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.
Laboratory of Molecular Pathology, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Debora
D
Salani
Laura
L
Rosanò
Valeriana
V
Di Castro
Francesca
F
Spinella
Aldo
A
Venuti
Robert J
RJ
Padley
Maria Rita
MR
Nicotra
Pier Giorgio
PG
Natali
Anna
A
Bagnato
D000077868:Atrasentan; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D044022:Receptor, Endothelin A; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D000077868:Atrasentan