Stage Specific Inhibitory Effects and Associated Mechanisms of Silibinin on Tumor Progression and Metastasis in TRAMP Model

Herein, employing transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we assessed the ‘stage specific’ efficacy of silibinin feeding against prostate cancer (PCa) initiation, progression, angiogenesis and metastasis, and associated molecular events involved in silibinin effects during these stages. Male TRAMP mice starting at 4, 12, 20 and 30 weeks of age were fed with control or 1% silibinin-supplemented diet for 8-15 weeks in stage-specific manners. At the end of studies, silibinin-fed mice showed less severe prostatic lesions compared to positive controls. During early stages of prostate tumor development, silibinin mediated its efficacy mostly via anti-proliferative mechanisms. Feeding of silibinin to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via anti-proliferative effect, and inhibition of angiogenesis as evidenced by decreased expressions of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD-31), vascular endothelial growth factor (VEGF) and associated receptor, VEGF-R2, hypoxia-inducible factor-1α (HIF-1α) and inducible nitric oxide synthase (iNOS). Metastasis to distant organs was decreased in silibinin-fed mice, which was associated with a decreased expression of matrix metalloproteinases (MMPs), mesenchymal markers snail-1 and fibronectin in the prostatic tissue and retention of epithelial characteristics. Together, these findings are both novel and highly significant in establishing the dual efficacy of silibinin where it inhibits progression of primary prostatic tumor and also shows protective efficacy against angiogenesis and late stage metastasis. These effects of silibinin could have potential implications to improve the morbidity and survival in PCa patients.