title: Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro.
abstract: Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR.
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. zhangqiao@bucm.edu.cn.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. wangshifeng@bucm.edu.cn.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. louisyang@bucm.edu.cn.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Pharmacogenetics, HD Biosciences, Co., Ltd., 590 Ruiqing Road, Zhangjiang Hi-Tech Park East Campus, Pudong New Area, Shanghai 201201, China. pkssn12@gmail.com.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Sun
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. Zhangyuxinwjzy@163.com.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. collean_zhang@163.com.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Technical Department, ACEA Biosciences Inc., No. 5 Sandunxiyuan Road, Hangzhou 310030, China. paddy.yang@aceabio.com.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing 100101, China. lishiyou@big.ac.cn.
authors.forename: Shiyou
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjingzhonghuan South Road, Chaoyang District, Beijing 100102, China. yjqiao@263.net.
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Qiao
mesh_terms: D002109:Caffeic Acids / Q000494:pharmacology*; D054715:Cardiotoxins / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007773:Lactates / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D009369:Neoplasms / Q000473:pathology*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D002109:Caffeic Acids; D054715:Cardiotoxins; D065130:Endothelin A Receptor Antagonists; D007773:Lactates; D044022:Receptor, Endothelin A; C066201:salvianolic acid A
keywords: Salvianolic acid A; antagonist; anticancer; cardiotoxicity; endothelin A receptor