Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-020-72960-1
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [GRK1727, RI-1056-11]
- University Hospital of Schleswig-Holstein (Campus Lubeck)
- DFG [EXC 22167-390884018]
- Sao Paulo Research Foundation - FAPESP [2020/01688-0]
- Al Jalila Foundation (Dubai, United Arab Emirates) [AJF201709]
- Office of Graduate Studies, College of Medicine & Health Sciences, United Arab Emirates University (Al Ain, United Arab Emirates)
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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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