This competitive revision is in response to the Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications, for the parent grant (R01CA121105) entitled """"""""SMAC in chemoprevention of colon cancer"""""""". Since common epithelial cancers are resistant to most therapeutic treatments, much hope has been placed on prevention of cancer through the use of chemical agents or dietary manipulation. The widely used nonsteroidal antiinflammatory drugs (NSAIDs) are effective in chemoprevention of colorectal cancer, which is the second leading cause of cancer related death in the United States. However, the mechanisms underlying the anti-neoplastic effects of NSAIDs remain unclear. Substantial evidence has indicated that the chemopreventive activities of NSAIDs are mediated by induction of apoptosis. The parent project (R01CA121105) has been aimed at studying how SMAC, a mitochondrial apoptogenic protein, contributes to the anti-neoplastic effects of NSAIDs. The ongoing studies have demonstrated that SMAC plays an essential role in NSAID-induced apoptosis and NSAID-mediated chemoprevention. Agents that mimic the function of SMAC can enhance the apoptotic response to sulindac, an NSAID commonly used in chemoprevention. In this Competitive Revision application, we propose to test the hypothesis that activation of SMAC in mice can improve the chemopreventive activities of sulindac. We will create an intestine-specific SMAC transgenic mouse model and cross the SMAC transgenic mice with APCMin/+ mice, and determine if SMAC activation augments tumor phenotypes and improves the chemopreventive effects of sulindac in APCMin/+ mice through apoptosis induction. The proposed study will significantly accelerate the tempo of scientific research proposed in the parent project by providing a novel chemoprevention model and new insights into the anti-neoplastic effects of NSAIDs. In the long run, the results of these studies may help to develop improved strategies and agents for chemoprevention of colon cancer.
Despite improvements in early detection and treatment of cancer, overall mortality rates for most cancers of epithelial origin, such as those of colon, breast, lung and prostate, have not declined. Much hope has recently been placed on prevention of human cancers through the use of chemical agents or dietary manipulation. This project seeks to determine whether activation of SMAC, a critical regulator of cancer cell death, can improve the chemopreventive effects of nonsteroidal antiinflammatory drugs (NSAIDs). The results could be useful for developing improved strategies and novel agents for better chemoprevention of human cancer.
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