Acquisition of Chemoresistance in Gliomas Is Associated with Increased Mitochondrial Coupling and Decreased ROS Production 英文参考文献.docVIP
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Acquisition of Chemoresistance in Gliomas Is Associated with Increased Mitochondrial Coupling and Decreased ROS Production 英文参考文献
AcquisitionofChemoresistanceinGliomasIsAssociated
withIncreasedMitochondrialCouplingandDecreased
ROSProduction
ClaudiaR.Oliva1,DouglasR.Moellering2,G.YanceyGillespie1,CorinneE.Griguer1,3*
1DivisionofNeurosurgery,DepartmentofSurgery,UniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica, 2DepartmentofNutrition
Sciences,UniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica,3CenterforFreeRadicalBiology,UniversityofAlabamaatBirmingham,
Birmingham,Alabama,UnitedStatesofAmerica
Abstract
Temozolomide (TMZ) is an alkylating agent used for treating gliomas. Chemoresistance is a severe limitation to TMZ
therapy; there is a critical need to understand the underlying mechanisms that determine tumor response to TMZ. We
recently reported that chemoresistance to TMZ is related to a remodeling of the entire electron transport chain, with
significant increases in the activity of complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and
geneticmanipulationofCcOreverseschemoresistance.Therefore,totestthehypothesisthatTMZ-resistancearisesfrom
tightermitochondrialcouplinganddecreasedproductionofreactiveoxygenspecies(ROS),wehaveassessedmitochondrial
function in TMZ-sensitive and -resistant glioma cells, and in TMZ-resistant glioblastoma multiform (GBM) xenograft lines
(xenolines).MaximumADP-stimulated(state3)ratesofmitochondrialoxygenconsumptionweregreaterinTMZ-resistant
cells and xenolines, and basal respiration (state 2), proton leak (state 4), and mitochondrial ROS production were
significantlylowerinTMZ-resistantcells.Furthermore,TMZ-resistantcellsconsumedlessglucoseandproducedlesslactic
acid.ChemoresistantcellswereinsensitivetotheoxidativestressinducedbyTMZandhydrogenperoxidechallenges,but
treatment with the oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and reversed
chemoresistance.Importantly,treatmentwiththeantioxidantN-acetyl-cysteineinhibitedTMZ-dependentROSgeneration
inchemosensitive
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