Blockage of vascular endothelial growth factor receptors by tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth of hepatocellular carcinoma with metastatic potential by angiogenesis-independent effect

Abstract

Hepatocellular Carcinoma (HCC) is one of the most common malignancies and is responsible for more than one million deaths worldwide. Vascular endothelial growth factor (VEGF) receptors with tyrosine kinase activity are highly expressed in many human tumors. Therefore, inhibition of VEGF receptors could be a potential target for anticancer therapy. PTK787/ZK222584 (PTK787) is a potent tyrosine kinase inhibitor. In the previous studies, the antitumor activity of PTK787 was attributed to the inhibition of VEGF signaling in the tumor vasculature, and a direct antitumor effect on solid tumor was not reported. In this study, we investigated the direct effect of PTK787 in nude mice bearing human HCC xenograft with metastatic potential. Tumor tissues from a metastatic HCC nude mice model established by metastatic human HCC cell lines were implanted orthotopically in the liver of nude mice. The effect of PTK787 on proliferation of metastatic human HCC cell lines was studied by MTT assay. The in vitro effect of PTK787 on metastatic HCC cell line apoptosis and cell cycle distribution were evaluated by flow cytometry. Our results demonstrated that PTK787 oral administration to mice at 50 mg/kg/day resulted in a significant reduction in tumor growth of HCC xenografts in nude mice. PTK787 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis in vitro. Furthermore, PTK787 treatment induced a delay in cell cycle progression and a G1 arrest together with a partial G2/M block. In conclusion, this study demonstrated that PTK787 is a potent inhibitor of tumor growth in HCC with metastatic potential. The inhibition of tumor volume by PTK787 may through direct effects on inhibition of tumor cell proliferation, induction of tumor cell apoptosis and blocking tumor cell cycle progression. Our data suggest that blockage of VEGF receptors may provide an effective therapeutic approach for human HCC.