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Suppression of Advanced Human Prostate Tumor Growth in Athymic Mice by Silibinin Feeding Is Associated with Reduced Cell Proliferation, Increased Apoptosis, and Inhibition of Angiogenesis¹

Department of Pharmaceutical Sciences, School of Pharmacy [R. P. S., G. S., S. D., C. A., R. A.], University of Colorado Cancer Center [R. A.], University of Colorado Health Sciences Center, Denver, Colorado 80262

Recently, we observed that dietary feeding of silibinin strongly prevents and inhibits the growth of advanced human prostate tumor xenografts in athymic nude mice without any apparent signs of toxicity together with increased secretion of insulin-like growth factor-binding protein 3 from the tumor in to mouse plasma (R. P. Singh et al., Cancer Res., 62: 3063–3069, 2002). In the present study, we investigated the effect of silibinin feeding [0.05% and 0.1% (w/w) in diet for 60 days] on the prognostic biomarkers (namely, proliferation, apoptosis, and angiogenesis) in the prostate tumor xenografts of the above-reported study. Immunohistochemical analysis of the tumors for proliferating cell nuclear antigen and Ki-67 showed that silibinin decreases proliferation index by 28–60% and 30–60% (P < 0.001) as compared with their controls, respectively. In situ detection of apoptosis by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling staining of tumors showed a 7.4–8.1-fold (P < 0.001) increase in apoptotic cells in silibinin-fed groups over that of control group. Silibinin also increased activated caspase 3-positive cells by 2.3–3.6-fold (P < 0.001). CD31 staining for tumor vasculature showed a significant decrease (21–38%; P < 0.001) in tumor microvessel density in silibinin-fed groups of tumors as compared with control group of tumors. Tumor sections were also analyzed for vascular endothelial growth factor and insulin-like growth factor-binding protein 3 protein expression, and a slightly decreased and a moderately increased cytoplasmic immunostaining in silibinin-fed groups were observed as compared with the control group, respectively. Together, these results suggest that inhibition of advanced human prostate tumor xenograft growth in athymic nude mice by silibinin is associated with its in vivo antiproliferative, proapoptotic, and antiangiogenic efficacy in prostate tumor.

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