Dietary feeding of silibinin inhibits prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate model.
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 approximately 7-fold (P < 0.001) increase in apoptotic cells at the highest silibinin dose. As potential mechanisms of silibinin efficacy, an approximately 50% (P < 0.05) decrease in insulin-like growth factor (IGF) receptor type I beta and an approximately 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.
Raina
Komal
K
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Blouin
Marie-José
MJ
Singh
Rana P
RP
Majeed
Noreen
N
Deep
Gagan
G
Varghese
Leyon
L
Glodé
L Michael
LM
Greenberg
Norman M
NM
Hwang
David
D
Cohen
Pinchas
P
Pollak
Michael N
MN
Agarwal
Rajesh
R
D000230:Adenocarcinoma / Q000517:prevention & control* / Q000628:therapy*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000517:prevention & control* / Q000628:therapy*; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use; D013045:Species Specificity
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D012838:Silymarin; D000077385:Silybin