Abstract 3779: Combination chemoprevention of hepatocellular carcinoma using acyclic retinoid

Abstract

Abstract Background and aims: A malfunction of retinoid X receptor-α (RXRα) due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR: the same material as NIK-333), which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit both the Ras activity and phosphorylation of the ERK and RXRα proteins. The effects of a combination of ACR plus other agents on the inhibition of cell growth in human HCC cells were herein examined to develop a more effective strategy for the prevention of HCC. Methods and results: The combination of ACR plus vitamin K2, which inhibits the phosphorylation of the RXRα protein through the inhibition of Ras/MAPK activation, synergistically induced apoptosis and inhibited the growth of human HCC cells without affecting the growth of normal human hepatocytes. ACR and trastuzumab, the humanized anti-HER2 monoclonal antibody, also synergistically inhibited the activation of HER2, a member of receptor tyrosine kinase (RTK), and its downstream signaling pathways, thus subsequently inhibiting the phosphorylation of RXRα and the growth of HCC cells. ACR in combination with valproic acid, a histone deacetylase inhibitor, also synergistically inhibited the growth of human HCC cells and this was associated with the inhibition of phosphorylation of the RXRα and Akt proteins by valproic acid. Conclusion: The combination of ACR plus a specific agent that targets RTK and its downstream signaling pathways, including the Ras/MAPK and PI3K/Akt pathways, may be able to inhibit the phosphorylation of RXRα and it may therefore be a promising strategy to prevent the development of HCC. ACR, which targets phosphorylated RXRα, may thus play a critical role in preventing the development of HCC when it is used either alone or in combination with other agents. 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 3779.