Chemoprevention of intestinal tumorigenesis in APCmin/+ mice by silibinin.
Chemoprevention is a practical and translational approach to reduce the risk of various cancers including colorectal cancer (CRC), which is a major cause of cancer-related deaths in the United States. Accordingly, here we assessed chemopreventive efficacy and associated mechanisms of long-term silibinin feeding on spontaneous intestinal tumorigenesis in the APC(min/+) mice model. Six-week-old APC(min/+) mice were p.o. fed with vehicle control (0.5% carboxymethyl cellulose and 0.025% Tween 20 in distilled water) or 750 mg silibinin/kg body weight in vehicle for 5 d/wk for 13 weeks and then sacrificed. Silibinin feeding strongly prevented intestinal tumorigenesis in terms of polyp formation in proximal, middle, and distal portions of small intestine by 27% (P < 0.001), 34% (P < 0.001), and 49% (P < 0.001), respectively. In colon, we observed 55% (P < 0.01) reduction in number of polyps by silibinin treatment. In size distribution analysis, silibinin showed significant decrease in large-size polyps (>3 mm) by 66% (P < 0.01) and 88% (P < 0.001) in middle and distal portions of small intestine, respectively. More importantly, silibinin caused a complete suppression in >3 mm sized polyps and 92% reduction in >2 to 3 mm sized polyps in colon. Molecular analyses of polyps suggested that silibinin exerts its chemopreventive efficacy by inhibiting cell proliferation, inflammation, and angiogenesis; inducing apoptosis; decreasing beta-catenin levels and transcriptional activity; and modulating the expression profile of cytokines. These results show for the first time the efficacy and associated mechanisms of long-term p.o. silibinin feeding against spontaneous intestinal tumorigenesis in the APC(min/+) mice model, suggesting its chemopreventive potential against intestinal cancers including CRC.
Rajamanickam
Subapriya
S
Department of Pharmaceutical Sciences, School of Pharmacy and University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado 80045, USA.
Velmurugan
Balaiya
B
Kaur
Manjinder
M
Singh
Rana P
RP
Agarwal
Rajesh
R
D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D007417:Intestinal Polyps / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism
D000975:Antioxidants; D012838:Silymarin; D051176:beta Catenin; D019938:Cyclin D1; D000077385:Silybin; D051546:Cyclooxygenase 2; D015232:Dinoprostone