Chemoprevention of colorectal cancer using agents such as non-steroidal anti- inflammatory drugs (NSAIDs) has emerged as a promising strategy to reduce the morbidity and mortality of this disease. However, the anti-neoplastic mechanisms of NSAIDs and other chemopreventive agents remain unclear. We have been investigating the mechanisms of NSAID-mediated chemoprevention with the long-term objective of developing improved strategies for reducing cancer risk. Our recent preliminary studies demonstrate that NSAIDs kill colon cancer cells by triggering a crosstalk between the extrinsic and intrinsic apoptotic pathways through Bid, a proapoptotic Bcl-2 family protein. Deficiency in Bid almost completely abolished the chemopreventive effect of the NSAID sulindac in APC/Min mice, a commonly used chemoprevention model. NSAID treatment preferentially induced apoptosis in intestinal stem cells with oncogenic Wnt signaling. Adenoma samples from patients taking NSAIDs were also found to have enhanced apoptosis induction in cells with stem cell characteristics and aberrant Wnt signaling. We therefore hypothesize that NSAIDs inhibit intestinal tumor formation by eliminating oncogenic intestinal stem cells through Bid-mediated apoptosis. To test this hypothesis, we will investigate: 1) the mechanism by which NSAIDs specifically activate Bid to kill tumor cells;2) selective killing of oncogenic stem cells by NSAI-induced and Bid-mediated apoptosis;3) role of Bid-mediated oncogenic stem cell apoptosis in chemoprevention by NSAIDs in mice;4) killing of oncogenic stem cells by NSAIDs in chemoprevention of adenoma patients. These studies will delineate the critical activity and molecular targets of NSAIDs in chemoprevention of colorectal cancer, and shed insight on why NSAID chemoprevention is beneficial for some, but not all patients. The results of these studies may open up the possibility for future development of chemopreventive agents with improved efficacy and specificity, and could be useful for rational design of more effective strategies to improve outcomes of chemoprevention of colorectal cancer.
Colorectal cancer is one of the leading causes of cancer-related death in the United States. The proposed studies will help to understand the mechanisms underlying the chemopreventive activity of non-steroidal anti- inflammatory drugs (NSAIDs) against colorectal cancer. In the long run, the results of these studies could be useful for rational design of more effective strategies and agents to improve outcomes of chemoprevention of colorectal cancer.
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