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: Laura Rosanò, Valeriana Di Castro, Francesca Spinella, Samantha Decandia, Pier Giorgio Natali, Anna Bagnato
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 231 Issue 6 Pg. 1132-5 (Jun 2006) ISSN: 1535-3702 [Print] England
• PMID: 16741063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin-1
• Pyrrolidines
• RNA, Messenger
• ZD4054

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endothelin A Receptor Antagonists
• Endothelin-1 (pharmacology, physiology)
• Female
• Humans
• Ovarian Neoplasms (drug therapy, metabolism)
• Pyrrolidines (chemistry, pharmacology, therapeutic use)
• RNA, Messenger (metabolism)