Abstract 5045: AUY922, a heat shock protein 90 inhibitor, has antitumor effects in human hepatocellular carcinoma cells

Abstract

Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer death worldwide. Recently, molecular targeted therapy (MTT) agent, sorafenib, was shown efficacious in this dreadful cancer. However, HCC appears to be a cancer without single driver mutation, targeting multiple proteins in cancer cells might be an alternative strategy for better efficacy. Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone regulating various important proteins associated with pivotal signal transduction and cancer progression of HCC. This study sought to explore whether HSP90 can be a potential target of HCC treatment. AUY922, a highly potent non-geldanamycin HSP90 inhibitor, suppressed cell growth of Huh7 and HepG2 cells with IC50 below 10nM. Flow cytometry analysis showed that G2/M arrest and sub G1 increase were induced after AUY922 treatment. AUY922 downregulated the expressions of Akt and cell cycle regulatory proteins, including Chk1, cdc2, Aurora B, and cyclin B1. Morphologic observation of AUY922-treated Huh7 cells demonstrated the formation of giant, micronucleated cells and multipolar mitosis, a picture compatible with mitotic cell death. Finally, treatment of BALB/c nude mice with 50mg/kg of AUY922 three times a week significantly suppressed the growth of Huh7 tumor xenografts. Our data provide the evidence that AUY922 inhibit HCC cells growth at least partially through mitotic cell death, and inhibiting HSP90 by AUY922 is a potentially useful therapeutic strategy for HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5045. doi:10.1158/1538-7445.AM2011-5045