Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5-fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities

Therapies aimed at destruction of the tumor vasculature are now recognized as a promising approach against cancer, and it has been reported that the combination treatment with an angiogenic inhibitor and conventional chemotherapeutic drug exerted synergistic anti-cancerous effects. We previously reported that the clinically used angiotensin-converting enzyme inhibitor (ACE-I) exerted potent-anti-angiogenic activities. The aim of our current study was to examine the combined effect of ACE-I and 5-fluorouracil (5-FU), which is widely used for hepatogastrointestinal tumors, on hepatocellular carcinoma (HCC) growth and hepatocarcinogenesis. When used individually at low doses, neither 5-FU nor ACE-I exerted significant inhibitory effects on the HCC growth. However, the combination treatment of 5-FU and ACE-I showed a potent inhibitory effect on HCC growth along with suppression of neovascularization in the tumor. The expression level of the vascular endothelial growth factor, a potent angiogenic factor, was also suppressed, almost in conjunction with tumor growth inhibition. Furthermore, 5-FU and ACE-I treatment resulted in a marked increase of apoptosis in the tumor. In the hepatocarcinogenesis model, the combination treatment with 5-FU and ACE-I also showed a marked inhibitory effect on the development of preneoplastic lesions. The in vitro study demonstrated that this combination treatment inhibited endothelial cell tubular formation. Collectively, the combination treatment of 5-FU and ACE-I exerted a marked synergistic inhibitory effect on HCC growth via suppression of angiogenesis. This regimen also showed a chemopreventive effect against hepatocarcinogenesis. Since both 5-FU and ACE-I are widely used in clinical practice, this combination therapy may be an effective new therapeutic strategy against HCC in the future.