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

Laura Rosanò, Valeriana Di Castro, Francesca Spinella, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticlepeer-review

Abstract

The autocrine endothelin (ET)-1/endothelin A receptor (ETAR) 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 ETAR 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 ETAR, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ETAR- 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 ETAR-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.

Original languageEnglish
Pages (from-to)2003-2011
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 1 2007

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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