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ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole

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Abstract

Endothelin-1 (ET-1) and endothelin A receptor (ETAR) contribute to the development and progression of breast carcinomas by modulating cell proliferation, angiogenesis, and anti-apoptosis. We investigated antitumoral effects of the specific ETAR antagonist ZD4054 in breast cancer cells and xenografts, and assessed antitumoral efficacy of the combinations of ZD4054 with aromatase inhibitors and fulvestrant. Gene expression changes were assessed by quantitative real-time PCR. Cell proliferation was measured using alamarBlue®; migration and invasion assays were performed using modified Boyden chambers. Evaluating the antitumoral efficacy of ZD4054 in vivo, different breast cancer models were employed using nude mice xenografts. ZD4054 reduced ET-1 and ETAR expression in MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cells in a concentration-dependent manner. ZD4054 inhibited invasion by up to 37.1% (P = 0.022). Combinations of ZD4054 with either anastrozole or letrozole produced significant reductions in migration of aromatase-overexpressing MCF-7aro cells (P < 0.05). Combination of ZD4054 with fulvestrant reduced MCF-7 cell migration and invasion by 36.0% (P = 0.027) and 56.7% (P < 0.001), respectively, with effects significantly exceeding those seen with either compound alone. Regarding tumor volume reduction in vivo, ZD4054 (10 mg/kg) was equipotent to fulvestrant (200 mg/kg) and exhibited additive effects with anastrozole (0.5 mg/kg). These data are the first indicating that selective ETAR antagonism by ZD4054 displays antitumoral activity on breast cancer cells in vitro and in vivo. Our data strongly support a rationale for the clinical use of ZD4054 in combination with endocrine therapies.

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Acknowledgments

We thank Barbara Kloke and Birgit Pers for their excellent technical assistance. Funding was provided by Münster University Hospital “Innovative Medizinische Forschung” IMF grants WÜ 120332 and WÜ 110527.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48129, Munster, Germany

    Martin Smollich, Martin Götte, Jeanett Fischgräbe, Isabel Radke, Ludwig Kiesel & Pia Wülfing

  2. Department of Pharmacology and Experimental Therapeutics, University of Maryland, Baltimore, MD, USA

    Luciana F. Macedo & Angela Brodie

  3. Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, 91010, CA, USA

    Shiuan Chen

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  1. Martin Smollich
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  2. Martin Götte
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Correspondence to Pia Wülfing.

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Smollich, M., Götte, M., Fischgräbe, J. et al. ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole. Breast Cancer Res Treat 123, 345–357 (2010). https://doi.org/10.1007/s10549-009-0644-2

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