Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition.
Two highly potent and selective cystic fibrosis (CF) transmembrane regulator (CFTR) inhibitors have been identified by high-throughput screening: the thiazolidinone CFTR(inh)-172 [3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]- 2-thioxo-4-thiazolidinone] and the glycine hydrazide GlyH-101 [N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide]. Inhibition of the CFTR chloride channel by these compounds has been suggested to be of pharmacological interest in the treatment of secretory diarrheas and polycystic kidney disease. In addition, functional inhibition of CFTR by CFTR(inh)-172 has been proposed to be sufficient to mimic the CF inflammatory profile. In the present study, we investigated the effects of the two compounds on reactive oxygen species (ROS) production and mitochondrial membrane potential in several cell lines: the CFTR-deficient human lung epithelial IB3-1 (expressing the heterozygous F508del/W1282X mutation), the isogenic CFTR-corrected C38, and HeLa and A549 as non-CFTR-expressing controls. Both inhibitors were able to induce a rapid increase in ROS levels and depolarize mitochondria in the four cell types, suggesting that these effects are independent of CFTR inhibition. In HeLa cells, these events were associated with a decrease in the rate of oxygen consumption, with GlyH-101 demonstrating a higher potency than CFTR(inh)-172. The impact of CFTR inhibitors on inflammatory parameters was also tested in HeLa cells. CFTR(inh)-172, but not GlyH-101, induced nuclear translocation of nuclear factor-kappaB (NF-kappaB). CFTR(inh)-172 slightly decreased interleukin-8 secretion, whereas GlyH-101 induced a slight increase. These results support the conclusion that CFTR inhibitors may exert nonspecific effects regarding ROS production, mitochondrial failure, and activation of the NF-kappaB signaling pathway, independently of CFTR inhibition.
Kelly
Mairead
M
Institut National de la Santé et de la Recherche Médicale, U845, Centre de Recherche Croissance and Signalization, 156 Rue de Vaugirard, Paris, France.
Trudel
Stephanie
S
Brouillard
Franck
F
Bouillaud
Frederick
F
Colas
Julien
J
Nguyen-Khoa
Thao
T
Ollero
Mario
M
Edelman
Aleksander
A
Fritsch
Janine
J
D000154:Aconitate Hydratase / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology*; D002460:Cell Line; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000235:genetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D018118:Chloride Channels; D006834:Hydrazines; D016209:Interleukin-8; C548779:N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000154:Aconitate Hydratase; D005998:Glycine