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
N1 - Funding Information:
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).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
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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U2 - 10.1038/s41598-020-72960-1
DO - 10.1038/s41598-020-72960-1
M3 - Article
C2 - 32985601
AN - SCOPUS:85091679144
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 15931
ER -