Aurora kinase inhibitor VX-680 enhances sensitivity of esophageal squamous cell carcinoma cells to cisplatin chemotherapy.

Abstract

Esophageal squamous cell carcinoma (ESCC) is malignant cancer with a high mortality rate. Cisplatin is one of the most potent chemotherapy agents used in the treatment of ESCC. However, chemoresistance and severe adverse effects of cisplatin become major obstacles to clinical utility. The combination treatment with molecule-targeted drugs and chemotherapy agents is a promising treatment strategy for cancer to improve antineoplastic responses. VX-680 is a potent inhibitor of Aurora kinases. This study was performed to investigate if VX-680 and cisplatin can synergistically inhibit the malignant behavior of ESCC cells. The results obtained from 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay and combination index analysis demonstrated that the combination of VX-680 and cisplatin synergistically enhanced cytotoxic effects in ESCC cells. 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride staining and western blot analysis suggested that VX-680 increased cisplatin-mediated cell apoptosis. Further analysis revealed that VX-680 combined with cisplatin could attenuate cell migration and angiogenesis confirmed by wound-healing assay and tube formation assay. Subsequently, VX-680 and cisplatin combined treatment significantly promoted cell-cell cohesion, and reduced cell-extracellular matrix interaction, as analyzed by the cell dissociation assay and cell-matrix attachment assay. In addition, the combination of VX-680 and cisplatin markedly decreased the expressions of matrix metalloproteinases-2 (MMP-2), vascular endothelial growth factor (VEGF), p-extracellular signal-regulated protein kinase and p-RAC-α serine/threonine-protein kinase compared to VX-680 or cisplatin only treatment. Altogether, these findings strongly suggest that the combination of VX-680 and cisplatin could exert a synergistic antitumor effect in ESCC cells and this combination might represent a promising therapeutic strategy against ESCC.