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

• Published in: Scientific reports 2020-09, Vol.10 (1), p.15931-15931, Article 15931
• Main Authors: Kappes, Lucy, Amer, Ruba L., Sommerlatte, Sabine, Bashir, Ghada, Plattfaut, Corinna, Gieseler, Frank, Gemoll, Timo, Busch, Hauke, Altahrawi, Abeer, Al-Sbiei, Ashraf, Haneefa, Shoja M., Arafat, Kholoud, Schimke, Lena F., Khawanky, Nadia El, Schulze-Forster, Kai, Heidecke, Harald, Kerstein-Staehle, Anja, Marschner, Gabriele, Pitann, Silke, Ochs, Hans D., Mueller, Antje, Attoub, Samir, Fernandez-Cabezudo, Maria J., Riemekasten, Gabriela, al-Ramadi, Basel K., Cabral-Marques, Otavio
• Format: Article
• Language: English
• Subjects: 631/67/1059/153; 692/4028/67/1059/602; Animals; Antihypertensive Agents - pharmacology; Apoptosis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Movement; Cell Proliferation; Endothelin A Receptor Antagonists - pharmacology; Female; Humanities and Social Sciences; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Neoplasm Invasiveness; Phenylpropionates - pharmacology; Pyridazines - pharmacology; Science; Science (multidisciplinary); Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-72960-1

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.