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

^*Korrespondierende/r Autor/-in für diese Arbeit

22 Zitate (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.

Originalsprache	Englisch
Aufsatznummer	15931
Zeitschrift	Scientific Reports
Jahrgang	10
Ausgabenummer	1
Seiten (von - bis)	15931
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-020-72960-1
Publikationsstatus	Veröffentlicht - 28.09.2020

Fördermittel

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).

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Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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10.1038/s41598-020-72960-1

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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. Artikel 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.",

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

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doi = "10.1038/s41598-020-72960-1",

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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, Jg. 10, Nr. 1, 15931, S. 15931. https://doi.org/10.1038/s41598-020-72960-1

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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

M3 - Journal articles

C2 - 32985601

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

Abstract

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