An Aqueous Extract of Fagonia cretica Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Breast Cancer Cells via FOXO3a and p53 Expression 英文参考文献.docVIP

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An Aqueous Extract of Fagonia cretica Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Breast Cancer Cells via FOXO3a and p53 Expression 英文参考文献.doc

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An Aqueous Extract of Fagonia cretica Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Breast Cancer Cells via FOXO3a and p53 Expression 英文参考文献

AnAqueousExtractofFagoniacreticaInducesDNA Damage,CellCycleArrestandApoptosisinBreast CancerCellsviaFOXO3aandp53Expression MattLam1,AmtulR.Carmichael2,HelenR.Griffiths1* 1SchoolofLifeandHealthSciences,AstonUniversity,Birmingham,UnitedKingdom,2RussellHall,DudleyGroupHospitals,Dudley,UnitedKingdom Abstract Background:Plantshaveprovedtobeanimportantsourceofanti-cancerdrugs.Herewehaveinvestigatedthecytotoxic actionofanaqueousextractofFagoniacretica,usedwidelyasaherbaltea-basedtreatmentforbreastcancer. Methodology/PrincipalFindings:UsingflowcytometricanalysisofcellslabeledwithcyclinA,annexinVandpropidium iodide, we describe a time and dose-dependent arrest of the cell cycle in G0/G1 phase of the cell cycle and apoptosis following extract treatment in MCF-7 (WT-p53) and MDA-MB-231 (mutant-p53) human breast cancer cell lines with a markedly reduced effect on primary human mammary epithelial cells. Analysis of p53 protein expression and of its downstreamtranscriptiontargets,p21andBAX,revealedap53associatedgrowtharrestwithin5hoursofextracttreatment and apoptosis within 24hours. DNA double strand breaks measured as c-H2AX were detected early in both MCF-7 and MDA-MB-231cells.However,lossofcellviabilitywasonlypartlyduetoap53-drivenresponse;asMDA-MB-231andp53- knockdownMCF-7cellsbothunderwentcellcyclearrestanddeathfollowingextracttreatment.p53-independentgrowth arrest and cytotoxicity following DNA damage has been previously ascribed to FOXO3a expression. Here, in MCF-7 and MDA-MB-231cells, FOXO3a expressionwasincreased significantlywithin 3hours ofextract treatmentandFOXO3siRNA reducedtheextract-inducedlossofcellviabilityinbothcelllines. Conclusions/Significance:OurresultsdemonstrateforthefirsttimethatanaqueousextractofFagoniacreticacaninduce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response.WealsoshowthatFOXO3aisrequiredforactivityintheabsenceofp53.OurfindingsindicatethatFagoniacretica aqueous extract c