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.

Abstract

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.

• Authors: Alpna Tyagi, Rana P Singh, Kumaraguruparan Ramasamy, Komal Raina, Elizabeth F Redente, Lori D Dwyer-Nield, Richard A Radcliffe, Alvin M Malkinson, Rajesh Agarwal
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 2 Issue 1 Pg. 74-83 (Jan 2009) ISSN: 1940-6215 [Electronic] United States
• PMID: 19139021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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