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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.docVIP

Ethacrynic Acid Exhibits Selective Toxicity to Chronic Lymphocytic Leukemia Cells by Inhibition of the Wntβ-Catenin Pathway 英文参考文献.doc

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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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