CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds

Caci, Emanuela; Folli, Chiara; Zegarra‐Moran, Olga; Ma, Tonghui; Springsteel, Mark F.; Sammelson, Robert Erik; Nantz, Michael H.; Kurth, Mark J.; Verkman, A. S.; Galietta, Luis J. V.

doi:10.1152/ajplung.00351.2002

Cited by 58 publications

(58 citation statements)

References 26 publications

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“…Interestingly, the level of SCN Ϫ transport reached in the presence of the blocker was lower than that measured in resting conditions, before addition of forskolin. This may be explained by the fact that a fraction of CFTR is active in nonstimulated epithelia, as we have already reported in a previous study (33). The involvement of CFTR was further confirmed by carrying out similar experiments in CF epithelia (Fig.…”

Section: Resultssupporting

confidence: 86%

Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels

Pedemonte

Caci

Sondo

et al. 2007

The Journal of Immunology

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133

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SCN− (thiocyanate) is an important physiological anion involved in innate defense of mucosal surfaces. SCN− is oxidized by H2O2, a reaction catalyzed by lactoperoxidase, to produce OSCN− (hypothiocyanite), a molecule with antimicrobial activity. Given the importance of the availability of SCN− in the airway surface fluid, we studied transepithelial SCN− transport in the human bronchial epithelium. We found evidence for at least three mechanisms for basolateral to apical SCN− flux. cAMP and Ca2+ regulatory pathways controlled SCN− transport through cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels, respectively, the latter mechanism being significantly increased by treatment with IL-4. Stimulation with IL-4 also induced the strong up-regulation of an electroneutral SCN−/Cl− exchange. Global gene expression analysis with microarrays and functional studies indicated pendrin (SLC26A4) as the protein responsible for this SCN− transport. Measurements of H2O2 production at the apical surface of bronchial cells indicated that the extent of SCN− transport is important to modulate the conversion of this oxidant molecule by the lactoperoxidase system. Our studies indicate that the human bronchial epithelium expresses various SCN− transport mechanisms under resting and stimulated conditions. Defects in SCN− transport in the airways may be responsible for susceptibility to infections and/or decreased ability to scavenge oxidants.

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Section: Resultssupporting

confidence: 86%

Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels

Pedemonte

Caci

Sondo

et al. 2007

The Journal of Immunology

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133

150

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“…Forskolin (20 M) treatments were for 5 min and H89 (10 M) pretreatment for 20 min. Potentiator treatments were at the previously published EC 50 (VRT-532, 5 M; UC CF-152, 50 M; PG-01, 300 nM; SF-03, 30 nM; UCCF-853, 3 M; ⌬F508 act-02, 70 nM; genistein, 30 M; UCCF-029, 2 M; UCCF-180, 10 M) (7,26,32,37,41,51), except where otherwise specified. After drug treatment, cells were lysed in buffer (1% NP-40, 50 mM Tris·HCl, pH 7.5, 200 mM NaCl, 5 mM MgCl 2, 15% glycerol) with protease (Complete mini protease cocktail, Roche Diagnostics) and phosphatase inhibitors [Na 3VO4 (0.2 mM), NaF (10 mM), MoO4 (1 mM), and ␤-glycerophosphate (50 mM)].…”

Section: Methodsmentioning

confidence: 99%

Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators

Pyle

Ehrhardt

Mitchell

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Prior studies have revealed multiple chemical classes of CFTR activators that likely function by direct interaction with CFTR, including flavones/isoflavones, benzo [c]quinoliziniums, xanthines, benzimidazolones, fluorescein derivatives, and benzoflavones (Illek et al, 2000;Galietta et al, 2001;Ma et al, 2002b;Caci et al, 2003;Springsteel et al, 2003). Various ΔF508-CFTR "potentiators" have been identified, including VX-770, phenylglycines, sulfonamides, and tetrahydrobenzothiophenes Pedemonte et al, 2005;Van Goor et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Novel Amino-Carbonitrile-Pyrazole Identified in a Small Molecule Screen Activates Wild-Type and ∆F508 Cystic Fibrosis Transmembrane Conductance Regulator in the Absence of a cAMP Agonist

Namkung

Park

Seo

2013

Molecular Pharmacology

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Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) Cl 2 channel. We developed a phenotype-based high-throughput screen to identify small-molecule activators of human airway epithelial Ca 21 -activated Cl 2 channels (CaCCs) for CF therapy. Unexpectedly, screening of ∼110,000 synthetic small molecules revealed an amino-carbonitrile-pyrazole, C act -A1, that activated CFTR but not CaCC Cl 2 conductance. C act -A1 produced large and sustained CFTR Cl 2 currents in CFTR-expressing Fisher rat thyroid (FRT) cells and in primary cultures of human bronchial epithelial (HBE) cells, without increasing intracellular cAMP and in the absence of a cAMP agonist. C act -A1 produced linear whole-cell currents. C act -A1 also activated DF508-CFTR Cl 2 currents in low temperature-rescued ΔF508-CFTR-expressing FRT cells and CF-HBE cells (from homozygous ΔF508 patients) in the absence of a cAMP agonist, and showed additive effects with forskolin. In contrast, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770) and genistein produced little or no ΔF508-CFTR Cl 2 current in the absence of a cAMP agonist. In FRT cells expressing G551D-CFTR and in CF nasal polyp epithelial cells (from a heterozygous G551D/ Y1092X-CFTR patient), C act -A1 produced little Cl 2 current by itself but showed synergy with forskolin. The amino-carbonitrilepyrazole C act -A1 identified here is unique among prior CFTRactivating compounds, as it strongly activated wild-type and ΔF508-CFTR in the absence of a cAMP agonist. Increasing ΔF508-CFTR Cl 2 conductance by an "activator," as defined by activation in the absence of cAMP stimulation, provides a novel strategy for CF therapy that is different from that of a "potentiator," which requires cAMP elevation.

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CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds

Cited by 58 publications

References 26 publications

Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels

Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels

Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators

Novel Amino-Carbonitrile-Pyrazole Identified in a Small Molecule Screen Activates Wild-Type and ∆F508 Cystic Fibrosis Transmembrane Conductance Regulator in the Absence of a cAMP Agonist

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