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

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA.
Clinical Cancer Research (Impact Factor: 8.72). 01/2009; 14(23):7773-80. DOI: 10.1158/1078-0432.CCR-08-1309
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "e l s e v i e r . c o m / l o c a t e / y b b r c VEGFR and nuclear factor-kappa B (NF-jB) [12] [13]. Therefore, by targeting IR activated pro-survival pathways, silibinin may prove to be effective in countering undesirable attributes of IR in these cells and hence improve radio-therapeutic response. "
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    • "Therefore, pharmacologic inhibition of EMT may be instrumental in cancer prevention and treatment. Some flavonoids such as paeoniflorin, proanthocyanidin and silibinin have been reported to reverse EMT (Prasad & Katiyar, 2012; Singh et al., 2008; Zeng et al., 2013 "
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    • "In this regard, it is worth noting that a landmark study showing that the addition of silibinin, which is the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant47484950, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation51 may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib. Silibinin appears to operate as a potent natural agent leading to the reversal of EMT by decreasing the levels of key EMT TFs (e.g., SLUG) and increasing the expression levels of E-cadherin525354. Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells5556. "
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