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Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance.doc

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Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

AnticancerAgentShikoninIsanIncompetentInducerof CancerDrugResistance HaoWu,JianshengXie,QiangrongPan,BeibeiWang,DanqingHu,XunHu* CancerInstitute,theSecondAffiliatedHospital,ZhejiangUniversitySchoolofMedicine,Hangzhou,Zhejiang,China Abstract Purpose:Cancerdrugresistanceisamajorobstacleforthesuccessofchemotherapy.Sincemostclinicalanticancerdrugs couldinducedrugresistance,itisdesiredtodevelopcandidatedrugsthatarehighlyefficaciousbutincompetenttoinduce drugresistance.Numerouspreviousstudieshaveproventhatshikoninanditsanalogsnotonlyarehighlytumoricidalbut alsocanbypassdrug-transporterandapoptoticdefectmediateddrugresistance.Thepurposeofthisstudyistoinvestigate ifornotshikoninisaweakinducerofcancerdrugresistance. ExperimentalDesign:Differentcelllines(K562,MCF-7,andaMDRcelllineK562/Adr),afterrepeatedlytreatedwithshikonin for18months,wereassayedfordrugresistanceandgeneexpressionprofiling. Results:After18-monthtreatment,cellsonlydevelopedamere2-foldresistancetoshikoninandamarginalresistanceto cisplatinandpaclitaxel,withoutcrossresistancetoshikoninanalogsandotheranticanceragents.Geneexpressionprofiles demonstratedthatcancercellsdidstronglyrespondtoshikonintreatmentbutfailedtoeffectivelymobilizedrugresistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of bII-tubulin, which physically interactedwithshikonin. Conclusion: Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drugresistanceandcancircumventcancerdrugresistance.Thesemeritsmakeshikoninanditsanalogspotentialcandidates forcancertherapywithadvantagesofavoidinginductionofdrugresistanceandbypassingexistingdrugresistance. Citation:WuH,XieJ,PanQ,WangB,HuD,etal.(2013)AnticancerAgentShikoninIsanIncompetentInducerofCancerDrugResistance.PLoSONE8(1):e52706. doi:10.1371/journal.pone.0052706 Editor:ArunRishi,WayneStateUniversity,UnitedStatesofAmerica ReceivedJune28,2012;AcceptedNovember19,2012;PublishedJanuary3,2013 Copyright:?2013Wueta