Abstract 2469: Combination of branched-amino acids and ACE inhibitor attenuates the insulin resistance-based hepatocarcinogenesis via angiogenesis suppression

Abstract

Abstract A strong correlation between insulin resistance (IR) and hepatocellular carcinoma (HCC) has recently been identified, although little is known about the possible mechanisms involved. IR is a consistent finding in patients with type 2 diabetes mellitus (DM), and a close interaction between DM and HCC has been documented. Since neovascularization plays an important role in HCC including hepatocarcinogenesis, an angiostatic therapy would be a promising approach for chemoprevention against HCC. The aims of this study were to elucidate the role of angiogenesis in IR-based hepatocarcinogenesis, and to elucidate the therapeutic effect of combination of clinically used branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitor (ACE-I), in conjunction with neovascularization. The combined effects on the development of liver enzyme-altered pre-neoplastic lesions, angiogenesis, and several indices were elucidated in obese diabetic rats. We also performed several sets of in-vitro experiments to examine the mechanisms involved. The IR status directly accelerated hepatocarcinogenesis, and treatment with both BCAA and ACE-I markedly inhibited the development of pre-neoplastic lesions under the condition of IR along with suppression of angiogenesis and VEGF expression in the liver. The combination treatment with BCAA and ACE-I exerted more potent inhibitory effects than single-agent treatments. Our in-vitro study demonstrated that BCAA and ACE-I inhibited the endothelial tubular formation almost in parallel with suppression of development of pre-neoplastic lesions. This combination regimen with BCAA and ACE-I showed a marked chemopreventive effect against hepatocarcinogenesis along with suppression of neovascularization and VEGF expression in obese diabetic rat as compared with either single-agent treatment. These inhibitory effects were achieved at clinically comparable low doses. Since both BCAA and ACE-I are widely used in the clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2469.