Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model.
Herein, using 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 ages 4, 12, 20, and 30 weeks of age were fed with control or 1% silibinin-supplemented diet for 8 to 15 weeks in stage-specific manners. At the end of studies, silibinin-fed mice showed less severe prostatic lesions compared with positive controls. During early stages of prostate tumor development, silibinin mediated its efficacy mostly via antiproliferative mechanisms. Feeding of silibinin to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via antiproliferative effect, and inhibition of angiogenesis as evidenced by decreased expressions of platelet endothelial cell adhesion molecule-1/CD-31, vascular endothelial growth factor, and associated receptor, vascular endothelial growth factor R2, hypoxia-inducible factor-1alpha, and inducible nitric oxide synthase. Metastasis to distant organs was decreased in silibinin-fed mice, which was associated with a decreased expression of matrix metalloproteinases, 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.
Raina
Komal
K
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA.
Rajamanickam
Subapriya
S
Singh
Rana P
RP
Deep
Gagan
G
Chittezhath
Manesh
M
Agarwal
Rajesh
R
D000230:Adenocarcinoma / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008113:Liver Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D020944:Silybum marianum; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011467:Prostate / Q000187:drug effects; D019048:Prostatic Intraepithelial Neoplasia / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D012838:Silymarin; D042461:Vascular Endothelial Growth Factor A; D000077385:Silybin; D052247:Nitric Oxide Synthase Type II