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Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3.
PLoS One. 2018; 13(9):e0204041.Plos

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.

Authors+Show Affiliations

Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, United States of America.Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30248140

Citation

Gao, Xianlong, et al. "Partial Agonist Activity of Α1-adrenergic Receptor Antagonists for Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3." PloS One, vol. 13, no. 9, 2018, pp. e0204041.
Gao X, Abdelkarim H, Albee LJ, et al. Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. PLoS ONE. 2018;13(9):e0204041.
Gao, X., Abdelkarim, H., Albee, L. J., Volkman, B. F., Gaponenko, V., & Majetschak, M. (2018). Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. PloS One, 13(9), e0204041. https://doi.org/10.1371/journal.pone.0204041
Gao X, et al. Partial Agonist Activity of Α1-adrenergic Receptor Antagonists for Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3. PLoS ONE. 2018;13(9):e0204041. PubMed PMID: 30248140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. AU - Gao,Xianlong, AU - Abdelkarim,Hazem, AU - Albee,Lauren J, AU - Volkman,Brian F, AU - Gaponenko,Vadim, AU - Majetschak,Matthias, Y1 - 2018/09/24/ PY - 2018/08/04/received PY - 2018/09/01/accepted PY - 2018/9/25/entrez PY - 2018/9/25/pubmed PY - 2019/3/7/medline SP - e0204041 EP - e0204041 JF - PloS one JO - PLoS ONE VL - 13 IS - 9 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/30248140/Partial_agonist_activity_of_α1-adrenergic_receptor_antagonists_for_chemokine_(C-X-C_motif)_receptor_4_and_atypical_chemokine_receptor_3 L2 - http://dx.plos.org/10.1371/journal.pone.0204041 DB - PRIME DP - Unbound Medicine ER -