Combination of Interferon-β and the Angiotensin-Converting Enzyme Inhibitor, Perindopril, Attenuates Murine Hepatocellular Carcinoma Development and Angiogenesis.

Abstract

PURPOSE: Angiogenesis is now recognized as a crucial step in the development of tumors, including hepatocellular carcinoma (HCC). The aim of this study was to elucidate the combined effect of the clinically used angiotensin I-converting enzyme (ACE) inhibitor, perindopril (PE), and IFN-beta on the development and angiogenesis of murine HCC at clinically comparable low doses. EXPERIMENTAL DESIGN: PE and IFN were administered at doses of 2 mg/kg/day and 1 x 10(4) IU/twice a week, respectively. RESULTS: Both PE and IFN significantly suppressed HCC development and inhibited neovascularization in the tumor, although the effect of low-dose IFN was weaker than that of PE. A combination regimen of PE plus IFN was effective; IFN significantly augmented the tumoricidal effect of PE. These inhibitory effects of PE plus IFN could be detected even on established tumors. The potent angiogenic factor, vascular endothelial growth factor, was markedly suppressed by combined treatment with PE and IFN, whereas these agents produced a marked increase of apoptosis in the tumor. The in vitro studies exhibited that PE and IFN inhibited endothelial cell tubular formation. IFN also suppressed endothelial cell proliferation, whereas neither IFN nor PE showed any inhibitory effect on proliferation of HCC cells. CONCLUSION: The combination treatment of PE and IFN at clinically comparable low doses could inhibit HCC development and angiogenesis and suppress vascular endothelial growth factor as well. Because both agents are widely used in clinical practice, this combination regimen may represent a potential new strategy for HCC therapy in the future.