Hepatocellular carcinoma (HCC) is one of the most common and recurrent malignancies worldwide. Many risk factors including HBV infection play a major role in the etiology of HCC. However, there are no effective chemopreventive and therapeutic agents for HCC treatments currently. Accordingly, drug development is urgent to control HCC progression. Oxidative stress is one of the key players in tumorigenesis. Since HBV products such as HBV X protein (HBx) induced oxidative stress in liver cells, antioxidants of natural and synthetic origins are considered to be potential agents against HBV-associated HCC. Previously we have generated the HBx transgenic mice and demonstrated that overexpression of HBx led to HCC development in 90-100% of transgenic males at 16-month old. The HBx transgenic mouse thus provides an in vivo platform to evaluate anticarcinogenic agents prior to clinical investigations. Silymarin, a mixture of herbal compounds from milk thistle, is a popular dietary supplement taken by patients with chronic liver diseases. However, its therapeutic effect on HCC has not been well studied. In this study, silymarin and its major component, silibinin, were evaluated for the efficacy against carcinogenesis using the HBx transgenic model. To study the therapeutic effects on early stage of liver pathogenesis, silymarin and silibinin (30-300mg/kg/day) was orally administrated to the HBx transgenic males from 4 weeks to 6 weeks of age. Our data indicated that silymarin, but not silibinin, can reduce liver damages and recover liver architecture in a dose-dependent manner. To study the chemopreventive effects on later stages of liver carcinogenesis, silymarin (300mg/kg/day) was administrated to the HBx transgenic males from 13 months to 16 months of age. Our data demonstrated that there was no HCC detected in 100% (12/12) of the transgenic males at 16-month old after treatment of silymarin for 3 months. However, small hyperplastic nodules, measured about 1 mm to 3 mm in diameter, were detected in 92% (11/12) of the HBx transgenic mice. In addition, we have demonstrated that silymarin decreased the intracellular ROS levels of transgenic hepatocytes in a dose dependent manner. Electron microscopic examination further indicated that silymarin treatment recovered the ultrastructure of hepatocytes. Together, these data indicated that silymarin exerted therapeutic effects on early stage of liver damages, prevented HCC formation and delayed liver pathogenesis process at later stage of the HBx-mediated liver carcinogenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA