Silibinin suppresses growth of human colorectal carcinoma SW480 cells in culture and xenograft through down-regulation of beta-catenin-dependent signaling

Neoplasia. 2010 May;12(5):415-24. doi: 10.1593/neo.10188.


Mutations in APC/beta-catenin resulting in an aberrant activation of Wnt/beta-catenin pathway are common in colorectal cancer (CRC), suggesting that targeting the beta-catenin pathway with chemopreventive/anticancer agents could be a potential translational approach to control CRC. Using human CRC cell lines harboring mutant (SW480) versus wildtype (HCT116) APC gene and alteration in beta-catenin pathway, herein we performed both in vitro and in vivo studies to examine for the first time whether silibinin targets beta-catenin pathway in its efficacy against CRC. Silibinin treatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of beta-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the beta-catenin pathway and associated biologic responses. Other studies, therefore, were performed only in SW480 cells where silibinin significantly decreased beta-catenin-dependent T-cell factor-4 (TCF-4) transcriptional activity and protein expression of beta-catenin target genes such as c-Myc and cyclin D1. Silibinin also decreased cyclin-dependent kinase 8 (CDK8), a CRC oncoprotein that positively regulates beta-catenin activity, and cyclin C expression. In a SW480 tumor xenograft study, 100- and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth by 26% to 46% (P < .001). Analyses of xenografts showed that similar to cell culture findings, silibinin decreases proliferation and expression of beta-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Together, these findings suggest that silibinin inhibits the growth of SW480 tumors carrying the mutant APC gene by down-regulating CDK8 and beta-catenin signaling and, therefore, could be an effective agent against CRC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Cyclin-Dependent Kinase 8 / drug effects
  • Cyclin-Dependent Kinase 8 / metabolism
  • Down-Regulation
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • HCT116 Cells
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Signal Transduction / drug effects*
  • Silybin
  • Silymarin / pharmacology*
  • Wnt Proteins / drug effects
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Xenograft Model Antitumor Assays
  • beta Catenin / drug effects*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Antineoplastic Agents
  • Antioxidants
  • Silymarin
  • Wnt Proteins
  • beta Catenin
  • Silybin
  • Cyclin-Dependent Kinase 8