Department of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, Germany.
Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
Sci Rep. 2020 Sep 28;10(1):15931. doi: 10.1038/s41598-020-72960-1.
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.
几项研究报告称，内皮素 A 型受体 (ETAR) 在肿瘤进展中起着核心作用，导致转移的形成。在这里，我们研究了已获 FDA 批准的 ETAR 拮抗剂安贝生坦的体外和体内抗肿瘤作用，该药目前用于治疗肺动脉高压患者。在体外，安贝生坦抑制了不同肿瘤细胞（COLO-357 转移性胰腺腺癌、OvCar3 卵巢癌、MDA-MB-231 乳腺腺癌和 HL-60 早幼粒细胞白血病）自发和诱导的迁移/侵袭能力。使用 RNAseq 进行的全转录组分析表明，安贝生坦对静止和 PAR2 激活的 COLO-357 细胞的整个转录组具有抑制作用，这些作用往往趋于正常化至未受刺激的状态。最后，在转移性乳腺癌的临床前小鼠模型中，用安贝生坦治疗可有效减少转移到肺部和肝脏。重要的是，这与动物存活率的显著提高有关。总之，我们的工作表明安贝生坦在治疗癌症转移方面有新的治疗应用。
