Aurora kinases as novel drug targets in gastroenteropancreatic neuroendocrine tumor disease: Antiproliferative and pro-apoptotic effects of ZM 447439, a new aurora kinase inhibitor, in BON and QGP-1 cells

Abstract

22023 Background: The serine/threonine protein kinases aurora A and B, key regulators of mitosis, are emerging as novel drug targets for cancer treatment. Aurora B overexpression has been previously documented by immunohistochemistry in several types of human tumors. In gastroenteropancreatic neuroendocrine tumors (GEP-NETs) the therapeutic possibilities are still not satisfactory. Therefore, we assessed aurora B expression in a series of well-differentiated GEP-NETs and studied the effects of a novel aurora kinase A and B inhibitor (ZM 447439) in our well-differentiated human GEP-NET cell lines BON and QGP-1. Materials and Methods: Tumor specimens from 102 patients (40 foregut, 55 midgut, 7 hindgut) were studied immunohistochemically for aurora kinase expression. The cell lines BON and QGP-1 were treated with increasing concentrations of ZM 447439 (Tocris) with or without coincubation with Streptozocin, Doxorubicin, Octreotide and SOM-230. Growth inhibition was measured with crystal violet assays, apoptosis induction with caspase 3/7 activation and DNA fragmentation. Cell cycle analysis was evaluated by performing FACS analysis. Results: The immunohistochemical analysis of aurora B in our patient collective demonstrated an overexpression in a significant portion of tumors, compared with normal epithelium. Moreover, we demonstrate that ZM 447439 inhibited dose-dependently proliferation of BON and QGP-1 cells. Treatment with ZM 447439 induced apoptosis and dose-dependently led to a cell cycle arrest. In addition, combined treatment with the somatostatin analogues Octreotide and SOM-230 in BON cells and with Streptozocin and Doxorubicin in QGP-1 cells, ZM 447439 augmented significantly the antiproliferative effects of Octreotide, Streptozocin and Doxorubicin, but not in combination with SOM-230. Conclusion: Our results suggest that aurora B may represent a valid target in well differentiated GEP- NETs, since aurora B is overexpressed in these tumors, and aurora kinase inhibition by ZM 447439 seems to be a promising new therapeutic approach, which should be evaluated in further clinical trials. No significant financial relationships to disclose.