Abstract 1781: LGI147, a novel small-molecule inhibitor of the mitotic kinesin Eg5, shows anticancer effects in human hepatocellular carcinoma

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, for which novel therapies are urgently needed. Recently, the inhibitors of mitotic kinesin Eg5 emerge as potential anticancer therapeutics. The aim of this study was to investigate the anticancer activity of a potent Eg5 inhibitor, LGI147, as targeted therapy of HCC. Method: Antiproliferative effect of LGI147 (kindly provided by Novartis), a highly selective inhibitor of mitotic kinesin Eg5, was tested in three liver cancer cell lines (Hep3B, HepG2, PLC/PRF/5). Cell viability was measured by trypan blue exclusion assay. Mitotic perturbation was visualized by immunofluorescence staining and confocal microscopy. Cell cycle profiles were assessed by flow cytometry. Apoptosis was estimated by analysis of sub-G1 fraction, Annexin V expression and immunoblotting of apoptotic proteins. Results: LGI147 induced a dose-dependent growth inhibition with IC50s ranging from 43.47 pM to 53.59 pM in the tested HCC cell lines. LGI147 treatment for 24 hours led to inhibition of Eg5 activity and induction of abnormal mitosis in a dose-dependent manner. Polypolar spindle defects in mitosis, disturbed cell cycle progression, and induction of apoptosis were observed in the HCC cells treated with LGI147. Conclusions: These findings show that LGI147 has potent anticancer effects in human HCC. Inhibitors of mitotic kinesin Eg5 may deserve further exploration as molecular targeted agents against HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1781. doi:1538-7445.AM2012-1781