Cell cycle progression and chemoprevention

Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world. Although much has been learned about the molecular events leading to CRC, there is still no cure for advanced and metastatic stages. Improved strategies for prevention of the disease are warranted. Findings from epidemiological and clinical studies as well as animal models of colon carcinogenesis implicate that some non-steroidal anti-inflammatory drugs (NSAIDS), salicylate derivatives, and COX-2 inhibitors may be effective against the development of CRC. There is growing evidence that the effect of these chemopreventive compounds work through specific pathways that interact with the regulation of several genes. Unequivocal lines of research suggested that these compounds alter cell growth and induce programmed cell death, although the biochemical pathways involved is still obscure. Inhere we hypothesize that these compounds (or at least some of them) activate protective mechanisms of genome integrity in colorectal cells. This proposal aims to investigate the mechanisms by which these compounds exert their chemopreventive action with particular interest to the effects on cell-cycle progression and cellular checkpoint activation. The compounds that we will be analysing in particular are mesalazine (5-aminosalicylic acid), aspirin (acetylsalicylic acid), sulindac, and celecoxib, a novel COX-2 inhibitor. A proper understanding of the biochemical mechanisms behind chemoprevention of CRC is the basis for innovative research leading to the development of more effective compounds. The molecular prevention of this otherwise deadly disease will become more important considering the recent incline in CRC prevalence in Western populations and the associated health-care costs.