TheRoleofStatinsinCancerTherapy.docx

上传人:b****7 文档编号:11096547 上传时间:2023-02-25 格式:DOCX 页数:21 大小:30.89KB
下载 相关 举报
TheRoleofStatinsinCancerTherapy.docx_第1页
第1页 / 共21页
TheRoleofStatinsinCancerTherapy.docx_第2页
第2页 / 共21页
TheRoleofStatinsinCancerTherapy.docx_第3页
第3页 / 共21页
TheRoleofStatinsinCancerTherapy.docx_第4页
第4页 / 共21页
TheRoleofStatinsinCancerTherapy.docx_第5页
第5页 / 共21页
点击查看更多>>
下载资源
资源描述

TheRoleofStatinsinCancerTherapy.docx

《TheRoleofStatinsinCancerTherapy.docx》由会员分享,可在线阅读,更多相关《TheRoleofStatinsinCancerTherapy.docx(21页珍藏版)》请在冰豆网上搜索。

TheRoleofStatinsinCancerTherapy.docx

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

展开阅读全文
相关资源
猜你喜欢
相关搜索

当前位置:首页 > 人文社科 > 法律资料

copyright@ 2008-2022 冰豆网网站版权所有

经营许可证编号:鄂ICP备2022015515号-1