Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

Graeme W. Carlile; Renaud Robert; Julie Goepp; Elizabeth Matthes; Jie Liao; Bart Kus; Sean D. Macknight; Daniela Rotin; John W. Hanrahan; David Y. Thomas

doi:10.1016/j.jcf.2014.06.001

Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

Graeme W. Carlile^*, Renaud Robert, Julie Goepp, Elizabeth Matthes, Jie Liao, Bart Kus, Sean D. Macknight, Daniela Rotin, John W. Hanrahan, David Y. Thomas

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o^- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o^- monolayers increased the short-circuit current (I_sc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.

Original language	English (US)
Pages (from-to)	16-25
Number of pages	10
Journal	Journal of Cystic Fibrosis
Volume	14
Issue number	1
DOIs	https://doi.org/10.1016/j.jcf.2014.06.001
State	Published - Jan 1 2015

Keywords

Cystic fibrosis
NSAID
Protein folding
Protein trafficking

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Pulmonary and Respiratory Medicine

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10.1016/j.jcf.2014.06.001

Cite this

@article{c0221467b2c54bbcabdb6df63ff3a6bf,

title = "Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking",

abstract = "Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o- monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.",

keywords = "Cystic fibrosis, NSAID, Protein folding, Protein trafficking",

author = "Carlile, {Graeme W.} and Renaud Robert and Julie Goepp and Elizabeth Matthes and Jie Liao and Bart Kus and Macknight, {Sean D.} and Daniela Rotin and Hanrahan, {John W.} and Thomas, {David Y.}",

note = "Funding Information: We thank Bob Scholte, Hugo de Jonge and Martina Witt (Erasmus Univ., Rotterdam NL) for the Cftr tm1 Eur mice, JP Clancy (Cincinnati Children's Hospital Medical Center) for CFBE41o − cells, and Robert Bridges (Rosalind Franklin Univ. Chicago) for VRT-325. We also thank the Canadian Institutes of Health Research ( CIHR-CPG-95270 ) and the Canada Foundation for Innovation ( CFI-6 (21375)) . Publisher Copyright: {\textcopyright} 2014 European Cystic Fibrosis Society.",

year = "2015",

month = jan,

day = "1",

doi = "10.1016/j.jcf.2014.06.001",

language = "English (US)",

volume = "14",

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journal = "Journal of Cystic Fibrosis",

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TY - JOUR

T1 - Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

AU - Carlile, Graeme W.

AU - Robert, Renaud

AU - Goepp, Julie

AU - Matthes, Elizabeth

AU - Liao, Jie

AU - Kus, Bart

AU - Macknight, Sean D.

AU - Rotin, Daniela

AU - Hanrahan, John W.

AU - Thomas, David Y.

N1 - Funding Information: We thank Bob Scholte, Hugo de Jonge and Martina Witt (Erasmus Univ., Rotterdam NL) for the Cftr tm1 Eur mice, JP Clancy (Cincinnati Children's Hospital Medical Center) for CFBE41o − cells, and Robert Bridges (Rosalind Franklin Univ. Chicago) for VRT-325. We also thank the Canadian Institutes of Health Research ( CIHR-CPG-95270 ) and the Canada Foundation for Innovation ( CFI-6 (21375)) . Publisher Copyright: © 2014 European Cystic Fibrosis Society.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o- monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.

AB - Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o- monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.

KW - Cystic fibrosis

KW - NSAID

KW - Protein folding

KW - Protein trafficking

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JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

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ER -

Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

Abstract

Keywords

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