Original Articles
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Apr 28, 2009; 15(16): 1943-1950
Published online Apr 28, 2009. doi: 10.3748/wjg.15.1943
Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice
Wei Cui, Fan Gu, Ke-Qin Hu
Wei Cui, Ke-Qin Hu, Division of Gastroenterology and Chao Family Comprehensive Cancer Center, University of California, Orange School of Medicine, Orange, CA 92868, United States
Fan Gu, Department of Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Author contributions: Cui W and Gu F contributed to the study design, analyzed and interpreted the data, and prepared the manuscript; Cui W performed the experiments; Hu KQ designed the study, interpreted the data and wrote the manuscript.
Correspondence to: Ke-Qin Hu, Division of Gastroenterology, University of California, Irvine Medical Center, 101 The City Drive, Building 53, Suite 113, Orange, CA 92868, United States. kqhu@uci.edu
Telephone: +1-714-4566745  
Fax: +1-714-4563283
Received: December 10, 2008
Revised: March 16, 2009
Accepted: March 23, 2009
Published online: April 28, 2009
Abstract

AIM: To investigate the in vivo effects and mechanisms of silibinin on the growth of hepatocellular carcinoma (HCC) xenografts in nude mice.

METHODS: Nude mice bearing HuH7 xenografts were used to assess the anti-HCC effects and mechanisms of silibinin.

RESULTS: Silibinin resulted in a potent dose-dependent reduction of HuH7 xenografts in association with a significant decrease in Ki-67 and α-fetoprotein production, nuclear NF-κB content, polo-like kinase 1, Rb phosphorylation, and E2F1/DP1 complex, but increased p27/CDK4 complex and checkpoint kinase 1 expression, suggesting that the in vivo effects of silibinin are mediated by inhibiting G1-S transition of the cell cycle. Silibinin-induced apoptosis of HuH7 xenografts was associated with inhibited survivin phosphorylation. Silibinin-reduced growth of HuH7 xenografts was associated with decreased p-ERK, increased PTEN expression and the activity of silibinin was correlated with decreased p-Akt production, indicating involvement of PTEN/PI3K/Akt and ERK pathways in its in vivo anti-HCC effects. Silibinin-reduced growth of HuH7 xenografts was also associated with a significant increase in AC-H3 and AC-H4 expression and the production of superoxide dismutase (SOD)-1.

CONCLUSION: Silibinin reduces HCC xenograft growth through the inhibition of cell proliferation, cell cycle progression and PTEN/P-Akt and ERK signaling, inducing cell apoptosis, and increasing histone acetylation and SOD-1 expression.

Keywords: Apoptosis, Cell cycle, Chemoprevention, Hepatocellular carcinoma, Histone acetylation, Silibinin