Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc −/+ mice
1 Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, 733 N. Broadway St, BRB Bldg #849, Baltimore, MD 21205, USA
2 Department of Biomedical Laboratory Science, Yonsei University, 1 Yonseidae-gil, Wonju, Gangwon-do 220-710, Republic of Korea
BMC Cancer 2013, 13:157 doi:10.1186/1471-2407-13-157Published: 27 March 2013
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.
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.
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.
Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas.