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

简介(申请人提供)：结肠癌是美国第三种最常见的癌症，也是导致癌症死亡的第二大常见原因。丁酸盐是组蛋白脱乙酰酶(HDAC)的抑制剂，由结肠中膳食纤维的厌氧细菌发酵自然产生，已被广泛测试为结肠癌的化学预防药物。然而，对丁酸盐作用机制的缺乏阻碍了其在临床预防试验中的成功。我们最近发现，表达野生型腺瘤性息肉病结肠(APC)的结肠癌对HDAC抑制剂诱导的细胞凋亡敏感，而表达突变型APC的结肠癌具有耐药性(Huang和Guo，Cancer Research，2006)。由于APC在结肠癌中经常发生突变，是导致结肠癌发生的最早的突变之一，我们的数据预测大多数结肠癌对丁酸盐作为预防药物的反应失败。我们的初步数据表明，在带有突变的APC的结肠癌细胞中，对丁酸诱导的凋亡的抵抗是未能下调抗凋亡蛋白Survivin的结果。为了克服这种对丁酸的耐药性，我们已经确定了3，3‘-二吲哚甲烷作为候选药物，用于下调Survivin并增强丁酸诱导表达突变APC的结肠癌细胞的凋亡。我们的长期目标是开发更有效的结肠癌预防策略。本项目的目的是验证我们的中心假设，即3，3‘-二吲哚甲烷可以下调Survivin的表达，并增强丁酸盐在预防APCmin/+小鼠家族性腺瘤性息肉病中的作用。APCmin/+小鼠模型广泛用于结肠癌预防研究。为了验证我们的假设，我们提出了以下具体目标：1)确定丁酸盐和3，3‘-二吲哚甲烷联合使用APCmin/+小鼠预防癌症的效果；2)确定丁酸盐和3，3’-二吲哚甲烷联合使用背后的关键细胞凋亡调节机制。在这个项目完成后，我们希望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：将建立一种使用丁酸盐预防结肠癌的新的有效方法，新的知识将有助于在预防试验中提高临床对丁酸盐的反应。由于APC在结肠癌患者中经常发生突变，这项研究的结果具有明确的临床意义。

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.