Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy 英文参考文献.docVIP

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Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy 英文参考文献.doc

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Pyrvinium Targets the Unfolded Protein Response to Hypoglycemia and Its Anti-Tumor Activity Is Enhanced by Combination Therapy 英文参考文献

PyrviniumTargetstheUnfoldedProteinResponseto HypoglycemiaandItsAnti-TumorActivityIsEnhanced byCombinationTherapy De-HuaYu1*,JamesMacdonald1,GuohongLiu1,AmyS.Lee1,2,MimiLy1,TimothyDavis1,NingKe1, DeminZhou1,FlossieWong-Staal1,Qi-XiangLi1* 1iTherXPharmaceuticals,Inc.,SanDiego,California,UnitedStatesofAmerica,2DepartmentofBiochemistryandMolecularBiology,USC/NorrisComprehensiveCancer Center,KeckSchoolofMedicineoftheUniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica Abstract We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (,10 fold). It was also reported by othersto have anti-tumor activityinvivoandselectivetoxicityagainstcancercellsunderglucosestarvationinvitro,butwithunknownmechanism. Here,weprovideevidencethatpyrviniumsuppressesthetranscriptionalactivationofGRP78andGRP94inducedbyglucose deprivationor2-deoxyglucose(2DG,aglycolysisinhibitor),butnotbytunicamycinorA23187.OtherUPRpathwaysinduced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgenepartiallyprotectedcellsfrompyrviniuminducedcelldeathunderglucosestarvation,suggestingthatsuppression oftheUPRisinvolvedinpyrviniummediatedcytotoxicityunderglucosestarvation.Xenograftexperimentsshowedrather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicindemonstratedsignificantlyenhancedefficacyinvivo,supportingamechanistictreatmentconceptbasedon tumorhypoglycemiaandUPR. Citation:YuD-H,MacdonaldJ,LiuG,LeeAS,LyM,etal.(2008)PyrviniumTargetstheUnfoldedProteinResponsetoHypoglycemiaandItsAnti-TumorActivityIs EnhancedbyCombinationTherapy.PLoSONE3(12):e3951.doi:10.1371/journal.pone.0003951 Editor:Dong-YanJin,UniversityofHongKong,China ReceivedAugust14,2008;AcceptedNovember13,2008;PublishedDecember16,2008 Copyright:?2008Yuetal.Thisisanopen-acces