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

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.

• Authors: 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 Ochs, Antje Mueller, Samir Attoub, Maria J Fernandez-Cabezudo, Gabriela Riemekasten, Basel K Al-Ramadi, Otavio Cabral-Marques
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 15931 (09 28 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32985601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Endothelin A Receptor Antagonists
• Phenylpropionates
• Pyridazines
• ambrisentan

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Apoptosis
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Endothelin A Receptor Antagonists (pharmacology)
• Female
• Humans
• Liver Neoplasms (drug therapy, metabolism, secondary)
• Lung Neoplasms (drug therapy, metabolism, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Phenylpropionates (pharmacology)
• Pyridazines (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays