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

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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. ; El Khawanky, Nadia ; 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

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1, p. 15-pg., 2020-09-28.

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. (AU)

• FAPESP's process: 20/01688-0 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections
• Grantee: Otávio Cabral Marques
• Support Opportunities: Scholarships in Brazil - Young Researchers