CURCUMIN--MECHANISMS OF CHEMOPREVENTION

The mechanism by which curcumin inhibits gastrointestinal tumorigenesis appears to be similar to that of sulindac, a NSAID chemopreventive agent which is highly effective in causing regression of polyps in familial polyposis patients. However, the advantage of curcumin is that it is a safe dietary component, with minimal to no toxic affects, unlike sulindac. Both curcumin and sulindac stimulate p21 expression, cell cycle arrest and apoptosis, which are likely fundamental to their mechanisms of action. This is related to, but distinctly different from, mechanisms we have investigated underlying the effect of short chain fatty acids on apoptosis of colonic epithelial cells, which also involves mitochondrial function as a critical event in the entry of cells into this pathway. The goal of this application is to determine in detail the molecular and cellular events responsible for the mechanism of action of curcumin, and to compare that to sulindac, an established, effective chemopreventive agent. We will do this both in colonic carcinoma cells in culture, and in novel mouse genetic models we have available. Studies will focus on components of the cell cycle machinery (eg. P21/waf1/cip1, cyclin D1 levels and activity) and how they are related to release of cytochrome C from the mitochondria, the dissipation of the mitochondrial membrane potential, and cleavage of caspase-3 in the apoptotic pathway. These preclinical data on mechanism and efficacy of curcumin will help determine the nature of future clinical intervention studies with curcumin: if the mechanisms appear identical to that by which sulindac functions, then a clinical study design in which curcumin is compared to sulindac, or other NSAIDs would be warranted. On the other hand, differences in mechanism could suggest a study design in which curcumin was combined with sulindac or to other NSAIDs in a prevention trial to test whether the two agents give additive, or synergistic, effects.