Antiproliferative Effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cycle Progression 英文参考文献.docVIP
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Antiproliferative Effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cycle Progression 英文参考文献
AntiproliferativeEffectofAscorbicAcidIsAssociated
withtheInhibitionofGenesNecessarytoCellCycle
Progression
SophieBelin1,FerdinandKaya1,GhislaineDuisit1,SarahGiacometti2,JosephCiccolini2,MichelFonte′s1*
1EA4263,TherapyofGeneticDisorder,Faculte′ deMe′decinedelaTimone,Marseille,France,2UPRESEA3286,LaboratoryofPharmacokineticandToxicokinetic,Faculte′
dePharmacie,Marseille,France
Abstract
Background:Ascorbicacid(AA),orVitaminC,ismostwellknownasanutritionalsupplementwithantioxidantproperties.
Recently,wedemonstratedthathighconcentrationsofAAactonPMP22geneexpressionandpartiallycorrecttheCharcot-
Marie-Toothdiseasephenotypeinamousemodel.ThisisduetothecapacityofAA,butnototherantioxidants,todown-
modulatecAMPintracellularconcentrationbyacompetitiveinhibitionoftheadenylatecyclaseenzymaticactivity.Because
ofthecriticalroleofcAMPinintracellularsignalling,wedecidedtoexplorethepossibilitythatascorbicacidcouldmodulate
theexpressionofothergenes.
MethodsandFindings:Usinghumanpangenomicmicroarrays,wefoundthatAAinhibitedtheexpressionoftwocategories
ofgenesnecessaryforcellcycleprogression,tRNAsynthetasesandtranslationinitiationfactorsubunits.Ininvitroassays,we
demonstratedthatAAinducedtheS-phasearrestofproliferativenormalandtumorcells.HighestconcentrationsofAAleaded
to necrotic cell death. However, quiescent cells were not susceptible to AA toxicity, suggesting the blockage of protein
synthesiswasmainlydetrimentalinmetabolically-activecells.Usinganimalmodels,wefoundthathighconcentrationsofAA
inhibited tumor progression in nude mice grafted with HT29 cells (derived from human colon carcinoma). Consistently,
expressionoftRNAsynthetasesandieF2appearedtobespecificallydecreasedintumorsuponAAtreatment.
Conclusions:AAhasanantiproliferativeactivity,atelevatedconcentrationthatcouldbeobtainedusingIVinjection.This
activityhasbeenobservedinvitroaswellinvivoandlikelyresultsfromtheinhibitionofexpressionofgenesinvolvedin
proteinsynthesis.Implicationsforaclinicaluseinanticancertherapieswillbediscu
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