Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α 英文参考文献.docVIP

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Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α 英文参考文献.doc

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Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α 英文参考文献

RadiosensitizationofNormoxicandHypoxicH1339Lung TumorCellsbyHeatShockProtein90InhibitionIs IndependentofHypoxiaInducibleFactor-1a DanielaSchilling1,2,ChristineBayer1,WeiLi3,MichaelMolls1,PeterVaupel1,GabrieleMulthoff1,2* 1DepartmentofRadiationOncology,KlinikumrechtsderIsar,TechnischeUniversita¨t Mu¨nchen,Munich,Germany,2ClinicalCooperationGroup(CCG)‘‘InnateImmunity in Tumor Biology’’, Helmholtz Zentrum Mu¨nchen, Munich, Germany, 3Department of Dermatology, University of Southern California Keck School of Medicine, Los Angeles,California,UnitedStatesofAmerica Abstract Background:Ionizingirradiationisacommonlyacceptedtreatmentmodalityforlungcancerpatients.However,theclinical outcomeishamperedbynormaltissuetoxicityandtumorhypoxia.Sincetumorsoftenhavehigherlevelsofactiveheat shockprotein90(Hsp90)thannormaltissues,targetingofHsp90mightprovideapromisingstrategytosensitizetumors towardsirradiation.Hsp90clientproteinsincludeoncogenicsignalingproteins,cellcycleactivators,growthfactorreceptors andhypoxiainduciblefactor-1a(HIF-1a).OverexpressionofHIF-1aisassumedtopromotemalignanttransformationand tumorprogressionandthusmightreducetheaccessibilitytoradiotherapy. Methodology/Principal Findings: Herein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17- allylamino-17-demethoxygeldanamycin(17-AAG),asacontrol,onHIF-1alevelsandradiosensitivityoflungcarcinomacells undernormoxicandhypoxicconditions.NVP-AUY922exhibitedasimilarbiologicalactivitytothatof17-AAG,butatonly1/ 10ofthedose.Asexpected,bothinhibitorsreducedbasalandhypoxia-inducedHIF-1alevelsinEPLC-272Hlungcarcinoma cells. However, despite a down-regulation of HIF-1a upon Hsp90 inhibition, sensitivity towards irradiation remained unalteredinEPLC-272Hcellsundernormoxicandhypoxicconditions.Incontrast,treatmentofH1339lungcarcinomacells withNVP-AUY922and17-AAGresultedinasignificantup-regulationoftheirinitiallyhighHIF-1alevelsandaconcomitant increaseinradiosensitivity. Conclusions/Significance: In summary, o