ORIGINAL ARTICLE In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma Alexander Dewerth • Timo Wonner • Justus Lieber • Verena Ellerkamp • Steven W. Warmann • Jo ¨rg Fuchs • Sorin Armeanu-Ebinger Accepted: 26 March 2012 / Published online: 18 April 2012 Ó Springer-Verlag 2012 Abstract Purpose Hepatoblastoma (HB) has a poor prognosis in advanced stages. The aim of this study was to enhance effec- tiveness of chemotherapy with antineoplastic kinase inhibitors. Methods Viability was monitored in HB cells (HUH6, HepT1) in monolayer and spheroid cultures treated with kinase inhibitors VX-680, Wee1-InhibitorII, and SU11274 alone or in combination with cisplatin (CDDP) using MTT assays. Apoptosis was revealed by Caspase-3 assay. Western blot and immunohistochemical analyses were performed to determine histone H3 phosphorylation. Results Among the kinase inhibitors strongest anti-pro- liferative effect on HB cells was documented for VX-680. HUH6 cells responded more sensitively to the Aurora kinase inhibitor as HepT1 cells (IC 50 8 and 16.6 lM, respectively). While VX-680 and CDDP showed no addi- tive effects, the combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. The inhibition with VX-680 led to reduced histone H3 phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei. Conclusion The data provide evidence that VX-680 might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis. Keywords Kinase Á Aurora Kinase A Á Wee kinase Á Met Á Histone deacetylation Á Hepatoblastoma Á Multidrug resistance Introduction Hepatoblastoma (HB), accounting for 1 % of all infantile cancer diagnoses, is the most common malignant liver tumor in childhood [1, 2]. Although there have been great achievements in treating patients with standard risk HB in the past decades, treatment results for those with high-risk HB still remain poor [3]. In the latter case a developing multidrug resistance during multiple chemotherapy cycles often appears to be the major challenge [4, 5]. One option to overcome this problem is the recently, widely discussed and explored molecular targeted therapy. Recent advances have been made in identifying molecules which are crucial for the malignant phenotype [6]. Substances targeting those specific molecules are, e.g. small molecule kinase inhibitors such as the Aurora kinase inhibitor VX-680. Aurora kinases A, B, and C are serine/threonine kinases which are essen- tial for cell proliferation and which play a key role dur- ing mitosis. They are overexpressed in several tumors suggesting an important role in tumorigenicity [7–9]. While A. Dewerth Á T. Wonner Á J. Lieber Á V. Ellerkamp Á S. W. Warmann Á J. Fuchs Á S. Armeanu-Ebinger (&) Department of Pediatric Surgery and Pediatric Urology, University Children’s Hospital, Hoppe-Seyler-Strasse 3, 72076 Tu ¨bingen, Germany e-mail: sorin.armeanu-ebinger@med.uni-tuebingen.de A. Dewerth e-mail: alexander.dewerth@med.uni-tuebingen.de T. Wonner e-mail: timo.wonner@student.uni-tuebingen.de J. Lieber e-mail: justus.lieber@med.uni-tuebingen.de V. Ellerkamp e-mail: verena.ellerkamp@med.uni-tuebingen.de S. W. Warmann e-mail: steven.warmann@med.uni-tuebingen.de J. Fuchs e-mail: joerg.fuchs@med.uni-tuebingen.de 123 Pediatr Surg Int (2012) 28:579–589 DOI 10.1007/s00383-012-3086-6