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

描述（由申请人提供）：结肠癌是美国第三大最常见的癌症，也是第二大最常见的癌症死亡原因。丁酸盐是一种组蛋白去乙酰化酶（HDAC）的抑制剂，由结肠中膳食纤维的厌氧细菌发酵自然产生，作为结肠癌的化学预防剂已被广泛测试。然而，对丁酸盐的作用机制的了解不足，阻碍了其在临床预防试验中的成功。我们最近发现，表达野生型大肠腺瘤性息肉病（APC）的结肠癌对HDAC抑制剂诱导的细胞凋亡敏感，而表达突变型APC的结肠癌则具有耐药性（Huang and 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，突变型APC结肠癌细胞对丁酸盐诱导的凋亡的抗性是由于抗凋亡蛋白survivin下调失败的结果。为了克服这种对丁酸盐的耐药性，我们确定了3,3 '-二吲哚基甲烷作为一种候选药物，用于下调survivin并增强表达突变型APC的结肠癌细胞中丁酸盐诱导的凋亡。我们的长期目标是制定更有效的结肠癌预防策略。在结肠癌预防研究中广泛使用的小鼠模型APCmin/+小鼠中，3,3′-二吲哚基甲烷可下调survivin，增强丁酸盐对家族性腺瘤性息肉病的预防作用，本项目旨在验证我们的中心假设。为了验证我们的假设，我们提出了以下具体目标：1)通过APCmin/+小鼠，确定丁酸盐和3,3 '-二吲哚基甲烷组合对癌症的预防作用；2)确定丁酸盐与3,3′-二吲哚基甲烷结合的关键细胞凋亡调控机制。在这个项目完成后，我们期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：建立一种新的、有效的使用丁酸盐预防结肠癌的方法，这一新知识将有助于提高丁酸盐预防试验的临床反应。由于APC在结肠癌患者中经常发生突变，因此本研究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.