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, Gabriele Marschner, Silke Pitann, Hans D. Ochs, Antje Mueller, Samir Attoub, Maria J. Fernández-Cabezudo, Gabriela Riemekasten, Basel K. al-Ramadi, Otávio Cabral-Marques
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.