The Aurora kinase A inhibitor MLN8237 Enhances Cisplatin-induced Cell Death in Esophageal Adenocarcinoma Cells
Menée sur des lignées cellulaires d'adénocarcinome de l'œsophage et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé MLN8237, un inhibiteur de la protéine kinase Aurora-A, seul ou en combinaison avec du cisplatine
Esophageal adenocarcinomas (EACs) are poorly responsive to chemotherapeutics. This study aimed to determine the levels of Aurora kinas A (AURKA) and the therapeutic potential of MLN8237, an investigational AURKA inhibitor, alone and in combination with Cisplatin. Using quantitative real time polymerase chain reaction we detected frequent AURKA gene amplification (15/34, 44%) and mRNA overexpression (37/44, 84%) in EACs (p<0.01). Immunohistochemistry analysis demonstrated overexpression of AURKA in more than two-thirds of EACs tissue samples (92/132, 70%) (p<0.001). Using FLO-1, OE19 and OE33 EAC cell lines, with constitutive AURKA overexpression and mutant-p53, we observed inhibition of colony formation with a single treatment of 0.5µM MLN8237 (p<0.05). This effect was further enhanced in combination with 2.5µM Cisplatin (p<0.001). 24hrs after treatment with the MLN8237 or MLN8237 and Cisplatin, cell cycle analyses demonstrated a sharp increase in the percentage of polyploid cells (p<0.001). This was followed by an increase in the percentage of cells in the sub-G1-phase at 72hrs, concordant with the occurrence of cell death (p<0.001). Western blot analysis demonstrated higher induction of TAp73β, PUMA, NOXA, cleaved caspase 3 and cleaved PARP with the combined treatment, as compared to a single agent treatment. Using xenograft models, we demonstrated an enhanced anti-tumor role for the MLN8237 and Cisplatin combination, as compared to single agent treatments (p<0.001). In conclusion, this study demonstrates frequent overexpression of AURKA and suggests that MLN8237 could be an effective anti-tumor agent, which can be combined with CDDP for a better therapeutic outcome in EACs.
http://mct.aacrjournals.org/content/early/2012/02/01/1535-7163.MCT-11-0623.abstract