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Research Articles

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

¹ Molecular Pathology and ² Immunology Laboratories, Regina Elena Cancer Institute, Via delle Messi d'Oro, ³ Molecular Biology and Pathology Institute, National Research Council, Rome, Italy

Requests for reprints: Anna Bagnato, Molecular Pathology Laboratory, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy. Phone: 39-6-52662565; Fax: 39-6-52662600. E-mail: bagnato{at}ifo.it

Abstract

The autocrine endothelin (ET)-1/endothelin A receptor (ET_AR) pathway is an important regulator of several processes involved in ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET_AR receptor as a potential target for improving ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of ZD4054, an orally active antagonist that specifically binds ET_AR, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ET_AR-positive cell lines HEY, OVCA 433, SKOV-3, and A-2780, ZD4054 effectively inhibited the basal and ET-1–induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. ZD4054 treatment also resulted in a reduction of ET_AR-driven angiogenesis and invasive mediators, such as vascular endothelial growth factor, cyclooxygenase-1/2, and matrix metalloproteinase (MMP). The combination of ZD4054 and paclitaxel led to the potentiation of all these effects, indicating that ZD4054, by blocking the ET_AR-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to paclitaxel. In HEY ovarian cancer xenografts, ZD4054 significantly inhibited tumor growth to the same degree as paclitaxel. Furthermore, ZD4054-dependent tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of ZD4054 and paclitaxel produced additive antitumor effects, with 40% of mice remaining tumor-free, supporting a rationale for the clinical use of ZD4054 as monotherapy or in combination with cytotoxic drugs. [Mol Cancer Ther 2007;6(7):2003–11]

Grant support: Associazione Italiana Ricerca Sul Cancro, Ministero della Salute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/ 5/07; revised 5/ 4/07; accepted 5/25/07.

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