Identification of New Small Molecule Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Protein: In Vitro and in Vivo Studies

Muanprasat, Chatchai; Kaewmokul, Santi; Chatsudthipong, Varanuj

doi:10.1248/bpb.30.502

Cited by 17 publications

(14 citation statements)

References 25 publications

(47 reference statements)

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“…CaCC has been found in the small intestine as well as in T84 cells . Several CFTR inhibitors, such as glibenclamide, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, GlyH-101, and 2-[N-(3-hydroxy-4-carboxyphenyl)amino]-4-(4-methylphenyl)-thiazole (INH 1), have also been found to inhibit CaCC (McCarty et al, 1993;Rabe et al, 1995;Dawson et al, 1999;Muanprasat et al, 2004Muanprasat et al, , 2007. Therefore, to determine its target specificity, dihydroisosteviol was tested in T84 cells as a blocker of Ca 2ϩ -induced Cl Ϫ secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, several efforts have been made to search for promising drugs that could be used to treat cholera more efficiently. These methods include inhibitors of cholera toxin receptor binding (Pickens et al, 2004), 5-hydroxytryptamine receptor antagonists (Mourad et al, 1995;Turvill and Farthing, 1997), somatostatin receptor agonists (Farthing, 1996), enkephalinase inhibitors (Cézard et al, 2001), and CFTR inhibitors (Muanprasat et al, 2004(Muanprasat et al, , 2007. Several natural products isolated from plants have also been used as sources of pharmaceuticals and as ingredients of traditional medicines (Phillipson, 1994).…”

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confidence: 99%

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A Natural Plant-Derived Dihydroisosteviol Prevents Cholera Toxin-Induced Intestinal Fluid Secretion

Pariwat

Homvisasevongsa²,

Muanprasat³

et al. 2007

J Pharmacol Exp Ther

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Stevioside and its major metabolite, steviol, have been reported to affect ion transport in many types of tissues, such as the kidney, pancreas, and intestine. The effect of stevioside, steviol, and its analogs on intestinal Cl Ϫ secretion was investigated in a human T84 epithelial cell line. Short-circuit current measurements showed that steviol and analogs isosteviol, dihydroisosteviol, and isosteviol 16-oxime inhibited in a dosedependent manner forskolin-induced Cl Ϫ secretion with IC 50 values of 101, 100, 9.6, and 50 M, respectively, whereas the parent compound stevioside had no effect. Apical Cl Ϫ current measurement indicated that dihydroisosteviol targeted the cystic fibrosis transmembrane regulator (CFTR). The inhibitory action of dihydroisosteviol was reversible and was not associated with changes in the intracellular cAMP level. In addition, dihydroisosteviol did not affect calcium-activated chloride secretion and T84 cell viability. In vivo studies using a mouse closed-loop model of cholera toxin-induced intestinal fluid secretion showed that intraluminal injection of 50 M dihydroisosteviol reduced intestinal fluid secretion by 88.2% without altering fluid absorption. These results indicate that dihydroisosteviol and similar compounds could be a new class of CFTR inhibitors that may be useful for further development as antidiarrheal agents.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Natural Plant-Derived Dihydroisosteviol Prevents Cholera Toxin-Induced Intestinal Fluid Secretion

Pariwat

Homvisasevongsa²,

Muanprasat³

et al. 2007

J Pharmacol Exp Ther

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“…In light of the results from dose-inhibition studies in T84 and MDCK cells, ISLQ is less potent than other CFTR inhibitors identified to date (12,28,31,32). However, the potential for therapeutic applications of ISLQ should not be underrated, as ISLQ also has other biological activities that, in conjunction with its inhibitory effect on CFTR, may be of added benefit in the treatment of cholera and/or PKD.…”

Section: CLmentioning

confidence: 99%

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

et al. 2012

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Abstract. Overstimulation of cAMP-activated Cl− secretion can cause secretory diarrhea. Isoliquiritigenin (ISLQ) is a plant-derived chalcone that has a wide range of biological activities. The present study thus aimed to investigate the effect of ISLQ on cAMP-activated Cl − secretion in human intestinal epithelium, especially the underlying mechanism and therapeutic application. Short-circuit current analysis of human intestinal epithelial (T84) cell monolayers revealed that ISLQ dose-dependently inhibited cAMP-activated Cl − secretion with an IC 50 of approximately 20 μM. ISLQ had no effect on either basal short-circuit current or Ca 2+ -activated Cl − secretion. Apical Cl − current analysis of T84 cell monolayers indicated that ISLQ blocked mainly the cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channels, but not other unidentified cAMPdependent Cl − channels. ISLQ did not affect intracellular cAMP levels or cell viability. ISLQ completely abolished the cholera toxin-induced transepithelial Cl − secretion in T84 cells and reduced the cholera toxin-induced intestinal fluid secretion in mouse closed loop models by 90%. Similarly, ISLQ completely inhibited the cAMP-activated apical Cl − current across monolayers of Madin-Darby Canine Kidney (MDCK) cells and retarded cyst growth in MDCK cyst models by 90%. This study reveals a novel action of ISLQ as a potent CFTR inhibitor with therapeutic potential for treatment of cholera and polycystic kidney disease.

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“…17) This cell model has been extensively employed to identify novel CFTR modulators and to characterize their mechanisms of action. [18][19][20][21] To our surprise, apical Cl − current analysis of FRT-CFTR cell monolayers demonstrated that DHIS had no effect on CFTR-mediated Cl − transport. This result led us to speculate that the inhibition of CFTR-mediated Cl − current by DHIS in T84 cells is not due to the direct effect on CFTR, but rather a result of action on other proteins that regulate CFTR function.…”

Section: Discussionmentioning

confidence: 91%

Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell

Muanprasat

Sirianant

Sawasvirojwong

et al. 2013

Biological & Pharmaceutical Bulletin

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Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.

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Identification of New Small Molecule Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Protein: In Vitro and in Vivo Studies

Cited by 17 publications

References 25 publications

A Natural Plant-Derived Dihydroisosteviol Prevents Cholera Toxin-Induced Intestinal Fluid Secretion

A Natural Plant-Derived Dihydroisosteviol Prevents Cholera Toxin-Induced Intestinal Fluid Secretion

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell

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