Ethacrynic Acid Exhibits Selective Toxicity to Chronic Lymphocytic Leukemia Cells by Inhibition of the Wntβ-Catenin Pathway 英文参考文献.docVIP
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Ethacrynic Acid Exhibits Selective Toxicity to Chronic Lymphocytic Leukemia Cells by Inhibition of the Wntβ-Catenin Pathway 英文参考文献
EthacrynicAcidExhibitsSelectiveToxicitytoChronic
LymphocyticLeukemiaCellsbyInhibitionoftheWnt/b-
CateninPathway
DeshengLu1*,JerryX.Liu1,TomoyukiEndo1,HaowenZhou1,ShiyinYao1,KarlWillert2,IngoG.H.
Schmidt-Wolf3,ThomasJ.Kipps1,DennisA.Carson1*
1MooresCancerCenter,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2DepartmentofCellularandMolecularMedicine,Universityof
CaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,3CenterforIntegratedOncology,UniversityofBonn,Bonn,Germany
Abstract
Background: Aberrant activation of Wnt/b-catenin signaling promotes the development of several cancers. It has been
demonstrated that the Wnt signaling pathway is activated in chronic lymphocytic leukemia (CLL) cells, and that
uncontrolledWnt/b-cateninsignalingmaycontributetothedefectinapoptosisthatcharacterizesthismalignancy.Thus,
theWntsignalingpathwayisanattractivecandidatefordevelopingtargetedtherapiesforCLL.
Methodology/Principal Findings: The diuretic agent ethacrynic acid (EA) was identified as a Wnt inhibitor using a cell-
based Wnt reporter assay. In vitro assays further confirmed the inhibitory effect of EA on Wnt/b-catenin signaling. Cell
viabilityassaysshowedthatEAselectivelyinducedcelldeathinprimaryCLLcells.ExposureofCLLcellstoEAdecreasedthe
expressionofWnt/b-catenintargetgenes,includingLEF-1,cyclinD1andfibronectin.Immuneco-precipitationexperiments
demonstratedthatEAcoulddirectlybindtoLEF-1proteinanddestabilizetheLEF-1/b-catenincomplex.N-acetyl-L-cysteine
(NAC),whichcanreactwiththea,b-unsaturatedketoneinEA,butnototheranti-oxidants,preventedthedrug’sinhibition
ofWnt/b-cateninactivationanditsabilitytoinduceapoptosisinCLLcells.
Conclusions/Significance: Our studies indicate that EA selectively suppresses CLL survival due to inhibition of Wnt/b-
cateninsignaling.AntagonizingWntsignalinginCLLwithEAorrelateddrugsmayrepresentaneffectivetreatmentofthis
disease.
Citation:LuD,LiuJX,EndoT,ZhouH,YaoS,etal.(2009)EthacrynicAcidExhibitsSelectiveToxicitytoChronic
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