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.