TheRoleofStatinsinCancerTherapy.docx
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TheRoleofStatinsinCancerTherapy
TheRoleofStatinsinCancerTherapy
【关键词】HMG-CoA,reductase,inhibitor,•,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