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Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors
BACKGROUND AND PURPOSE: For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR,...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128068/ https://www.ncbi.nlm.nih.gov/pubmed/24758416 http://dx.doi.org/10.1111/bph.12726 |
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author | Melis, N Tauc, M Cougnon, M Bendahhou, S Giuliano, S Rubera, I Duranton, C |
author_facet | Melis, N Tauc, M Cougnon, M Bendahhou, S Giuliano, S Rubera, I Duranton, C |
author_sort | Melis, N |
collection | PubMed |
description | BACKGROUND AND PURPOSE: For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR, CFTR(inh)-172 and GlyH-101, were described and are now widely used to inhibit specifically CFTR. However, despite some evidence, the effects of both drugs on other types of Cl(−)-conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in CFTR-expressing and non–CFTR-expressing cells. EXPERIMENTAL APPROACH: Using patch-clamp technique, we tested the effects of CFTR(inh)-172 and GlyH-101 inhibitors on three distinct types of Cl(−) currents: the CFTR-like conductance, the volume-sensitive outwardly rectifying Cl(−) conductance (VSORC) and finally the Ca(2+)-dependent Cl(−) conductance (CaCC). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines. KEY RESULTS: We confirmed that these two compounds were potent inhibitors of the CFTR-mediated Cl(−) conductance. However,GlyH-101 also inhibited the VSORC conductance and the CaCC at concentrations used to inhibit CFTR. The CFTR(inh)-172 did not affect the CaCC but did inhibit the VSORC, at concentrations higher than 5 µM. Neither inhibitor (20 µM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations. CONCLUSIONS AND IMPLICATIONS: Both inhibitors affected Cl(−) conductances apart from CFTR. Our results provided insights into their use in mouse models. |
format | Online Article Text |
id | pubmed-4128068 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-41280682014-12-31 Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors Melis, N Tauc, M Cougnon, M Bendahhou, S Giuliano, S Rubera, I Duranton, C Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR, CFTR(inh)-172 and GlyH-101, were described and are now widely used to inhibit specifically CFTR. However, despite some evidence, the effects of both drugs on other types of Cl(−)-conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in CFTR-expressing and non–CFTR-expressing cells. EXPERIMENTAL APPROACH: Using patch-clamp technique, we tested the effects of CFTR(inh)-172 and GlyH-101 inhibitors on three distinct types of Cl(−) currents: the CFTR-like conductance, the volume-sensitive outwardly rectifying Cl(−) conductance (VSORC) and finally the Ca(2+)-dependent Cl(−) conductance (CaCC). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines. KEY RESULTS: We confirmed that these two compounds were potent inhibitors of the CFTR-mediated Cl(−) conductance. However,GlyH-101 also inhibited the VSORC conductance and the CaCC at concentrations used to inhibit CFTR. The CFTR(inh)-172 did not affect the CaCC but did inhibit the VSORC, at concentrations higher than 5 µM. Neither inhibitor (20 µM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations. CONCLUSIONS AND IMPLICATIONS: Both inhibitors affected Cl(−) conductances apart from CFTR. Our results provided insights into their use in mouse models. Blackwell Publishing Ltd 2014-08 2014-07-17 /pmc/articles/PMC4128068/ /pubmed/24758416 http://dx.doi.org/10.1111/bph.12726 Text en © 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Research Papers Melis, N Tauc, M Cougnon, M Bendahhou, S Giuliano, S Rubera, I Duranton, C Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title | Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title_full | Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title_fullStr | Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title_full_unstemmed | Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title_short | Revisiting CFTR inhibition: a comparative study of CFTR(inh)-172 and GlyH-101 inhibitors |
title_sort | revisiting cftr inhibition: a comparative study of cftr(inh)-172 and glyh-101 inhibitors |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128068/ https://www.ncbi.nlm.nih.gov/pubmed/24758416 http://dx.doi.org/10.1111/bph.12726 |
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