Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage-associated cytokines and nuclear factor-kappaB and signal transducers and activators of transcription 3

Cancer Prev Res (Phila). 2009 Jan;2(1):74-83. doi: 10.1158/1940-6207.CAPR-08-0095.


The latency period for lung tumor progression offers a window of opportunity for therapeutic intervention. Herein, we studied the effect of oral silibinin (742 mg/kg body weight, 5 d/wk for 10 weeks) on the growth and progression of established lung adenocarcinomas in A/J mice. Silibinin strongly decreased both tumor number and tumor size, an antitumor effect that correlates with reduced antiangiogenic activity. Silibinin reduced microvessel size (50%, P < 0.01) with no change in the number of tumor microvessels and reduced (by 30%, P < 0.05) the formation of nestin-positive microvessels in tumors. Analysis of several proteins involved in new blood vessel formation showed that silibinin decreased the tumor expression of interleukin-13 (47%) and tumor necrosis factor-alpha (47%), and increased tissue inhibitor of metalloproteinase-1 (2-fold) and tissue inhibitor of metalloproteinase-2 (7-fold) expression, without significant changes in vascular endothelial growth factor levels. Hypoxia- inducible factor-1 alpha expression and nuclear localization were also decreased by silibinin treatment. Cytokines secreted by tumor cells and tumor-associated macrophages regulate angiogenesis by activating nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription (STAT). Silibinin decreased the phosphorylation of p65NF-kappaB (ser276, 38%; P < 0.01) and STAT-3 (ser727, 16%; P < 0.01) in tumor cells and decreased the lung macrophage population. Angiopoietin-2 (Ang-2) and Ang-receptor tyrosine kinase (Tie-2) expression were increased by silibinin. Therapeutic efficacy of silibinin in lung tumor growth inhibition and regression by antiangiogenic mechanisms seem to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1 alpha, NF-kappaB, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2.

Publication types

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

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cytokines / drug effects
  • Cytokines / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Male
  • Mice
  • Microvessels / drug effects
  • NF-kappa B / drug effects
  • NF-kappa B / immunology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / immunology
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / immunology
  • Signal Transduction / drug effects
  • Silybin
  • Silymarin / pharmacology


  • Angiogenesis Inhibitors
  • Cytokines
  • NF-kappa B
  • STAT3 Transcription Factor
  • Silymarin
  • Stat3 protein, mouse
  • Silybin