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CANCER

ZD4054, a Potent Endothelin Receptor A Antagonist, Inhibits Ovarian Carcinoma Cell Proliferation

Laura Rosanò^*, Valeriana Di Castro^*, Francesca Spinella^*, Samantha Decandia^*, Pier Giorgio Natali and Anna Bagnato^*,1

^* Molecular Pathology and Ultrastructure Laboratory, and Immunology Laboratory, Regina Elena Cancer Institute, Rome, Italy

To whom requests for reprints should be addressed at ¹ Molecular Pathology Laboratory, Regina Elena Cancer Institute, Via delle Messi d’Oro 156, 00158 Rome, Italy. E-mail: bagnato{at}ifo.it

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_AR), 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_AR 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_AR antagonist, on the ET-1–induced mitogenic effect in OVCA 433 and HEY ovarian carcinoma cell lines secreting ET-1 and expressing ET_AR and ET_BR mRNA. We show that ET_AR blockade by ZD4054 inhibits ET-1–induced mitogenic effects, while the ET_BR 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_AR antagonist may be a potential candidate in developing novel treatment of ovarian carcinoma.

Key Words: ovarian cancer • ET-1 • ET_A receptor • ZD 4054

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