TY - JOUR
T1 - Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis
AU - Kappes, Lucy
AU - Amer, Ruba L.
AU - Sommerlatte, Sabine
AU - Bashir, Ghada
AU - Plattfaut, Corinna
AU - Gieseler, Frank
AU - Gemoll, Timo
AU - Busch, Hauke
AU - Altahrawi, Abeer
AU - Al-Sbiei, Ashraf
AU - Haneefa, Shoja M.
AU - Arafat, Kholoud
AU - Schimke, Lena F.
AU - Khawanky, Nadia El
AU - Schulze-Forster, Kai
AU - Heidecke, Harald
AU - Kerstein-Staehle, Anja
AU - Marschner, Gabriele
AU - Pitann, Silke
AU - Ochs, Hans D.
AU - Mueller, Antje
AU - Attoub, Samir
AU - Fernandez-Cabezudo, Maria J.
AU - Riemekasten, Gabriela
AU - al-Ramadi, Basel K.
AU - Cabral-Marques, Otavio
PY - 2020/9/28
Y1 - 2020/9/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091679144&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-72960-1
DO - 10.1038/s41598-020-72960-1
M3 - Journal articles
C2 - 32985601
AN - SCOPUS:85091679144
SN - 2045-2322
VL - 10
SP - 15931
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15931
ER -
