Radiotherapy is one of the treatment options for hepatocellular carcinoma (HCC), but the unsatisfactory results are mainly due to insufficient dose to the tumor from hepatic intolerance. As compared to advanced technology of radiotherapy, the experience in the combined use of the effective molecular target and radiotherapy remains limited. This study was aimed to assess the effect of combining a novel Aurora kinase inhibitor, VE465, with radiotherapy, by testing the in vitro and in vivo models of human HCC. Human HCC cell line Huh-7, was treated with combined irradiation and the low- toxic dose of VE465. A significant effect on enhancing the radiation induced cell death was found in clonogenic assay. VE-465 induced proliferation blockade, histone H3 (Ser10) dephosphorylation, mitotic disturbance, and apoptosis in Huh-7 cells. The in vivo efficacy of combining VE465 with radiotherapy was investigated in the ectopic xenograft subcutaneous tumor and orthotopic liver tumor models of severe combined immunodeficient mice. Pretreatment with daily i.p. administration of VE465 (20 mg/kg) significantly enhanced the therapeutic effect of radiotherapy (5 Gy per day for 5 days) on Huh-7 derived ectopic xenograft tumor model by 54%. This differential tumor suppression correlated with the modulation of intratumoral biomarker stainings associated with histone 3 phosphorylation inhibition and apoptosis regulation. Furthermore, VE465 improved intrahepatic tumor control and survival of radiotherapy (4 Gy per day for 5 days) treated Huh-7 derived orthotopic liver tumor model by 17.2%, reduction in tumor size. The synergistic effect of combining VE465 with radiotherapy in HCC was associated with histone3 phosphorylation inhibition and cell cycle regulation. We conclude that VE465 is a potent inhibitor of Aurora kinase with clinical value in therapeutic strategies for radiotherapy to HCC.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A37.