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.