Details

Autor(en) / Beteiligte

• SINGH, Rana P
• RAINA, Komal
• DEEP, Gagan
• CHAN, Daniel
• AGARWAL, Rajesh

Titel

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

Ist Teil von

• Clinical cancer research, 2009-01, Vol.15 (2), p.613-621

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2009

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Purpose: 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. Experimental Design: 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.