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

Abstract

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) Â FVB; C57BL/6 (TRAMP) Â 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 f7-fold (P < 0.001) increase in apoptotic cells at the highest silibinin dose. As potential mechanisms of silibinin efficacy, an f50% (P < 0.05) decrease in insulin-like growth factor (IGF) receptor type IB and an f13-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 cyclindependent 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

Deletion ofp21/Cdkn1aconfers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

“…Importantly, as reported earlier for the TRAMP prostate, 19,24 prostate tumorigenesis in terms of its pathological manifestation was more apparent in dorsolateral lobe of prostate than in other lobes (anterior and ventral) in p21/TRAMP mice, thus detailed histopathological analysis was done on the dorsolateral lobe only (Figs. 1-3).…”

“…Using the modified classification by Shappell et al 36 as described by us earlier, 24 the TRAMP mouse prostate pathology was classified as: (1) low-grade PIN (LGPIN), which has intact gland profiles with foci of two or multilayers of atypical cells and elongated hyper chromatic nuclei; (2) highgrade PIN (HGPIN), which has enlarged diameter of glands, distorted duct profiles, having increased epithelial stratification and cribriform architecture, a larger number of hyperchromatic and pleomorphic nuclei, and lumen is almost completely filled with cells; (3) well differentiated (WD) adenocarcinoma, which has increased quantity of small glands; the basement membranes of glands display signs of invasion, and the spaces between the ducts are considerably reduced; (4) moderately differentiated (MD) adenocarcinoma, which is characterized by merged glands; the spaces between the ducts are completely lost; and (5) poorly differentiated (PD) adenocarcinoma, which displays a continuous sheet of undifferentiated cells.…”

“…[24][25][26][27] TRAMP was developed in C57BL/6 mice in which minimal rat probasin promoter (PB) drives the expression of SV-40 early genes (T/t; Tag) specifically in prostatic epithelium. 20,23 The transgene is under hormonal regulation, expressed at sexual maturity, which then induces spontaneous neoplastic epithelial transformation in the prostate.…”

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

“…1A). Accumulating evidence indicates that silibinin has anticancer activity in various tumor cells, including cancers of prostate (5)(6)(7)(8)(9), breast (10,11), skin (12), colon (13), lung (14), kidney (15,16), and bladder (17)(18)(19)(20). There is increasing interest in elucidating the mechanisms of action for silibinin as an effective agent for chemoprevention and chemotherapy against various types of cancers.…”

Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

“…20,21 The presence of normal tissue, low-grade prostate intraepithelial neoplasia (LG-PIN), high-grade PIN (HG-PIN), and adenocarcinoma was scored. The occurrence of poorly differentiated carcinomas (PDCs) also was evaluated.…”