Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc^-/+ mice

Background: Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Colorectal cancers have a prolonged latency following initiation that may span decades providing ample time for implementing a chemoprevention strategy that could block or reverse the progression to CRC. Cdk4 pathway alterations have been linked to a number of cancers including CRC. In these experiments we focused on the Cdk4 pathway and its role in intestinal tumorigenesis as a possible target in chemoprevention strategies. Methods: We evaluated the effect of Cdk4 blockade on the prevention of intestinal tumor formation by crossing Cdk4^-/- mice to Apc^-/+ mice. In addition, we tested the effect of the dietary compound silibinin on the Cdk4 pathway in Apc^-/+ mice and HT-29 colon cancer cells in culture. Results: Cdk4^-/- mice backcrossed to Apc^-/+ mice reduced intestinal adenoma formation compared to Apc^-/+ controls. Silibinin effectively targeted the Cdk4 pathway causing hypophosphorylation of the retinoblastoma protein, inhibited cell growth, and induced apoptosis. As a result silibinin blocked the development of intestinal adenomas by 52% in this genetic model (Apc^-/+ mice) of early events in colorectal cancer formation. No toxic abnormalities were detected in mice which received silibinin. Conclusions: Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas.