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

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.