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

Research output: Contribution to journalArticlepeer-review

5 Citations (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.

Original languageEnglish
Article number15931
JournalScientific reports
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • General

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