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.

Abstract

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.

• Authors: Rana P Singh, Komal Raina, Girish Sharma, Rajesh Agarwal
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 23 Pg. 7773-80 (Dec 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19047104 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Cadherins
• Silymarin
• Vimentin
• silybin-phytosome
• Silybin
• Matrix Metalloproteinases

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cadherins (drug effects)
• Cell Proliferation (drug effects)
• Disease Progression
• Immunohistochemistry
• Male
• Matrix Metalloproteinases (drug effects)
• Mice
• Mice, Transgenic
• Neoplasm Metastasis (drug therapy)
• Neovascularization, Pathologic (drug therapy)
• Prostatic Neoplasms (drug therapy)
• Silybin
• Silymarin (analogs & derivatives, pharmacology)
• Vimentin (drug effects)