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.
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