Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3

  • PLoS One. 2018 Sep 24;13(9):e0204041. doi: 10.1371/journal.pone.0204041.
Xianlong Gao  1 ,  Hazem Abdelkarim  2 ,  Lauren J Albee  3 ,  Brian F Volkman  4 ,  Vadim Gaponenko  2 ,  Matthias Majetschak  1
Affiliations
  • 1. Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
  • 2. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
  • 3. Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States of America.
  • 4. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
PMID: 30248140 DOI: 10.1371/journal.pone.0204041
Abstract

We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 and atypical Chemokine Receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple α1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in β-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both α1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin-4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely Other α1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of α1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as Cancer metastases or various autoimmune pathologies.

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