TheRoleofStatinsinCancerTherapyWord下载.docx

TheRoleofStatinsinCancerTherapyWord下载.docx

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#8226;

，Tumor，&

，Chemotherapy，&

，Inflammation，&

，Prevention

　　LEARNINGOBJECTIVES

　　Aftercompletingthiscourse，thereaderwillbeableto:

　　Explainhowstatins，usedinthetreatmentofhypercholesterolemia，maybeapplicabletocancerprevention.

　　Discusshowstatinspotentiallyinterferewithbiologicprocessesrelevanttocanceretiology.

　　Outlinethegapsinourunderstandinginthisareaoftheoreticalversusappliedmedicine.

　　ABSTRACT

　　Administrationof3-hydroxy-3-methylglutarylcoenzymeAreductaseinhibitors，orstatins，toambulatorypatientsisassociatedwithalowerincidenceoflong-termadversecardiovascularevents，includingdeath，myocardialinfarction，stroke，atrialfibrillation，andrenaldysfunction.However，increasingclinicalevidencesuggeststhatstatins，independentoftheireffectsonserumcholesterollevels，mayalsoplayapotentialroleinthepreventionandtreatmentofcancer.Specifically，statinshavebeenshowntoexertseveralbeneficialantineo-plasticproperties，includingdecreasedtumorgrowth，angiogenesis，andmetastasis.Thefeasibilityandefficacyofstatinsforthepreventionandtreatmentofcancerisreviewed.

　　INTRODUCTION

　　3-hydroxy-3-methylglutarylcoenzymeA（HMG-CoA）reductaseinhibitors，orstatins，arecommonly-useddrugsforthetreatmentofhypercholesterolemia[1，2].Statinsdecreaselow-densitylipoprotein（LDL）cholesterollevelsbyinhibitingHMG-CoAreductase.HMG-CoAreductaseinturncatalyzestheconversionofHMG-CoAintomevalonateandistherate-limitingstepinhepaticcholesterolbiosynthesis[3].Clinically，statintreatmentisassociatedwithareductioninatheroscleroticplaqueformationandastabilizationofpre-existing"

vulnerable"

atheroscleroticplaques[4].Moreover，statinshavebeenshowntodecreasetheincidenceofadversecardiovascularoutcomes，includingdeath，myocardialinfarction，stroke，atrialfibrillation，andrenaldysfunctioninambulatorypatientpopulations[2，513].Statinadministrationisalsoassociatedwithalowerincidenceofadversecardiovascularoutcomesafterinvasiveproceduressuchaspercutaneoustransluminalcoronaryangioplasty[9]andcardiac[14，15]，vascular[1618]，andnoncardiovascular[19]surgery.However，thebeneficialeffectsofstatintherapyarenotlimitedtopatientswithhypercholesterolemia.Severalrandomizedclinicaltrialshaveshownthat，eveninpatientswithnormaltotalandLDLcholesterollevels，statinadministrationisassociatedwithlesscardiovascularmorbidityandmortality[7，8].Statinsthusexertpleiotropiceffectsindependentoftheireffectsoncholesterol[20].

　　Althoughtheexactmechanismsbywhichstatinsreducethelikelihoodofcardiovasculareventshaveyettobefullyelucidated，themetaboliteofHMG-CoAreductase，mevalonicacid，isaprecursorofcholesterolandtheisoprenoidintermediatesfarnesylandgeranyl-geranylpyrophosphate.Theseintermediatesareessentialforthepost-translationalmodificationofintracellularG-proteins，suchasRho，Rac，andRas，thatregulateendothelial，platelet，andleukocytefunction[2123].Statinshavealsobeenshowntomodulatevascularremodelingbyinhibitingcellularmatrixmetalloproteinasesandtranscriptionfactors，suchasnuclearfactor-B[23].Inpatientswithacutecoronarysyndromesoridiopathicdilatedcardiomyopathy，statintherapyhasbeenshowntoreduceuntowardinflammatoryactivity，includingchangesinC-reactiveprotein（CRP），serumamyloidA，tumornecrosisfactoralpha（TNF-），interleukin-6，andbrainnatriureticpeptidelevels[21，24，25].Moreover，statinshavebeenreportedtodecreaseserumlevelsoftheinflammatorymarkerCRPwithin14daysofadministration，suggestinganacuteprotectiveroleforthesedrugs[26].Statinshavealsobeenshowntoreducetissueinjuryinmodelsofischemiaandreperfusioninseveralorgans，includingtheheart，lung，brain，kidney，andgut[19，2730].Further，statinshavebeenshowntoattenuatevasoconstrictionbyincreasingendothelialnitricoxide（NO）activity，abenefitseenwithin6weeksofthestartoftreatment[31].Statinsthusexertpleiotropiceffects，independentofcholesterolreduction，thathavedirectantiatherosclerotic，antithrombotic，andanti-inflammatoryimpacts[23，3234].

　　Increasingevidencesuggeststhatstatinsmightbeusefulforcancerpreventionand/ortreatmentthroughtheirinteractionswithessentialcellularfunctions，suchascellproliferationanddifferentiation[35，36].Forexample，bothinvitroandinvivostudieshavedemonstratedthatstatinsinhibittumorgrowthandinduceapoptosisinavarietyoftumorcells，includingmelanoma[37]，glioma[38]，neuroblastoma[39]，andleukemiacelllines[40].Additionally，severalclinicaltrialshavealsoassessedtheantitumoractivityofstatins[4146].Thepotentialroleofstatinsinbothcancerpreventionandtreatmentisreviewed.

　　ANTITUMOREFFECTSOFSTATINS

　　InhibitionofTumorCellGrowth

　　Cholesterolisamajorstructuralcomponentofcellmembranes，andthecholesterolbiosyntheticpathwayiscloselyrelatedtocell-growthprocesses.StatinsreducenotonlyserumcholesterollevelsbutalsomevalonatesynthesisbyinhibitingHMG-CoAreductase.Mevalonateisaprecursorofseveralmajorproductsregulatingthecellcycle，includingdolichol，geranylpyrophosphate（GPP）andfarnesyl-pyrophosphate（FPP）[3].DolicholhasastimulatoryeffectonDNAsynthesisandislinkedtoseveraltumorcellproteins[47].GPPandFPPcauseisoprenylationoftheintra-cellularG-proteinsRasandRho，whichinturnregulatethesignaltransductionofseveralmembranereceptorscrucialforthetranscriptionofgenesinvolvedincellproliferation，differentiation，andapoptosis.

　　RasandRhogenemutationsarefoundinavarietyofpancreas（90%），colon（50%），lung（30%），thyroid（50%），andmyeloidleukemia（30%）tumortypes[36].Statinsinhibitdolichol，GPPandFPPproduction，andblocktumorcellgrowthinvitroandinvivo[48].Forexample，lovastatinhasbeenshowntostabilizethecellcyclekinaseinhibitorsp21andp27，andtoarrestbreastcancercelllinesintheG1phaseofthecellcycle[49].Similarly，cerivastatinhasbeendemonstratedtoinhibitRas-andRho-mediatedcellproliferation[50].Theseobservationshaveledseveralinvestigatorstohypothesizethatstatinsmightinhibitthegrowthofavarietyoftumorcelltypes，includingprostate，gastric，andpancreaticcarcinoma，aswellascolonadenocarcinoma，neuroblastoma，glioblastoma，mesothelioma，melanoma，andacutemyeloidleukemiacells[42，5156].Interestingly，statinsalsomodifynormalendothelial，fibroblast，andsmoothmusclecellgrowth[57，58].However，normalcellsappeartobemoreresistanttotheantiproliferativeeffectsofstatinsrelativetotumorcells，whicharemuchmorelikelytoproliferate[59，60].

　　InhibitionofAngiogenesis

　　Angiogenesisplaysanimportantroleinprimarytumorgrowthandmetastasis[61].Statinshavebeenreportedtobothstimulate[6264]andinhibit[65，66]bloodvesselformationdependinguponthetumorcelltype[67].Forexample，high-dosecerivastatindecreasedtumorvascularizationby51%inamurineLewislungcancermodel[68].Statinshavebeenshowntodecreasevascularendothelialgrowthfactorproduction[69]andtoinhibitcapillarytubeformation[66，70].Incontrast，statinshavealsobeenshowntostimulateproteinkinaseB，whichinturnactivatesendothelialnitricoxidesynthase（eNOS）andincreasesproangiogenicactivity[64].ThisNO-mediatedeffectdependsoncaveolin，aproteinthatdownregulateseNOSactivity[71].Endothelialcellswithlowcaveolinexpressionseemtobeextremelysensitiveforstatin-inducedangiogenesis.Finally，thereisgrowingevidencethattheeffectsofstatinsonangiogenesisareconcentrationdependent.Weisetal.showedthatlowconcentrations（0.5mg/kgperday）ofcerivastatinandatorvastatinenhancedendothelialcellproliferation，whereashighconcentrations（2.5mg/kgperday）significantlyinhibitedangiogenesis[68].

　　InductionofApoptosis

　　Severalexperimentalcancermodelshaveshownthatstatinsexertproapoptoticpropertiesinavarietyoftumorcells.Forexample，lovastatininducesaprofoundapoptoticresponseincellsderivedfromjuvenilemonomyelocyticleukemia，pediatricsolidmalignancies（e.g.，rhabdomyosarcomaandmedulloblastoma），malignantmesothelioma，astrocytoma，andsquamouscellcarcinomaofthecervix，head，andneck[53，59，72，73].Further，thisstatin-mediatedapoptoticeffectisalsoseenincelllinestreatedwithcerivastatin[74，75].Infact，Wongetal.foundthatcerivastatinis10timesmorepotentininducingapoptosisinacutemyeloblasticleukemia（AML）celllinesthanotherstatins[75].Additionally，tumorcellsthemselvesdiffersignificantlyintheirsensitivitytostatin-inducedcelldeath.AMLcells[76]andneuroblastomacells[77]seemtobeparticularlysensitivetostatin-inducedapoptosis，whereasacutelymphoblasticleukemiacellsarerelativelyinsensitive.

　　Proposedmechanismsforstatin-mediatedapoptosisincludeanupregulationofproapoptoticproteinexpression（e.g.，Bax，Bim）[78]，combinedwithdecreasedanti-apoptoticproteinexpression（e.g.，Bcl-2）[40].Forexample，lovastatinincreasesBimproteinlevelsandinducescelldeathinhumanglioblastomacelllines[79].Theseeffectshavebeenseeninbothsolidtumorandhematologicmalignancies.Statinshavealsobeenshowntoactivatecaspaseproteasesinvolvedinprogrammedcelldeath.Cafforioetal.showedthatcerivastatincausedcelldeathinhumanmyelomatumorcellsbyactivatingcaspase-3