title: ZD4054, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma cell proliferation.
abstract: Endothelin-1 (ET-1) is present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumors, the presence of ET-1 correlates with tumor grade, enhanced neovascularization, and with vascular endothelial growth factor (VEGF) expression. ET-1 acts as an autocrine factor selectively through ET(A) receptor (ET(A)R), predominantly expressed in ovarian carcinoma cells resulting in increased VEGF production and VEGF-mediated angiogenic effects. Previous results demonstrated that in ovarian carcinoma cells, activation of the ET-1/ET(A)R axis promotes cell proliferation, neovascularization, and invasion, which are the principal hallmarks of tumor progression. The present study was designed to investigate the in vitro effects of trans, trans-2(4-methoxydhenyl)-4-(1-3-benzodiazol-5-yl)-1-(dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid (ZD4054), an orally active specific ET(A)R antagonist, on the ET-1-induced mitogenic effect in OVCA 433 and HEY ovarian carcinoma cell lines secreting ET-1 and expressing ET(A)R and ET(B)R mRNA. We show that ET(A)R blockade by ZD4054 inhibits ET-1-induced mitogenic effects, while the ET(B)R antagonist, BQ 788, is ineffective. In conclusion, our data demonstrate that ZD4054 is capable in inhibiting the proliferative activity of ET-1, indicating that this specific ET(A)R antagonist may be a potential candidate in developing novel treatment of ovarian carcinoma.
authors.affiliation: Molecular Pathology Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.forename: Valeriana
authors.initials: V
authors.lastname: Di Castro
authors.forename: Francesca
authors.initials: F
authors.lastname: Spinella
authors.forename: Samantha
authors.initials: S
authors.lastname: Decandia
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; C511404:ZD4054