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

Baktiar O. Karim, Ki Jong Rhee, Guosheng Liu, Dongfeng Zheng, David L. Huso

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number157
JournalBMC cancer
Volume13
DOIs
StatePublished - Mar 27 2013

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Keywords

  • Apc
  • Cdk4 inhibition
  • Chemoprevention
  • Silibinin

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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