Chemoprevention utility of silibinin and Cdk4 pathway inhibition in Apc −/+ ice

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

doi:10.1186/1471-2407-13-157

Abstract

BackgroundColorectal 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.MethodsWe 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.ResultsCdk4−/− 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.ConclusionsModification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas.

Highlights

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States
We found silibinin effectively opposes Cdk4 pathway activation at several points and administration as a chemopreventive agent resulted in reduced cell proliferation, increased apoptosis, and reduced adenoma development in Apc−/+ mice
Intestines from Apc−/+ mice were analyzed by immunohistochemistry for the expression and distribution of three central components of the Cdk4 signaling pathway downstream of Apc mutation, Cdk4, cyclin D1, and phosphorylated Rb (pRb)

Summary

Introduction

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Cdk pathway alterations have been linked to a number of cancers including CRC In these experiments we focused on the Cdk pathway and its role in intestinal tumorigenesis as a possible target in chemoprevention strategies. Disruption of cell cycle regulation through alterations in the Cdk pathway appears to play an important role in the development of a variety of cancers including colorectal cancer [1,2]. Some compounds derived from natural sources have been shown to inhibit the cell cycle at points regulated by various components of the Cdk pathway, blocking proliferation of cancer cells [16,17,18]. Recent studies suggest that silibinin has antiproliferative activity in vitro and in vivo and causes G1 arrest of the cell cycle (regulated by the Cdk pathway) [17]

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Conclusion