Chemoprevention of Intestinal Tumorigenesis in APC min/+ Mice by Silibinin

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 6; pp. 2368 - 2378
• Main Authors: Rajamanickam, Subapriya, Velmurugan, Balaiya, Kaur, Manjinder, Singh, Rana P., Agarwal, Rajesh
• Format: Journal Article
• Language: English
• Published: 09.03.2010
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-3249

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 APC min/+ mice model. Six-week old APC min/+ mice were orally-fed with vehicle control (0.5% carboxymethyl celluloseand 0.025% Tween 20 in distilled water) or 750 mg silibinin/kg body weight in vehicle for five days/week for 13 weeks and then sacrificed. Silibinin feeding strongly prevented intestinal tumorigenesis in terms of polyps 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 size polyps and 92% reduction in >2–3 mm size polyps in colon. Molecular analyses of polyps suggested that silibinin exerts its chemopreventive efficacy by inhibiting cell proliferation, inflammation and angiogenesis; inducing apoptosis; decreasing β-catenin levels and transcriptional activity; and modulating the expression profile of cytokines. These results for the first time show the efficacy and associated mechanisms of long-term oral silibinin-feeding against spontaneous intestinal tumorigenesis in APC min/+ mice model, suggesting for its chemopreventive potential against intestinal cancers including CRC.