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Growth Inhibition and Regression of Lung Tumors by Silibinin: Modulation of Angiogenesis by Macrophage-Associated Cytokines and Nuclear Factor-B and Signal Transducers and Activators of Transcription 3

Authors' Affiliations: ¹ Department of Pharmaceutical Sciences, School of Pharmacy, ² University of Colorado Cancer Center, University of Colorado Denver, Denver, Colorado; and ³ Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Requests for reprints: Rajesh Agarwal, University of Colorado Denver, Box C238, Denver, CO 80262. Phone: 303-315-1228; Fax: 303-315-6281; E-mail: Rajesh.Agarwal{at}UCHSC.edu.

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- (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 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-B (NF-B) and signal transducers and activators of transcription (STAT). Silibinin decreased the phosphorylation of p65NF-B (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, NF-B, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2.

Key Words: Silibinin • lung tumor • angiogenesis • macrophages • cytokines • NF-B • STAT3