Pharmaceutical Research

, 26:2558

Silibinin Suppresses Spontaneous Tumorigenesis in APCmin/+ Mouse Model by Modulating Beta-Catenin Pathway

Authors

  • Subapriya Rajamanickam
    • Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado Denver
  • Manjinder Kaur
    • Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado Denver
  • Balaiya Velmurugan
    • Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado Denver
  • Rana P. Singh
    • Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado Denver
    • Cancer Biology Laboratory, School of Life SciencesJawaharlal Nehru University
    • Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado Denver
    • University of Colorado Cancer CenterUniversity of Colorado Denver
Research Paper

DOI: 10.1007/s11095-009-9968-1

Cite this article as:
Rajamanickam, S., Kaur, M., Velmurugan, B. et al. Pharm Res (2009) 26: 2558. doi:10.1007/s11095-009-9968-1

ABSTRACT

Purpose

Here we assessed whether silibinin, a nontoxic chemopreventive agent, inhibits spontaneous intestinal tumorigenesis in APCmin/+ mouse model, a genetically predisposed animal model of human familial adenomatous polyposis (FAP).

Materials and Methods

Six-week-old APCmin/+ mice were divided into four groups and orally gavaged with 0.2 ml vehicle, or 250, 500 and 750 mg silibinin/kg body weight in 0.2 ml vehicle for five days/week. After 6 weeks, polyp burden was analyzed and tissues examined for molecular alterations.

Results

Silibinin treatments decreased total number of intestinal polyps by 34% (P < 0.01), 42% (P < 0.01) and 55% (P < 0.001), respectively. Immunohistochemical analysis showed that silibinin dose-dependently decreases (P < 0.001) proliferation and induces (P < 0.001) apoptosis only in intestinal polyps without any considerable effects on normal crypt-villi in APCmin/+ or wild-type mice. Further analysis of polyps showed that silibinin decreases β-catenin, cyclin D1, c-Myc and phospho-glycogen synthase kinase-3β expression. Silibinin treatment also decreased phospho-Akt, cyclooxygenase-2, inducible nitric oxide synthase, nitrotyrosine and nitrite levels in polyps, the well-known mediators of intestinal/colon carcinogenesis.

Conclusion

Together, these results establish silibinin efficacy in a well-established genetic model of FAP, APCmin/+ mouse, and suggest that this natural agent modulates various molecular pathways including β-catenin in its overall chemopreventive efficacy against intestinal carcinogenesis.

KEY WORDS

beta-cateninchemopreventioncolon cancerCOX-2silibinin

ABBREVIATIONS

APC

Adenomatous polyposis coli

COX-2

cyclooxygenase-2

CRC

colorectal cancer

FAP

familial adenomatous polyposis

GSK-3β

glycogen synthase kinase-3β

IHC

immunohistochemistry

iNOS

inducible nitric oxide synthase

Copyright information

© Springer Science+Business Media, LLC 2009