药理学专题-肿瘤细胞的代谢改变与抗肿瘤药物靶点的发现

药理学专题-肿瘤细胞的代谢改变与抗肿瘤药物靶点的发现ThechangesinmetabolismintumorandthefindingofnewtargetshigherproliferativeratesMetabolicactivitiesincancercellsaredramaticallyfast.morenutrienthungryandexcretemorewasteproductsresultinginabuild-upofmetabolitesinsidethecellandtheformationofamorehostileenvironmentoutsidethecellInordertodivide,acellneedstobothincreaseitssizeandreplicateitsDNA—processesthatarehugelymetabolicallydemandingandwhichrequirelargequantitiesofproteins,lipidsandnucleotides,aswellasenergyintheformofATPAboutmetabolicalterationofcancercellDrivers(AandB).Themetabolicderangementsincancercellsmayariseeitherfromtheselectionofcellsthathaveadaptedtothetumormicroenvironmentorfromaberrantsignalingduetooncogeneactivation.Advantages(C–E).Thealteredmetabolismofcancercellsislikelytoimbuethemwithseveralproliferativeandsurvivaladvantages,PotentialLiabilities(FandG).Thisalteredmetabolism,however,mayalsoconferseveralvulnerabilitiesoncancercells.WarburgeffectWhenglucoseentersthecellthroughaglucosetransporter,itisphosphorylatedbyHKtoglucose-6-phosphate,whichisfurthermetabolizedbyglycolysistopyruvateinthecytosol.Underaerobicconditions,normalcellsusepyruvatedehydrogenase(PDH)toconvertmostpyruvatetoacetyl-CoA.Theacetyl-CoAisthenoxidizedviatheTCAcycle,providingsourcesofATPsynthesis.Incontrast,themetabolicpathwaysofglucoseutilizationincancerarechangedfromATPgenerationbyoxidativephosphorylationtoATPgenerationthroughglycolysis.Also,forcellproliferationtooccur,cancercellsrequirethesynthesisofnewmacromolecules(forexle,nucleicacids,lipids,proteins).Keyenzymesthatmaybepromisingtargetsforcancertherapyarehighlightedinred.TCAenzymesthatareknowntobemutatedincancerareshowninpurple:IDH2,SDH,andFH.TheregulationofglucosemetabolismincancercellsWarburgEffectMiranJangetal.Cancercellmetabolism:implicationsfortherapeutictargets.Experimental&MolecularMedicine(2013)Oct4;45:e45DanielA.Tennantet.al,Targetingmetabolictransformationforcancertherapy.Nature,10267-277(2010)havebeenusedaschemotherapeuticagentsforseveralyearsUsedaschemotherapeuticagentsforseveralyearstargetthefinalstagesinthenucleotidesyntheticpathwaylackoftumourspecificityfewnewagentsintheclinicthatdirectlytargetthispathwaydirectedtowardsthepathwaysthatsupplyintermediatestobeusedinnucleotidebiosynthesis(PPP,TCA)1.TargetingnucleotidebiosynthesisItispossiblethatthenucleotidebuildingblocksnecessaryfornormalproliferatingcellscanbesuppliedbytheexogenouspoolofnutrients,suchasnucleosides.Butowingtopoorvascularizationandthehighproliferativeburdenofcancercells,tumorsmightrelymoreonendogenoussynthesisfromglucoseandglutamineBlockingearlystagesofnucleotidebiosynthesissuchasribose-5-phosphate(R5P)productioncouldprovideabettertherapeuticwindowthanthatshownbypreviousantimetabolictherapies.donotseemtohaveassignificantaneffectontumourgrowthasmonotherapyButcanresensitizetumorstootherchemotherapeuticagents(suchaspaclitaxel)Agentsusedincombinationwithglycolysisinhibitorsincludebothchemotherapyandradiotherapy2.Targetingglycolysis3.Targetingaminoacidmetabolismseveralusesinthetumorcellasubstrateforproteinsynthesisnon-essentialaminoacids(throughtransamination)replenishTCAcyclemetabolitelevelsanessentialstartingpointfornucleotidebiosynthesisinhibitstheproliferationoftumorcellsandpromotestheirdifferentiation；butwerefoundtobetoxicorraisedanimmunereactionmorespecificinhibitorsofthisenzymeareimportantintreatingglutamine-dependenttumorsDirecttargetsconsistofthemetabolicenzymesthemselves.Indirecttargetsincludesignalingpathwaysthatareactivatedorrepressedintumors,resultinginaberrantmetaboliccontrol.OncogenesandmetabolismOncogenesisgenerallyproceedsviatheprogressiveacquisitionofgeneticandepigeneticalterationsthattogetherinfluencevariouscellularprocesses,includingmetabolicpathways.Suchalterations,whichgenerallyinvolveeithertheinactivationofoncosuppressorgenesorthehyperactivationofoncogenes,notonlyallowformalignanttransformationbutalsosupportthesurvivalofestablishedtumours.Inhibitionofoncogenicdriversand/orthereconstitutionof(previouslylost)oncosuppressivefunctionsnormallyresultsinrobustantineoplasticeffectsfrequentlyinvolvesstressresponsepathways,offersanattractiveapproachforthedevelopmentofnoveltherapeuticstrategiesagainstcancer.

MolecularMechanismsofCancer-SpecificMetabolicReprogrammingAsaresultofoncogenicgain-of-functionevents(pink)orthelossoftumorsuppressors(green)affectingthePI3K/Akt/mTOR/HIFaxisand/orinactivationofthep53system,astereotypedpatternofmetabolicchangesisinduced,leadingtocancer-associatedalterationsinmetabolism.mTORisregulatedbythePI3K–PTEN–AKTpathway(seetheFigure),whichisoveractivatedinmanytypesofbothsporadicandhereditarycancer.ThislimitedsuccesscanbeexplainedbythenegativefeedbackloopdownstreamofmTORandbythespecificityofrapamycinformTORcomplex1.Asaconsequence,rapamycintreatmentleadstotheoveractivationofthePI3K–PTEN–AKTpathway.NewapproachesshouldfocusoninhibitingbothmTORC1andmTORC2complexes,andontreatmentsthatcombinemTORinhibitorswithothersignallingpathwayinhibitors(particularlythePI3K–PTEN–AKTpathway).TheclinicaloutcomeintrialsusingmTORinhibitorsasmonotherapyhasshownonlymodestresults.mTORandcancertherapy1.BryanT.Oronsky,FollowtheATP:tumorenergyproduction:aperspective.AnticancerAgentsMedChem.2014;14(9):1187-98.2.W.J.Israelsenetal.Cell155,397–409;2013SpecialenzymeAlteringdietAfurtherstrategytargetingenergygenerationintumorsistheuseoftheketogenicdiet:alow-carbohydrateandhigh-fat(specificallymedium-chaintriglyceride)diet.AlthoughnormalcellscanadapttousingketonebodiestoproduceATP,tumorcellsthatrelyonhighglycolyticfluxwouldnotbeexpectedtosurviveonthisalternativefuelsource.Althoughthischangeindietisnotlikelytobeamonotherapy,itmaywellprovetobeausefuladditiontootherantimetabolictherapiesSimultaneouslytargetingoncogeneandnononcogeneaddiction,whichoftenmanifestsatthelevelofmetabolismorstressresponses,isalsoapromisingapproach.Cancerisdefectiveinmitochondrialrespiration,whichdrivesaswitchtoanalternativeenergysource.Thebasisofseveralmechanismsoftumorresistancetobothradiotherapyandchemotherapyisintheaberrantmetabolismofatumor,andsothereactivationofamore‘no