Silibinin Suppresses Spontaneous Tumorigenesis in APCmin/+ Mouse Model by Modulating Beta-Catenin Pathway
- First Online:
- Cite this article as:
- Rajamanickam, S., Kaur, M., Velmurugan, B. et al. Pharm Res (2009) 26: 2558. doi:10.1007/s11095-009-9968-1
- 134 Views
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.
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.
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 WORDSbeta-cateninchemopreventioncolon cancerCOX-2silibinin
Adenomatous polyposis coli
familial adenomatous polyposis
glycogen synthase kinase-3β
inducible nitric oxide synthase