Antiangiogenic Therapy for Hepatocellular Carcinoma

Abstract

Angiogenesis plays a pivotal role in many pathological processes, including hepatocellular carcinoma (HCC). This indicates that antiangiogenic agents could be promising candidates for chemoprevention against HCC. Several inhibitors targeting receptor tyrosine kinases (RTKs) for the regulation of tumoral vascularization have been developed and employed in clinical practice, including sorafenib. However, there seem to be several issues for the long-term use of this agent as some patients have experienced adverse effects while taking sorafenib. Therefore, it is desirable for patients with chronic liver diseases to be administered sorafenib as little as possible by combining other safe-to-use antiangiogenic compounds. Various factors, such as renin-angiotensin-aldosterone system (RAAS) and insulin resistance (IR), reciprocally contribute to the promotion of angiogenesis. A blockade of RAAS with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin-II (AT-II) receptor blocker (ARB) markedly attenuates HCC in conjunction with the suppression of angiogenesis. Moreover, the IR status has demonstrated direct acceleration in the progression of HCC via the augmentation of tumoral neovascularization. These findings suggest that a combination therapy involving a lower dose of sorafenib with other clinically used agents [e.g., RAAS blockers, insulin sensitizer agents, and branched-chain amino acids (BCAA)] may reduce the adverse effects of sorafenib without attenuating the inhibitory effect against HCC in comparison to a high-dose administration.