Silibinin suppresses spontaneous tumorigenesis in APC min/+ mouse model by modulating beta-catenin pathway.
OBJECTIVE
Here we assessed whether silibinin, a nontoxic chemopreventive agent, inhibits spontaneous intestinal tumorigenesis in APC ( min/+) mouse model, a genetically predisposed animal model of human familial adenomatous polyposis (FAP).


METHODS
Six-week-old APC (min/+) 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 APC (min/+) or wild-type mice. Further analysis of polyps showed that silibinin decreases beta-catenin, cyclin D1, c-Myc and phospho-glycogen synthase kinase-3beta 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.


CONCLUSIONS
Together, these results establish silibinin efficacy in a well-established genetic model of FAP, APC (min/+) mouse, and suggest that this natural agent modulates various molecular pathways including beta-catenin in its overall chemopreventive efficacy against intestinal carcinogenesis.
Rajamanickam
Subapriya
S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, C238- P15, Research 2, 12700 19th Ave., Aurora, Colorado 80045, USA.
Kaur
Manjinder
M
Velmurugan
Balaiya
B
Singh
Rana P
RP
Agarwal
Rajesh
R
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000517:prevention & control; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D000975:Antioxidants; D012838:Silymarin; D051176:beta Catenin; D000077385:Silybin