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Silibinin Inhibits Established Prostate Tumor Growth, Progression, Invasion, and Metastasis and Suppresses Tumor Angiogenesis and Epithelial-Mesenchymal Transition in Transgenic Adenocarcinoma of the Mouse Prostate Model Mice

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, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262. Phone: 303-315-1381; Fax: 303-315-6281; E-mail: Rajesh.Agarwal{at}uchsc.edu.

Purpose: The chronic nature of prostate cancer growth and progression leading to metastasis provides a large window for intervention. Herein, for the first time, we investigated the effect and associated mechanisms of silibinin phosphatidylcholine (silybin-phytosome) on established prostate tumors in transgenic adenocarcinoma of the mouse prostate (TRAMP) model.

Experimental Design: Twenty-week-old TRAMP male mice having palpable prostate tumor were fed with control or 0.5% and 1%, w/w, silybin-phytosome diets for 11 weeks and then sacrificed.

Results: Dietary silibinin inhibited the growth of prostate tumors (up to 60%, P < 0.001) and suppressed tumor progression from prostatic intraepithelial neoplasia to differentiated adenocarcinoma and poorly differentiated adenocarcinoma, with a complete absence of poorly differentiated adenocarcinoma at higher doses. It also inhibited the incidence of tumor invasion of seminal vesicle (up to 81%, P < 0.001) with complete absence of distant metastasis. Silibinin moderately inhibited tumor cell proliferation and induced apoptosis, but strongly suppressed tumor microvessel density (up to 60%, P < 0.001), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2 expression. Antibody array analysis of plasma showed a decrease in the circulatory levels of vascular endothelial growth factor and basic fibroblast growth factor. Decreased levels of matrix metalloproteinases (MMP), snail-1, and vimentin, and an increased level of E-cadherin were also observed, indicating the anti–epithelial-mesenchymal transition effect of silibinin in tumors.

Conclusions: Overall, silibinin treatment of TRAMP mice bearing prostate tumor inhibited tumor growth, progression, local invasion, and distant metastasis involving suppression of tumor angiogenesis and epithelial-mesenchymal transition. These findings would have greater relevance for the ongoing phase II clinical trial with silibinin-phytosome in prostate cancer patients.

Commentary

The Challenge of Herbal Therapies for Prostate Cancer

Rupal S. Bhatt and Glenn J. Bubley
Clin. Cancer Res. 2008 14: 7581-7582. [Abstract] [Full Text] [PDF]