Cystic Fibrosis Transmembrane Regulator Inhibitors CFTRinh-172 and GlyH-101 Target Mitochondrial Functions, Independently of Chloride Channel Inhibition
Cystic Fibrosis Transmembrane Regulator Inhibitors CFTRinh-172 and GlyH-101 Target Mitochondrial Functions, Independently of Chloride Channel Inhibition
复制标题
DOI：
10.1124/jpet.109.162032
复制
发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Fritsch, Janine
中科院分区：
文献类型：
--
作者：
Kelly, Mairead;Trudel, Stephanie;Fritsch, Janine
通过高通量筛选，已经确定了两种高效和选择性的囊性纤维化跨膜调节因子抑制剂：噻唑烷酮CFTRinh-172[3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-硫氧-4-噻唑烷酮和甘氨酸肼[GlyH-101[N-(2-naphthalenyl)-((3，5-dibromo-2，4-dihydroxyphenyl)methylene)glycine肼]。这些化合物抑制CFTR氯通道在治疗分泌性腹泻和多囊肾病方面具有重要的药理学意义。此外，CFTRinh-172对CFTR的功能性抑制已被认为足以模拟CF的炎症特征。在本研究中，我们研究了这两种化合物对几种细胞系中活性氧(ROS)产生和线粒体膜电位的影响：CFTR缺陷的人肺上皮细胞IB3-1(表达杂合的F508del/W1282X突变)，等基因的CFTR校正的C38，以及作为不表达CFTR的对照的HeLa和A549。两种抑制剂都能诱导四种细胞中ROS水平的快速升高和线粒体的去极化，这表明这些作用不依赖于对CFTR的抑制。在HeLa细胞中，这些事件与氧耗率的下降有关，GlyH-101显示出比CFTRinh-172更高的效力。在HeLa细胞中也测试了CFTR抑制剂对炎症参数的影响。CFTRinh-172，而不是GlyH-101，可诱导核因子-kappa B(NF-kappa B)的核转位。CFTRinh-172使IL-8分泌略有减少，而GlyH-101诱导略有增加。这些结果支持这样的结论，即CFTR抑制剂可能在ROS的产生、线粒体的失效和NF-kappa B信号通路的激活方面发挥非特异性作用，而不是CFTR的抑制。
Two highly potent and selective cystic fibrosis (CF) transmembrane regulator (CFTR) inhibitors have been identified by high-throughput screening: the thiazolidinone CFTRinh-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 CFTRinh-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 CFTRinh-172. The impact of CFTR inhibitors on inflammatory parameters was also tested in HeLa cells. CFTRinh-172, but not GlyH-101, induced nuclear translocation of nuclear factor-kappa B (NF-kappa B). CFTRinh-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-kappa B signaling pathway, independently of CFTR inhibition.