Antitumor effect of tyrosine kinase inhibitor, AMN107, in hepatocellular carcinoma

Abstract

Hepatocellular Carcinoma (HCC) is one of the most common malignancies and is responsible for more than one million deaths worldwide. In Hong Kong, it is the second leading cause of cancer death. Surgical resection or liver transplantation is the treatment of choice when HCC is diagnosed at an early stage. However, around 70% of patients are inoperable because of advanced tumor growth or severe underlying cirrhosis. Targeted therapy could be one of the main options for HCC patients.

AMN107 is a novel and potent inhibitor of the protein tyrosine kinase activities of Bcr-Abl, c-kit and PDGFR. In the previous studies, the antitumor activity of AMN107 was attributed mainly to the treatment of chronic myeloid leukemia by targeting Bcr-Abl, and a direct antitumor effect in solid tumor was rarely reported. In this study, we investigated direct effect of AMN107 in nude mice bearing human HCC xenograft. Tumor tissues from a HCC nude mice established by human HCC cell lines were implanted orthotopically in the liver of nude mice. The in vitro effect of AMN107 on proliferation and apoptosis of human HCC cell lines was studied by MTT assay, flow cytometry and Western blot. Our results demonstrated that AMN107 oral administration to mice at 50mg/kg/day resulted in a significant reduction in tumor growth of HCC xenografts in nude mice. AMN107 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis in vitro. Furthermore, AMN107 downregulated bcl-xL expression in HCC cells. In addition, it is also found that PDGF could induced phosphorylation of ERK in HCC cell lines. The simulated effect by PDGF could be blocked by AMN107. In conclusion, this study demonstrated that AMN107 is potent inhibitors of tumor growth in HCC. The inhibition of tumor volumne by AMN107 may through direct effects on inhibition of tumor cell proliferation, induction of tumor cell apoptosis and blocking bcl-xL expression. AMN107 also inhibited the PDGF induced activation of ERK. Our data suggest that AMN107 may provide an effective therapy for human HCC.