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Dietary Feeding of Silibinin Inhibits Prostate Tumor Growth and Progression in Transgenic Adenocarcinoma of the Mouse Prostate Model

¹ Department of Pharmaceutical Sciences, School of Pharmacy, ² Department of Medicine, and ³ University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado; ⁴ Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada; ⁵ Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; ⁶ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁷ Mattel Children's Hospital, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Rajesh Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Street, Box C238, Denver, CO 80262. Phone: 303-315-1381; Fax: 303-315-6281; E-mail: Rajesh.Agarwal{at}uchsc.edu.

Herein, for the first time, we evaluated the chemopreventive efficacy of dietary silibinin against prostate cancer (PCa) growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice from two different genetic backgrounds [C57BL/6 (TRAMP) x FVB; C57BL/6 (TRAMP) x C57BL/6]. At 4 weeks of age, mice were fed control or 0.1% to 1% silibinin–supplemented diets until 23 to 24 weeks of age. Silibinin-fed groups had a lower tumor grade and higher incidence of prostatic intraepithelial neoplasia (PIN) at the expense of a strong decrease in adenocarcinoma incidence. Prostate tissue showed a 47% (P < 0.001) decrease in proliferating cell nuclear antigen (PCNA)–positive cells and an 7-fold (P < 0.001) increase in apoptotic cells at the highest silibinin dose. As potential mechanisms of silibinin efficacy, an 50% (P < 0.05) decrease in insulin-like growth factor (IGF) receptor type Iß and an 13-fold (P < 0.001) increase in IGF-binding protein 3 (IGFBP-3) protein levels were also observed. These changes were specific to tumors as they were not reflected in circulating IGF-IGFBP-3 system. Additionally, silibinin decreased protein expression of cyclin-dependent kinases (Cdk) by more than 90% (P < 0.001) with a concomitant increase in Cdk inhibitors, Cip1/p21 and Kip1/p27 (P < 0.05, for both). A dose-dependent decrease was also observed in cyclin B1, cyclin E, and cyclin A protein levels by silibinin. Together, these findings suggest that oral silibinin blocks PCa growth and progression at PIN stage in TRAMP mice via modulation of tumor IGF-IGFBP-3 axis and cell cycle regulation, and therefore it has practical and translational potential in suppressing growth and neoplastic conversion of PIN to PCa in humans. [Cancer Res 2007;67(22):11083–91]

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