Liver Cancer
Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 28, 2007; 13(40): 5299-5305
Published online Oct 28, 2007. doi: 10.3748/wjg.v13.i40.5299
Effects and mechanisms of silibinin on human hepatoma cell lines
John J Lah, Wei Cui, Ke-Qin Hu
John J Lah, Wei Cui, 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
Author contributions: All authors contributed equally to the work.
Supported by UCI institutional research grants from GI Division and Chao Family Comprehensive Cancer Center (K.-Q.H.)
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: +1-714-4567753
Received: April 7, 2007
Revised: July 25, 2007
Accepted: August 10, 2007
Published online: October 28, 2007
Abstract

AIM: To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma (HCC) cell growth.

METHODS: Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined.

RESULTS: We demonstrated that silibinin significantly reduced the growth of HuH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up-regulated p21/CDK4 and p27/CDK4 complexes, down-regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and up-regulated activated caspase-3 and -9. Silibinin's anti-angiogenic effects were indicated by down-regulated metalloproteinase-2 (MMP2) and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and decreased p-Akt production, indicating the role of PTEN/PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 (AC-H3 and AC-H4), indicating a possible role of altered histone acetylation in silibinin-reduced HCC cell proliferation.

CONCLUSION: Our results defined silibinin's in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.

Keywords: Hepatocellular carcinoma; HuH7 cells; Silibinin; Chemoprevention; Cell cycle; Cell cycle progression; Apoptosis; Acetylation of histone