GlyH-101 is a cell-permeable glycine hydrazide that selectively and reversibly blocks the cystic fibrosis transmembrane conductance regulator (CFTR) channel (Ki = 4.3 µM; Sonawane et al.). The CFTR protein is a chloride anion channel involved in the secretion of fluid in many epithelial tissues, such as the airways and intestine (Ma et al.). Defects in the CFTR gene alter ion transport which can lead to cystic fibrosis (Dalli et al.; Ma et al.).
CANCER RESEARCH
· Blocks CFTR and inhibits cell division by inducing hyperpolarization in human gastric cancer cells (Zhu et al.).
CANCER RESEARCH
· Blocks CFTR and inhibits cell division by inducing hyperpolarization in human gastric cancer cells (Zhu et al.).
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Protocols and Documentation
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Resources and Publications
Educational Materials (5)
Publications (4)
Involvement of AMP-activated Protein Kinase (AMPK) in Regulation of Cell Membrane Potential in a Gastric Cancer Cell Line. Scientific reports 2018
Abstract
Membrane potential (Vmem) is a key bioelectric property of non-excitable cells that plays important roles in regulating cell proliferation. However, the regulation of Vmem itself remains largely unexplored. We found that, under nutrient starvation, during which cell division is inhibited, MKN45 gastric cancer cells were in a hyperpolarized state associated with a high intracellular chloride concentration. AMP-activated protein kinase (AMPK) activity increased, and expression of cystic fibrosis transmembrane conductance regulator (CFTR) decreased, in nutrient-starved cells. Furthermore, the increase in intracellular chloride concentration level and Vmem hyperpolarization in nutrient-starved cells was suppressed by inhibition of AMPK activity. Intracellular chloride concentrations and hyperpolarization increased after over-activation of AMPK using the specific activator AICAR or suppression of CFTR activity using specific inhibitor GlyH-101. Under these conditions, proliferation of MKN45 cells was inhibited. These results reveal that AMPK controls the dynamic change in Vmem by regulating CFTR and influencing the intracellular chloride concentration, which in turn influences cell-cycle progression. These findings offer new insights into the mechanisms underlying cell-cycle arrest regulated by AMPK and CFTR.
CFTR inhibition provokes an inflammatory response associated with an imbalance of the annexin A1 pathway. The American journal of pathology 2010 jul
Abstract
Cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, is characterized by chronic bacterial infections and inflammation in the lung. Having previously shown that deletion of CFTR is associated with lower expression of the endogenous anti-inflammatory protein Annexin A1 (AnxA1), we investigated further this possible functional connection using a validated CFTR inhibitor. Treatment of mice with the CFTR inhibitor-172 (CFTR(172)) augmented the acute peritonitis promoted by zymosan, an effect associated with lower AnxA1 levels in peritoneal cells. Similar results were obtained with another, chemically distinct, CFTR inhibitor. The pro-inflammatory effect of CFTR(172) was lost in AnxA1(-/-), as well as CFTR(-/-) mice. Importantly, administration of hrAnxA1 and its peptido-mimetic to CFTR(-/-) animals or to animals treated with CFTR(172) corrected the exaggerated leukocyte migration seen in these animals. In vitro assays with human Polymorphonuclear leukocyte (PMN) demonstrated that CFTR(172) reduced cell-associated AnxA1 by promoting release of the protein in microparticles. We propose that the reduced impact of the counterregulatory properties of AnxA1 in CF cells contributes to the inflammatory phenotype characteristic of this disease. Thus, these findings provide an important insight into the mechanism underlying the inflammatory disease associated with CFTR inhibition while, at the same time, providing a novel pharmacological target for controlling the inflammatory phenotype of CF.
Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006 jan
Abstract
Enterotoxin-mediated secretory diarrheas such as cholera involve chloride secretion by enterocytes into the intestinal lumen by the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. We previously identified glycine hydrazide CFTR blockers that by electrophysiological studies appeared to block the CFTR anion pore at its lumen-facing surface. Here, we synthesize highly water-soluble, nonabsorbable malondihydrazides by coupling 2,4-disulfobenzaldehyde, 4-sulfophenylisothiocyante, and polyethylene glycol (PEG) moieties to 2-naphthalenylamino-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] propanedioic acid dihydrazide, and aminoacethydrazides by coupling PEG to [(N-2-naphthalenyl)-2-(2-hydroxyethyl)]-glycine-2-[(3,5-dibromo-2,4-dihydroxyphenyl) methylene] hydrazide. Compounds rapidly, fully and reversibly blocked CFTR-mediated chloride current with Ki of 2-8 microM when added to the apical surface of epithelial cell monolayers. Compounds did not pass across Caco-2 monolayers, and were absorbed by {\textless}2{\%}/hr in mouse intestine. Luminally added compounds blocked by {\textgreater}90{\%} cholera toxin-induced fluid secretion in mouse intestinal loops, without inhibiting intestinal fluid absorption. These orally administered, nonabsorbable, nontoxic CFTR inhibitors may reduce intestinal fluid losses in cholera.
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