bitory Effect of Silibinin against Azoxymethane-Induced R on Tumorigenesis in A/J Mice

ownloade pose: Colorectal cancer is the second leading cause of cancer-associated deaths, which suggests ore effort is needed to prevent/control this disease. Herein, for the first time, we investigate the efficacy of silibinin against azoxymethane-induced colon tumorigenesis in A/J mice. erimental Design: Five-week-old male mice were gavaged with vehicle or silibinin (250 and g/kg) for 25 weeks starting 2 weeks before initiation with azoxymethane (pretreatment regime) 16 weeks starting 2 weeks after the last azoxymethane injection (posttreatment regime). The mice then sacrificed, and colon tissues were examined for tumor multiplicity and size, and molecular rs for proliferation, apoptosis, inflammation, and angiogenesis. ults: Silibinin feeding showed a dose-dependent decrease in azoxymethane-induced colon tumoris with stronger efficacy in pretreatment versus posttreatment regimen. Mechanistic studies in tissue es showed that silibinin inhibits cell proliferation as evident by a decrease (P < 0.001) in proliferating clear antigen and cyclin D1, and increased Cip1/p21 levels. Silibinin also decreased (P < 0.001) the of inducible nitric oxide synthase, cyclooxygenase-2, and vascular endothelial growth factor, suggestanti-inflammatory and antiangiogenic potential in this model. Further, silibinin increased cleaved e-3 and poly(ADP-ribose) polymerase levels, indicating its apoptotic effect. In other studies, colonic sa and tumors expressed high levels of β-catenin, insulin-like growth factor-1 receptorβ, phospho gen synthase kinase-3β, and phospho protein kinase B/pAkt proteins in azoxymethane-treated mice, were strongly lowered (P < 0.001) by silibinin treatment. Moreover, azoxymethane reduced insulinowth factor binding protein-3 protein level, which was enhanced by silibinin. clusions: Silibinin targets β-catenin and IGF-1Rβ pathways for its chemopreventive efficacy against Con azoxymethane-induced colon carcinogenesis in A/J mice. Overall, these results support the translational potential of silibinin in colorectal cancer chemoprevention. Clin Cancer Res; 16(18); 4595–606. ©2010 AACR.