简介：Cisplatinbelongstoplatinum-baseddrugsandiswidelyusedincancerchemotherapy.Ototoxicityisoneofthemajordoselimitingside-effectsofcisplatin.Fortoxicitytooccurcisplatinmustfirstbetransportedfromthebloodstreamintocochlearcells.Threecoppertransportersareconsideredpathwaysforregulatingtheuptakeandtranslocationofcisplatinintocells:Ctr1,ATP7AandATP7B.Ourrecentstudywithcochlearorganotypicculturesshowsthatcochlearhaircellscanbedestroyedbycisplatinatlowconcentrationsfrom10μmto100μn.However,highdosesofcisplatincannotdamagehaircells,maybeduetointrinsicfeedbackreactionsthatincreaseexportofplatinumbyATP7Bwhentheplatinumconcentrationishighinextracellularspace.Cimitidineisaspecificcoppertransporterinhibitorthatcanblocktheentranceofcopperandplatinum,andmaypreventcisplatin-inducedcochlearhaircellinjury.Toevaluatethishypothesis,wetreatedcochlearorganotypiccultureswithcisplatin(10μmor50μm)alone,orcisplatincombinedwithcimitidineatconcentrationsrangingfrom10-2000μmfor48hours.cisplatinat10μmdamagedabout20%haircells.Incontrast,whencimitidine(10μm,100μmand2000μm)wasaddedtotheculture,near100%cochlearhaircellsurvived.Athigherconcentration(50μm),cisplatindestroyedabout80%ofcochlearhaircells.However,100μmcimitidinerescuedabout50%haircellsfromcisplatindamage,and2000μmcimitidineprotectedabout80%haircells.ThedataofwesternblotshowedthatCTR1andATP7Bexpressionswereincreasedincisplatintreatedcochleartissue,butcimitidinesignificantlyreducedCTR1andATP7B.Inaddition,ATP7Aexpressionwasdepressedalittleaftercisplatintreatment.ConsideringthatCtr1isinvolvedincopperandplatinuminflux,buttheATP7AandATP7Barecopperexporttransporters,theresultssuggestthatcimitidinecaneffectivelyblocktheentrancebycoppertransportersandstoptheinfluxofcisplatin.