Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

被引：42

作者：

Carlile, Graeme W. ^{[1
]}

Robert, Renaud ^{[2
]}

Goepp, Julie ^{[2
]}

Matthes, Elizabeth ^{[2
]}

Liao, Jie ^{[2
]}

Kus, Bart ^{[3
]}

Macknight, Sean D. ^{[1
]}

Rotin, Daniela ^{[3
]}

Hanrahan, John W. ^{[2
]}

Thomas, David Y. ^{[1
]}

机构：

[1] McGill Univ, Dept Biochem, Cyst Fibrosis Translat Res Ctr, Montreal, PQ H3G 1Y6, Canada

[2] McGill Univ, Dept Physiol, Cyst Fibrosis Translat Res Ctr, Montreal, PQ H3G 1Y6, Canada

[3] Univ Toronto, Dept Biochem, Hosp Sick Children, Toronto, ON M5G 1X8, Canada

来源：

JOURNAL OF CYSTIC FIBROSIS | 2015年 / 14卷 / 01期

基金：

加拿大创新基金会; 加拿大健康研究院;

关键词：

Cystic fibrosis; NSAID; Protein folding; Protein trafficking; F508DEL-CFTR TRAFFICKING; IN-VITRO; CFTR; INHIBITION; PROTEASOME; COMPOUND; CHILDREN; CORRECT; DEFECT; GENE;

D O I：

10.1016/j.jcf.2014.06.001

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

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 (1) 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. (C) 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

引用

页码：16 / 25

页数：10

共 30 条

[1] Lower airway inflammation in infants and young children with cystic fibrosis [J].

Armstrong, DS ;

Grimwood, K ;

Carlin, JB ;

Carzino, R ;

Gutierrez, JP ;

Hull, J ;

Olinsky, A ;

Phelan, EM ;

Robertson, CF ;

Phelan, PD .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 156 (04) :1197-1204

[2] Failure of cAMP agonists to activate rescued ΔF508 CFTR in CFBE41o- airway epithelial monolayers [J].

Bebok, Z ;

Collawn, JF ;

Wakefield, J ;

Parker, W ;

Li, Y ;

Varga, K ;

Sorscher, EJ ;

Clancy, JP .

JOURNAL OF PHYSIOLOGY-LONDON, 2005, 569 (02) :601-615

[3] Correctors of protein trafficking defects identified by a novel high-throughput screening assay [J].

Carlile, Graeme W. ;

Robert, Renaud ;

Zhang, Donglei ;

Teske, Katrina A. ;

Luo, Yishan ;

Hanrahan, John W. ;

Thomas, David Y. .

CHEMBIOCHEM, 2007, 8 (09) :1012-1020

[4] Correction of F508del-CFTR Trafficking by the Sponge Alkaloid Latonduine Is Modulated by Interaction with PARP [J].

Carlile, Graeme W. ;

Keyzers, Robert A. ;

Teske, Katrina A. ;

Robert, Renaud ;

Williams, David E. ;

Linington, Roger G. ;

Gray, Christopher A. ;

Centko, Ryan M. ;

Yan, Luping ;

Anjos, Suzana M. ;

Sampson, Heidi M. ;

Zhang, Donglei ;

Liao, Jie ;

Hanrahan, John W. ;

Andersen, Raymond J. ;

Thomas, David Y. .

CHEMISTRY & BIOLOGY, 2012, 19 (10) :1288-1299

[5] Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation [J].

Clancy, J. P. ;

Rowe, Steven M. ;

Accurso, Frank J. ;

Aitken, Moira L. ;

Amin, Raouf S. ;

Ashlock, Melissa A. ;

Ballmann, Manfred ;

Boyle, Michael P. ;

Bronsveld, Inez ;

Campbell, Preston W. ;

De Boeck, Kris ;

Donaldson, Scott H. ;

Dorkin, Henry L. ;

Dunitz, Jordan M. ;

Durie, Peter R. ;

Jain, Manu ;

Leonard, Anissa ;

Mccoy, Karen S. ;

Moss, Richard B. ;

Pilewski, Joseph M. ;

Rosenbluth, Daniel B. ;

Rubenstein, Ronald C. ;

Schechter, Michael S. ;

Botfield, Martyn ;

Ordonez, Claudia L. ;

Spencer-Green, George T. ;

Vernillet, Laurent ;

Wisseh, Steve ;

Yen, Karl ;

Konstan, Michael W. .

THORAX, 2012, 67 (01) :12-18

[6] Prostaglandin-endoperoxide synthase genes COX1 and COX2 - novel modifiers of disease severity in cystic fibrosis patients [J].

Czerska, K. ;

Sobczynska-Tomaszewska, A. ;

Sands, D. ;

Nowakowska, A. ;

Bak, D. ;

Wertheim, K. ;

Poznanski, J. ;

Zielenski, J. ;

Norek, A. ;

Bal, J. .

JOURNAL OF APPLIED GENETICS, 2010, 51 (03) :323-330

[7] Ibuprofen Modulates NF-κB Activity but Not IL-8 Production in Cystic Fibrosis Respiratory Epithelial Cells [J].

Dauletbaev, Nurlan ;

Lam, Joyce ;

Eklove, Daniel ;

Iskandar, Michele ;

Lands, Larry C. .

RESPIRATION, 2010, 79 (03) :234-242

[8] PROCESSING OF MUTANT CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR IS TEMPERATURE-SENSITIVE [J].

DENNING, GM ;

ANDERSON, MP ;

AMARA, JF ;

MARSHALL, J ;

SMITH, AE ;

WELSH, MJ .

NATURE, 1992, 358 (6389) :761-764

[9] Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated Cl- secretion [J].

Devor, DC ;

Schultz, BD .

JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (04) :679-687

[10] Gene transfer of CFTR to airway epithelia:: low levels of expression are sufficient to correct Cl- transport and overexpression can generate basolateral CFTR [J].

Farmen, SL ;

Karp, PH ;

Ng, P ;

Palmer, DJ ;

Koehler, DR ;

Hu, J ;

Beaudet, AL ;

Zabner, J ;

Welsh, MJ .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2005, 289 (06) :L1123-L1130

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