Role of Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Basic Aspects, Clinical Applications, and Future Prospects

Masahito      Shimizu; Kenji      Imai; Koji      Takai; Hisataka      Moriwaki

doi:10.2174/15680096112091119

Abstract

The poor prognosis for hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, development of effective strategies for preventing recurrence and secondary tumors will improve the clinical outcome of HCC patients. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis, and thus, may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), which inhibits Ras-MAPK activation and RXRα phosphorylation, successfully prevents HCC recurrence, thus improving patient survival. The fundamental concept of HCC chemoprevention by ACR is “clonal deletion,” which is defined as the removal of latent malignant clones from the liver before they expand into clinically detectable HCC. “Combination chemoprevention” using ACR as a key drug holds great promise of a new effective strategy for the prevention of HCC because of its synergism. ACR is also expected to prevent the development of HCC in obese people, who are at an increased risk to HCC, because this agent significantly inhibits obesity-related liver tumorigenesis in the rodent model. Here, we review the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research.

Keywords: Acyclic retinoid, chemoprevention, clonal deletion, combination therapy, HCC, obesity, phosphorylated RXRα, lectin-reactive α-fetoprotein factor 3, branched chain amino acids, diethylnitrosamine, extracellular signal-regulated kinase, hepatitis B virus, hepatocellular carcinoma, hepatitis C virus, histone deacetylase, human epidermal growth factor receptor-2, interferon