Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity 英文参考文献.docVIP

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Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity 英文参考文献.doc

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Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity 英文参考文献

DiclofenacInhibitsTumorGrowthinaMurineModelof PancreaticCancerbyModulationofVEGFLevelsand ArginaseActivity NinaMayorek*,NiliNaftali-Shani,MyriamGrunewald DevelopmentalBiologyandCancerResearch,InstituteforMedicalResearchIsrael-Canada(IMRIC),TheHebrewUniversity-HadassahMedicalSchool,Jerusalem,Israel Abstract Background:Diclofenacisoneoftheoldestanti-inflammatorydrugsinuse.Inadditiontoitsinhibitionofcyclooxygenases (COX), diclofenac potently inhibits phospholipase A2 (PLA2), thus yielding a broad anti-inflammatory effect. Since inflammationisanimportantfactorinthedevelopmentofpancreatictumorsweexploredthepotentialofdiclofenacto inhibittumorgrowthinmiceinoculatedwithPANCO2cellsorthotopically. Methodology/PrincipalFindings:Wefoundthatdiclofenactreatment(30mg/kg/bwfor11days)ofmiceinoculatedwith PANC02cells,reducedthetumorweightby60%,correlatingwithincreasedapoptosisoftumorcells.Sincethiseffectwas notobservedinvitroonculturedPANCO2cells,wetheorizedthatdiclofenacbeneficialtreatmentinvolvedothermediators presentinvivo.Indeed,diclofenacdrasticallydecreasedtumorvascularizationbydownregulatingVEGFinthetumorandin abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to otherCOX-2inhibitors,diclofenacincreasedarginaseactivity/arginase1proteincontentintumorstromacells,peritoneal macrophagesandwhitebloodcellsby2.4,4.8and2fold,respectively.Weproposethatthesubsequentargininedepletion anddecreaseinNOlevels,bothinserumandperitonealcavity,addstotumorgrowthinhibitionbymalnourishmentand poorvasculaturedevelopment. Conclusion/Significance: Inconclusion,diclofenacshowspronouncedantitumoralpropertiesinpancreaticcancermodel thatcancontributetofurthertreatmentdevelopment.Theabilityofdiclofenactoinducearginaseactivityintumorstroma, peritonealmacrophagesandwhitebloodcellsprovidesatooltostudyacontroversialissueofpro-andantitumoraleffects ofargininedepletion. Citation:MayorekN,Naftali-ShaniN,GrunewaldM(2010)DiclofenacInhibitsTumo