Silibinin suppresses growth of human prostate carcinoma PC-3 orthotopic xenograft via activation of extracellular signal-regulated kinase 1/2 and inhibition of signal transducers and activators of transcription signaling.
OBJECTIVE
Silibinin is currently under phase II clinical trial in prostate cancer patients; however, its antitumor effects and mechanisms are not completely understood. Herein, we studied the efficacy and associated mechanisms of silibinin against orthotopically growing advanced human prostate carcinoma PC-3 tumors.


METHODS
Athymic male mice were orthotopically implanted with PC-3 cells in prostate and 1 week later after surgical recovery were gavaged daily with silibinin (100 mg/kg body weight) for 7 weeks.


RESULTS
Silibinin treatment reduced the lower urogenital weight (including tumor, prostate, and seminal vesicle) by 40% (P < 0.05) without any toxicity in mice. Silibinin decreased proliferating cell nuclear antigen expression and proliferating cells (P < 0.001) but increased cleaved caspase-3-positive cells (P < 0.01) and apoptotic cells (P < 0.001) and suppressed tumor microvessel density (P < 0.001) and vascular endothelial growth factor expression (P = 0.02). Decreased levels of cyclin-dependent kinases 2, 4, and 6, CDC2, and cyclins D1, D3, E, and A were observed, indicating an inhibitory effect of silibinin on cell cycle progression. Silibinin showed a tremendous increase in extracellular signal-regulated kinase 1/2 phosphorylation but decreased c-Jun NH(2)-terminal kinase 1/2 and p38 mitogen-activated protein kinase phosphorylation. A moderate decrease in phosphorylated and total levels of Akt was also noted. A marked inhibitory effect of silibinin on signal transducers and activators of transcription (STAT) 1 (Tyr(701)), STAT1 (Ser(727)), STAT3 (Tyr(705)), STAT3 (Ser(727)), and STAT5 (Tyr(794)) phosphorylation together with a decrease in their total levels was also observed.


CONCLUSIONS
These findings provide evidence for antitumor efficacy of silibinin against orthotopically growing prostate tumor in mice with multitargeted mechanistic insights and support its clinical investigation in prostate cancer.
Singh
Rana P
RP
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado-Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.
Raina
Komal
K
Deep
Gagan
G
Chan
Daniel
D
Agarwal
Rajesh
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000975:Antioxidants; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012838:Silymarin; D042461:Vascular Endothelial Growth Factor A; D000077385:Silybin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3