作为预防剂的反应失败。我们的初步数据表明，具有突变型APC的结肠癌细胞对丁酸盐诱导的细胞凋亡的抵抗是未能下调抗细胞凋亡蛋白生存素的结果。为了克服这种对丁酸盐的抗性，我们已经鉴定了3，3 '-二吲哚基甲烷作为候选试剂，用于在表达突变APC的结肠癌细胞中下调存活素并增强丁酸盐诱导的细胞凋亡。我们的长期目标是制定更有效的结肠癌预防策略。本项目的目的是检验我们的中心假设，即3，3 '-二吲哚基甲烷可以下调存活素并增强丁酸盐在APC min/+小鼠中预防家族性腺瘤性息肉病的作用，APC min/+小鼠是广泛用于结肠癌预防研究的小鼠模型。为了验证我们的假设，我们提出了以下具体目标：1）使用APCmin/+小鼠确定丁酸盐和3，3 '-二吲哚基甲烷组合在癌症预防中的作用; 2）确定丁酸盐和3，3'-二吲哚基甲烷组合的关键凋亡调节机制。在该项目完成后，我们预计将开发出一种使用丁酸盐预防结肠癌的新策略，可以在未来的临床试验中进行测试。相关性：将建立一种新的和有效的方法，使用丁酸在结肠癌预防和新的知识将是有用的，以提高临床反应丁酸在预防试验。由于APC在结肠癌患者中经常发生突变，因此这项研究的结果具有明确的临床意义。