Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263737 Combination Therapy 英文参考文献.docVIP
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Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263737 Combination Therapy 英文参考文献
EfficientEliminationofCancerCellsby
Deoxyglucose-ABT-263/737CombinationTherapy
RyujiYamaguchi1,4*,EdithJanssen2,GuyPerkins3,MarkEllisman3,ShinichiKitada1,JohnC.Reed1
1ProgramofCellDeathandApoptosis,Sanford-BurnhamMedicalResearchInstitute,LaJolla,California,UnitedStatesofAmerica,2DivisionofMolecularImmunology,
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America, 3Department of Neurosciences, University of California San Diego, La Jolla,
California,UnitedStatesofAmerica,4DepartmentofMolecularBiology,KyushuUniversityMedicalSchool,Fukuoka,Japan
Abstract
Assingleagents,ABT-263andABT-737(ABT),molecularantagonistsoftheBcl-2family,bindtightlytoBcl-2,Bcl-xLandBcl-
w, but not to Mcl-1, and induce apoptosis only in limited cell types. The compound 2-deoxyglucose (2DG), in contrast,
partially blocks glycolysis, slowing cell growth but rarely causing cell death. Injected into an animal, 2DG accumulates
predominantlyintumorsbutdoesnotharmothertissues.However,whencellsthatwerehighlyresistanttoABTwerepre-
treated with 2DG for 3hours, ABT became a potent inducer of apoptosis, rapidly releasing cytochrome c from the
mitochondria andactivating caspasesat submicromolarconcentrations inaBak/Bax-dependentmanner.Bakis normally
sequesteredincomplexeswithMcl-1andBcl-xL.2DGprimescellsbyinterferingwithBak-Mcl-1association,makingiteasier
forABTtodissociateBakfromBcl-xL,freeingBaktoinduceapoptosis.AhighlyactiveglucosetransporterandBid,asan
agentofthemitochondrialapoptoticsignalamplificationloop,arenecessaryforefficientapoptosisinductioninthissystem.
Thiscombinationtreatmentofcancer-bearingmicewasveryeffectiveagainsttumorxenograftfromhormone-independent
highlymetastasizedchemo-resistanthumanprostatecancercells,suggestingthatthecombinationtreatmentmayprovide
asafeandeffectivealternativetogenotoxin-basedcancertherapies.
Citation:YamaguchiR,JanssenE,PerkinsG,EllismanM,KitadaS,etal.(2011)EfficientEliminationofCancerCellsbyDeoxyglucose-ABT-263/737Combination
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