ABT-627, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma growth in vitro

Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumours the presence of ET-1 is associated with enhanced neovascularization and with vascular endothelial growth factor (VEGF) expression. In these tumour cells, ET-1 acts as an autocrine growth factor selectively through the receptor ET_A, which is predominantly expressed in tumour cells. Furthermore, ET-1 produced by ovarian tumour cells stimulates VEGF production and VEGF-mediated angiogenic effects through ET_A binding. These results demonstrate that activation of the ET_A in ovarian carcinoma cells promotes cell proliferation, neovascularization and invasion, which are the principal hallmarks of malignant transformation. The present study was designed to investigate the effects of the ET_A-selective antagonist ABT-627 on the ET-1-induced mitogenic effect in both primary cultures (PMOV1 and PMOV2) and cell lines (OVCA 433 and HEY) of ovarian carcinoma. All tumour cells express the components of the ET-1 system and secrete ET-1. ET_A blockade by ABT-627 inhibits ET-1-induced mitogenic effects. The ET_B antagonist BQ-788 is ineffective although all cell lines express both ET_A and ET_B mRNAs. In conclusion, our results demonstrate that ABT-627 is capable of inhibiting the proliferative activity of ET-1, suggesting that this potent ET_A antagonist may provide a novel approach to the multidisciplinary treatment of ovarian carcinoma.