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.
Highlights
Endothelin-1 (ET-1) is a small vasoactive peptide overexpressed in plasma and tissue samples from patients with various solid cancers [1]
ET-1 effects are mediated by two distinct G protein-coupled receptors (GPCR), endothelin A receptor (ETAR) and endothelin B receptor (ETBR)
We demonstrate for the first time that Salvianolic acid A (Sal A) is a selective ETAR antagonist in both exogenous and endogenous cell lines and reveal the inhibitory effect of Sal A on the proliferation of multiple tumor cell lines
Summary
Endothelin-1 (ET-1) is a small vasoactive peptide overexpressed in plasma and tissue samples from patients with various solid cancers [1]. ET-1 effects are mediated by two distinct G protein-coupled receptors (GPCR), endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Endothelin receptors in cancer cells can be activated through either autocrine production of ligand or production of ligand from stromal cells that may be expressed physiologically, or in response to cancer cells in a paracrine loop [2,3]. ET-1 production has been detected in a number of human cancer cell lines, from such colorectal, stomach, breast, and prostate [4]. 2016, 17, 1244 to ovarian and prostate cancer cells stimulates proliferation [5,6] Sci. 2016, 17, 1244 to ovarian and prostate cancer cells stimulates proliferation [5,6]
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