Probing the Dynamics of Doxorubicin-DNA Intercalation during the Initial Activation of Apoptosis by Fluorescence Lifetime Imaging Microscopy (FLIM) 英文参考文献.docVIP

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Probing the Dynamics of Doxorubicin-DNA Intercalation during the Initial Activation of Apoptosis by Fluorescence Lifetime Imaging Microscopy (FLIM) 英文参考文献.doc

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Probing the Dynamics of Doxorubicin-DNA Intercalation during the Initial Activation of Apoptosis by Fluorescence Lifetime Imaging Microscopy (FLIM) 英文参考文献

ProbingtheDynamicsofDoxorubicin-DNAIntercalation duringtheInitialActivationofApoptosisby FluorescenceLifetimeImagingMicroscopy(FLIM) Nai-TzuChen1,2.,Chia-YanWu1.,Chao-YuChung3,YeukuangHwu4,Shih-HsunCheng1 ,Chung- YuanMou2*,Leu-WeiLo1* 1DivisionofMedicalEngineeringResearch,NationalHealthResearchInstitutes,Zhunan,Taiwan,2DepartmentofChemistry,NationalTaiwanUniversity,Taipei,Taiwan, 3NationalSynchrotronRadiationResearchCenter,Hsinchu,Taiwan,4InstituteofPhysics,AcademiaSinica,Taipei,Taiwan Abstract Doxorubicinisapotentanthracyclineantibiotic,commonlyusedtotreatawiderangeofcancers.Althoughpostulatedto intercalatebetweenDNAbases,manyofthedetailsofdoxorubicin’smechanismofactionremainunclear.Inthiswork,we demonstrate the ability of fluorescence lifetime imaging microscopy (FLIM) to dynamically monitor doxorubicin-DNA intercalationduringtheearlieststagesofapoptosis.Thefluorescencelifetimeofdoxorubicininnucleiisfoundtodecrease rapidly during the first 2 hours following drug administration, suggesting significant changes in the doxorubicin-DNA bindingsite’smicroenvironmentuponapoptosisinitiation.Decreasesindoxorubicinfluorescencelifetimeswerefoundto be concurrent with increases in phosphorylation of H2AX (an immediate signal of DNA double-strand breakage), but precededactivationofcaspase-3(alatesignatureofapoptosis)bymorethan150minutes.Time-dependentdoxorubicin FLIM analyses of the effects of pretreating cells with either Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)-hydrazine (a histone acetyltransferase inhibitor) or Trichostatin A (a histone deacetylase inhibitor) revealed significant correlation of fluorescencelifetimewiththestageofchromatindecondensation.Takentogether,ourfindingssuggestthatmonitoring the dynamics of doxorubicin fluorescence lifetimes can provide valuable information during the earliest phases of doxorubicin-inducedapoptosis;andimplicatethatFLIMcanserveasasensitive,high-resolutiontoolfortheelucidationof intercellularmechanismsandkineticsofanti-cancer