Effects of the CK2 Inhibitors CX-4945 and CX-5011 on Drug-Resistant Cells 英文参考文献.docVIP

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Effects of the CK2 Inhibitors CX-4945 and CX-5011 on Drug-Resistant Cells 英文参考文献.doc

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Effects of the CK2 Inhibitors CX-4945 and CX-5011 on Drug-Resistant Cells 英文参考文献

EffectsoftheCK2InhibitorsCX-4945andCX-5011on Drug-ResistantCells SofiaZanin1,ChristianBorgo1,CristinaGirardi1,SeanE.O’Brien2,YoshihikoMiyata3,LorenzoA.Pinna1,4, AriannaDonella-Deana1,MariaRuzzene1,4* 1DepartmentofBiomedicalSciencesandNationalResearchCouncilInstituteofNeurosciences,UniversityofPadova,Padova,Italy,2CylenePharmaceuticals,SanDiego, California,UnitedStatesofAmerica,3DepartmentofCellandDevelopmentalBiology,GraduateSchoolofBiostudies,KyotoUniversity,Kyoto,Japan,4VenetianInstitute ofMolecularMedicine,Padova,Italy Abstract CK2isapleiotropicproteinkinase,whichregulatesmanysurvivalpathwaysandplaysaglobalanti-apoptoticfunction.Itis highly expressed in tumor cells, and is presently considered apromising therapeutic target. Among the manyinhibitors availableforthiskinase,therecentlydevelopedCX-4945andCX-5011haveprovedtobeverypotent,selectiveandeffective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacyofthesecompoundstoovercomedrugresistance,amajorreasonsofcancertherapyfailure.Hereweaddressthis point,bystudyingtheireffectsinseveraltumorcelllines,eachavailableasvariantRresistanttodrug-inducedapoptosis, andnormal-sensitivevariantS.WefoundthattheinhibitionofendogenousCK2wasverysimilarinSandRtreatedcells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptoticresponsewasinducedbothinSandRvariantsofeachpairs.Moreover,thecombinedtreatmentofCX-4945plus vinblastinewasabletosensitizetovinblastineRcellsthatareotherwisealmostinsensitivetothisconventionalantitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945. In summary,wedemonstratedthatalltheRvariantsaresensitivetoCX-4945andCX-5011;sincesomeofthetreatedRlines expresstheextrusionpumpPgp,oftenresponsibleoftheMDRphenotype,wecanalsoconcludethatthetwoinhibitorscan successfullyovercometheMDRphenomenon. Citation:Zan