Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

Lucy Kappes; Ruba L. Amer; Sabine Sommerlatte; Ghada Bashir; Corinna Plattfaut; Frank Gieseler; Timo Gemoll; Hauke Busch; Abeer Altahrawi; Ashraf Al-Sbiei; Shoja M. Haneefa; Kholoud Arafat; Lena F. Schimke; Nadia El Khawanky; Kai Schulze-Forster; Harald Heidecke; Anja Kerstein-Staehle; Gabriele Marschner; Silke Pitann; Hans D. Ochs; Antje Mueller; Samir Attoub; Maria J. Fernandez-Cabezudo; Gabriela Riemekasten; Basel K. al-Ramadi; Otavio Cabral-Marques

doi:10.1038/s41598-020-72960-1

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

Lucy Kappes, Ruba L. Amer, Sabine Sommerlatte, Ghada Bashir, Corinna Plattfaut, Frank Gieseler, Timo Gemoll, Hauke Busch, Abeer Altahrawi, Ashraf Al-Sbiei, Shoja M. Haneefa, Kholoud Arafat, Lena F. Schimke, Nadia El Khawanky, Kai Schulze-Forster, Harald Heidecke, Anja Kerstein-Staehle, Gabriele Marschner, Silke Pitann, Hans D. OchsAntje Mueller, Samir Attoub, Maria J. Fernandez-Cabezudo, Gabriela Riemekasten, Basel K. al-Ramadi^*, Otavio Cabral-Marques

^*Corresponding author for this work

22 Citations (Scopus)

Abstract

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan’s inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

Original language	English
Article number	15931
Journal	Scientific Reports
Volume	10
Issue number	1
Pages (from-to)	15931
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-020-72960-1
Publication status	Published - 28.09.2020

Funding

The authors thank all healthy donors for their participation in this study. We acknowledge Deutsche Forschun-gsgemeinschaft (DFG, German Research Foundation) (GRK1727 program and DFG Grant RI-1056-11) and the University Hospital of Schleswig-Holstein (Campus Lübeck) for financial support and computational support by the “OmicsCluster” high performance computer infrastructure of the University of Lübeck. HB and GR acknowledge funding by the DFG under Germany’s Excellence Strategy – EXC 22167-390884018“. We acknowledge the São Paulo Research Foundation – FAPESP (Grant 2020/01688-0 to OCM) for financial support. The animal studies were supported by a grant from Al Jalila Foundation (Project #AJF201709; Dubai, United Arab Emirates) to BKa-R. RLA is supported by a student scholarship from the Office of Graduate Studies, College of Medicine & Health Sciences, United Arab Emirates University (Al Ain, United Arab Emirates).

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kappes, L., Amer, R. L., Sommerlatte, S., Bashir, G., Plattfaut, C., Gieseler, F., Gemoll, T., Busch, H., Altahrawi, A., Al-Sbiei, A., Haneefa, S. M., Arafat, K., Schimke, L. F., Khawanky, N. E., Schulze-Forster, K., Heidecke, H., Kerstein-Staehle, A., Marschner, G., Pitann, S., ... Cabral-Marques, O. (2020). Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis. Scientific Reports, 10(1), 15931. Article 15931. https://doi.org/10.1038/s41598-020-72960-1

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title = "Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis",

abstract = "Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan{\textquoteright}s inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.",

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Kappes, L, Amer, RL, Sommerlatte, S, Bashir, G, Plattfaut, C, Gieseler, F , Gemoll, T , Busch, H, Altahrawi, A, Al-Sbiei, A, Haneefa, SM, Arafat, K, Schimke, LF, Khawanky, NE, Schulze-Forster, K, Heidecke, H, Kerstein-Staehle, A, Marschner, G, Pitann, S, Ochs, HD, Mueller, A, Attoub, S, Fernandez-Cabezudo, MJ, Riemekasten, G, al-Ramadi, BK & Cabral-Marques, O 2020, 'Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis', Scientific Reports, vol. 10, no. 1, 15931, pp. 15931. https://doi.org/10.1038/s41598-020-72960-1

TY - JOUR

T1 - Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

AU - Kappes, Lucy

AU - Amer, Ruba L.

AU - Sommerlatte, Sabine

AU - Bashir, Ghada

AU - Plattfaut, Corinna

AU - Gieseler, Frank

AU - Gemoll, Timo

AU - Busch, Hauke

AU - Altahrawi, Abeer

AU - Al-Sbiei, Ashraf

AU - Haneefa, Shoja M.

AU - Arafat, Kholoud

AU - Schimke, Lena F.

AU - Khawanky, Nadia El

AU - Schulze-Forster, Kai

AU - Heidecke, Harald

AU - Kerstein-Staehle, Anja

AU - Marschner, Gabriele

AU - Pitann, Silke

AU - Ochs, Hans D.

AU - Mueller, Antje

AU - Attoub, Samir

AU - Fernandez-Cabezudo, Maria J.

AU - Riemekasten, Gabriela

AU - al-Ramadi, Basel K.

AU - Cabral-Marques, Otavio

PY - 2020/9/28

Y1 - 2020/9/28

N2 - Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan’s inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

AB - Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan’s inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

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DO - 10.1038/s41598-020-72960-1

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SN - 2045-2322

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Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

Abstract

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