Engineering5(2019)32–39Contents lists available at ScienceDirectEngineeringResearch
TraditionalChineseMedicine—Review
Artemisinin,theMagicDrugDiscoveredfromTraditionalChineseMedicine
JigangWanga,b,c,d,#,ChengchaoXuc,#,YinKwanWongd,#,YujieLia,b,FulongLiaoa,b,TingliangJianga,b,YouyouTua,b,?aArtemisininResearchCenter,ChinaAcademyofChineseMedicalSciences,Beijing100700,ChinaInstituteofChineseMateriaMedica,ChinaAcademyofChineseMedicalSciences,Beijing100700,ChinacDepartmentofPharmacology,YongLooLinSchoolofMedicine,NationalUniversityofSingapore,Singapore117600,SingaporedDepartmentofPhysiology,YongLooLinSchoolofMedicine,NationalUniversityofSingapore,Singapore117597,Singaporebarticleinfoabstract
Artemisinin and its derivatives represent the most important and in?uential class of drugs in the ?ght against malaria. Since the discovery of artemisinin in the early 1970s, the global community has made great strides in characterizing and understanding this remarkable phytochemical and its unique chemical and pharmacological properties. Today, even as artemisinin continues to serve as the foundation for antimalarial therapy, numerous challenges have surfaced in the continued application and development of this family of drugs. These challenges include the emergence of delayed treatment responses to artemisinins in malaria and efforts to apply artemisinins for non-malarial indications. Here, we provide an overview of the story of artemisinin in terms of its past, present, and future. In particular, we comment on the current understanding of the mechanism of action (MOA) of artemisinins, and emphasize the impor-tance of relating mechanistic studies to therapeutic outcomes, both in malarial and non-malarial contexts.
ó 2019 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license
Articlehistory:Received8June2018Revised1August2018Accepted12November2018Availableonline18December2018Keywords:ArtemisininMechanismofactionMalariaAnti-cancer1.IntroductionMalariahasbeenadebilitatingdiseasewithglobalin?uencesinceancienttimesandcontinuestobeoneofthemostwide-spreadanddamaginginfectiousdiseasestoday[1].Withthecauseofdiseasehavinglongbeenmisattributedto‘‘badair,”thetrans-missibleandparasiticnatureofmalariaremainedunknownuntiltheworksofCharlesLouisAlphonseLaveranandRonaldRossinthelate1800s.Their?ndingsestablishedthatprotozoabelongingtothegenusPlasmodiumcausedmalaria,andthatAnophelesmos-quitoesweretheprimaryvectorsofmalarialinfections.TheseobservationsmadeLaveranandRosstwooftheearliestrecipientsoftheNobelPrizeinPhysiologyorMedicine[2].Inthedecadesfollowingtheirdiscoveries,ground-breakingprogresshasbeenmadeinthebattleagainstthedisease.Thecru-sadelaunchedbytheChinesegovernmentinthelate1960stosearchforcuresformalariaultimatelyculminatedinthediscoveryofartemisinin.Artemisinin(anditsvariousderivatives,whichwe?Correspondingauthor.#E-mailaddress:yytu@icmm.ac.cn(Y.Tu).Theseauthorscontributedequally.
willrefertocollectivelyas‘‘artemisinin”unlessotherwisespeci-?ed)isasesquiterpenelactonecompound(Fig.1)withauniquechemicalstructurederivedfromthesweetwormwoodplant,ArtemisiaannuaL.(Fig.2).Sinceitsdiscovery,ithasbecomethemostimportantandeffectiveantimalarialdrug[3].Inmanyways,artemisininisatrulyfascinatingdrug.Fromthetumultuousprocessofitsdiscovery,whichwasdeeplytiedtotra-ditionalChinesemedicine(TCM),toitsremarkablepotencyandimpactasanantimalarialdrug,itisnotsurprisingthatartemisininhascapturedagreatdealofattentionsinceitsintroductiontotheworldstage[1].Over40yearsafteritsdiscovery,artemisininremainsourbulwarkagainstmalariaandisthefoundationofallmajorantimalarialtherapies[4].Yearsofresearchspanningarangeofdisciplineshavegoneintotheexplorationandelucidationofthemechanismsofartemisinininitsantimalarialrole[5].Beyondthat,effortshavebeenmadetorepurposeartemisininfornon-malarialapplications,therebyraisingconsiderableanticipa-tionoverthefuturedevelopmentofthisdrug[6].Withthatinmind,wefeelthatitisagoodtimetobroadlyreviewthetimelineofthisin?uentialdrug,spanningitspast,present,andfuture.Beginningwithalookbackatthestoryofthediscoveryanddevelopmentofartemisinin,wethenreviewJ.Wangetal./Engineering5(2019)32–3933Fig.1.Artemisininanditsclinicallyusedderivatives.Fig.2.ArtemisiaannuaL.inthe?eld.anddiscussthecontemporaryunderstandingofthemechanismofaction(MOA)ofartemisinininmalaria.Weconcludebylookingaheadatcurrenteffortstorepurposeartemisininforpossiblerolesoutsideofmalaria.Webelievethatthisarticlewillprovideawell-roundedbackgroundofartemisinin,alongwithrelevantinsightsintothesalienttopicssurroundingthisremarkabledrug.2.ThejourneyofdiscoveryWebeginwithabrieftracingoftheremarkablejourneythatledtothediscoveryanddevelopmentofartemisinin.RecordsofmalariainTCMdatebackthousandsofyears,andthesameistruefortheusageofArtemisia(Qinghao)plantsasmedicinalherbs.Firstmentionedasaspeci?cremedyformalarialsymptomsinGeHong’sZhouhouBeijiFang(HandbookofPrescriptionsforEmergency)datingbacktotheEasternJinDynasty(317–420AD),theapplicationofQinghaoandothertechniquesformalarialreliefwassubsequentlynotedinaseriesofhistoricalChinesemedicalwritingsthatincludedthein?uentialBencaoGangmu(CompendiumofMateriaMedica)byLiShizhen(MingDynasty,1368–1644AD).Thiswealthofancientknowledgewouldlaterprovetobeinstrumentalinthediscoveryanddevelopmentofartemisinin.IntheyearsfollowingWorldWarII,thedevelopmentanddeploymentofthepotentinsecticidedichloro-diphenyl-trichloro-ethane(DDT)andnewantimalarialdrugssuchaschloroquine(CQ)resultedingreatprogressincombatingmalaria.However,theWorldHealthOrganization(WHO)’scampaigninthe1950stocombatanderadicatemalariaaroundtheworldwaseventuallymetwithchallengesrelatedtoresistance.TheemergenceofDDT-resistantvectorsanddrug-resistantparasitesledtoareboundofthedisease,especiallyinregionssuchasSoutheastAsiaandsub-SaharanAfrica[7].Thissetbackpromptedanurgentneedfornovelantimalarialdrugs.Signi?canteffortshadbeenmadebytheUnitedStatesduetotheVietnamWarandtheprevalenceofdrug-resistantmalariainthatregion.TheChinesegovernmentalsoinitiatedeffortsinmalarialresearcharoundthistime.Inparticular,anationalprojectcalledProject523(namedafteritsdateofinau-guration,23May1967)wassetuptoconsolidatemalarialresearchonanationallevel[8].In1969,ProfessorYouyouTuwasselectedtoleadaresearchgroupwithintheprojectthatfocusedonscreeningTCMfornovelantimalarialdrugs.ThisworktookplaceattheInstituteofChineseMateriaMedicaoftheChinaAcademyofChineseMedicalSciences.DrawingfromamassiverepositoryofTCMknowledgethatincludedancientliterature,folklore,andoralinterviewswithprac-titioners,Tuandcolleaguesworkedfromalistofover2000herbalremedies,ofwhichsome640weredeemedtobepossible‘‘hits.”Fromthisselection,over380extractsfromapproximately200herbs(includingQinghao/Artemisiaextracts)wereeventuallycollectedandtested,mostlygivingunsatisfactoryresults[1,9].TheQinghaoextractneverthelessdrewparticularintereststartingaround1971,asitproducedpromisingbutinconsistentresults[1].This?ndingpromptedarevisitationoftheliterature,andledtoperhapsthemostimportantbreakthroughinthediscoveryprocess.ReturningtotheearliestrecordoftheuseofQinghaototreatmalarialsymptoms,whichwasinGeHong’sZhouhouBeijiFang(HandbookofPrescriptionsforEmergency),TunotedthattheinstructionsfortheQinghaoprescriptioninvolvedconsumingthestrained‘‘juice”oftheQinghaoplantimmersedinwater.Itwasnotablethattheinstructionmadenomentionofheatingthemedicine—somethingthatwasotherwisecommonforprescrip-tionsinTCM.DrawingfromtheliteratureandherownknowledgeofTCM,Tuarrivedattheideatomodifytheextractionprocesstouselow-temperatureconditions.Theextractsproducedfromthisnewprocedurewerefurtherpuri?edbyseparationoftheacidicandneutralphasesinordertoretainactivecomponentswhilereducingthetoxicityoftheoriginalextract.Theresultantsubstancedisplayedastriking100?fectivenessagainstrodentmalariainexperimentscarriedoutaroundOctober1971.ThisremarkableresultwasthenfullyreproducedinmonkeymalariaexperimentscarriedoutinlateDecemberofthesameyear,thusestablishingtheef?cacyoftheQinghaoextractbeyonddoubt[1].34J.Wangetal./Engineering5(2019)32–39Thebreakthroughhadbeenmade,butthejourneyofdrugdevelopmentwasbynomeanscomplete.ConditionsinChinaatthattimemadeitdif?culttoperformclinicaltrialsofnewdrugcandidatestoascertaintheirsafetyforhumans.Inanattempttoacceleratetheprocessduetotheseasonalandtime-sensitivenat-ureofmalarialresearch,Tuandcolleaguesdecidedtovolunteerthemselvesasthe?rsthumansubjectsfortoxicityanddose-?ndingtests[8].Thisactestablishedthesafetypro?leoftheQinghaoextractandenabledclinicaltrialstobecarriedoutimme-diately,inthelatterhalfof1972.Thetrials(whichwerecarriedoutinHainanProvinceandatthe302HospitalPLA(nowincorporatedintotheFifthMedicalCenteroftheChinesePLAGeneralHospital)inBeijing)provedsuccessful,andpavedthewayforQinghaoresearchtobepushedtothenationallevel.AsubsequentconcertedeffortonthepartoftheChinesescienti?ccommunityatlargedrovefurtherresearchanddevelopmentofQinghaoforward.TheactivecomponentoftheQinghaoextract,artemisinin(alsoknownasQinghaosu)itself,wasisolatedinNovember1972byTu’steamattheInstituteofChineseMateriaMedica.Theteamwouldlatergoontodevelopdihydroartemisinin(DHA),whichremainsoneofthemostpharmacologicallyrelevantderivativestoday.Incollabora-tionwithotherinstitutesacrossChina,furthergroundworkindrugdevelopment,includingthedeterminationofthestereo-structureofartemisininandfurtherderivatizationofartemisinin,wascarriedoutinthefollowingdecade[10,11].Theseefforts,amongothers,culminatedinthefourthmeetingoftheScienti?cWorkingGroupontheChemotherapyofMalariaheldinBeijingin1981,wherethe?ndingswerepresentedbyTuforthe?rsttime.Theresultswerepublishedin1982asaseriesofpapersunderthename‘‘ChinaCooperativeResearchGrouponQinghaosuandItsDerivativesasAntimalarials”[12,13];thusthegiftfromChinesemedicinewasdeliveredtotherestoftheworld.Inthesubsequentyearsofthe1980s,artemisininanditsderiva-tivesweresuccessfullyemployedinChinatotreatthousandsofmalariapatients[1].Astheproblemofdrug-resistantmalariacon-tinuedtoworsenelsewhere,itwasnotlongbeforethecommence-mentofclinicalstudieswithartemisinininotherendemicregionsinAsia[14–19].Consistentandencouragingresultsledtotheexpansionofsuchstudies,particularlytowardAfrica[19–24].Theevidencewasclearthatartemisinin-basedtherapy,especiallyincombinationwithaslower-actingantimalarialsuchasme?o-quineorpiperaquine,ledtosigni?cantimprovementsinparasiteclearanceandarapiddiminishingofsymptomsforbothuncompli-catedandseverePlasmodiumfalciparummalariainfection.Atthesametime,itstolerabilitywasshowntobeexcellent,asreportsoftoxicityandsafetyconcernsremainedminimal[25].Acrossmorethanadecade’sworthofindependentrandomizedclinicalstudiesandmeta-analyses,theoutstandingef?cacyandsafetyofartemisinin-basedtherapybecameincreasinglyclear.Finally,in2006,theWHOannouncedanalterationofitsstrategytofullyemployartemisinincombinationtherapies(ACTs)asthe?rst-linetreatmentagainstmalaria[26].ACTsremainthemosteffectiveandrecommendedantimalarialtherapiestoday[4].3.ThesearchforamechanismofactionIthasbeenmorethanadecadesincetheimplementationofACTsastheof?cial?rst-linetreatmentformalariaandoverthreedecadessincethediscoveryofartemisinin.Inthistime,theclinicalandpharmacologicalcharacteristicsofartemisinintherapyhavebeenextensivelyscrutinizedandreported[27–30].Althoughthespeci?csofvariousderivativescandiffer,artemisinindrugsarecharacterizedbyrapidactionandpotency,lowtoxicity,andashorthalf-life,whichmakescombinationtherapywithlonger-actingantimalarialdrugsidealandrecommended[30].Apartfromitspharmacologicalproperties,elucidatingtheMOAofadrugisimportantforoptimizingtreatmentregimens.Dosages,drugcom-binations,andevenconsiderationsofdrugresistancearecloselyrelatedtothemolecularbasisofadrug’sactivity.Itisthussome-whatsurprisingthatdespitedecadesofwidespreadapplication,ourunderstandingoftheMOAofartemisininremainsfairlyincom-plete.Here,weprovideabriefoverviewoftheprevailingunder-standingaswellasmorerecentdevelopmentsinmechanisticstudiesofartemisinin[31,32].Ingeneral,theoutstandingthera-peuticpropertiesofartemisinincanbethoughtofasaresultoftwomajorprocesses:itsuniquemechanismofactivation,anditsdownstreamactivityanddrugtargets.Thesemechanismscombinetoyieldahighlypotent,yethighlyspeci?c,drug.3.1.DrugactivationArtemisininanditsderivativesaresesquiterpenelactonesthatbearthe1,2,4-trioxanemoietyasthepharmacophore[33].Inparticular,theendoperoxidebridgewithinthisgroupiswellunderstoodtobeessentialforthepharmacologicalactivityofartemisinin[13,34,35].Artemisininsareprodrugsintwosenses:?rst,manyderivativesarerapidlyconvertedtoDHAinvivo,andsecond,theirMOAdependsonactivationbycleavageoftheendoperoxidebridge.Themechanismofthiscleavageremainsanissueinactiveresearch[36].Malarialparasitesarecharacterizedbyextensivehemoglobinuptakeanddigestionduringtheerythrocyticstageoftheirlifecycle[37,38].Thisreleasescopiousamountsoffreeredox-activehemeandfreeferrousiron(Fe2+),whicharethoughttounderlietheparasitespeci?cityofartemisi-nin.Indeed,hemoglobindigestionhasbeenstronglylinkedwithartemisininsusceptibilityinparasites[38,39].Multiplemodelshavebeenproposedwithregardtothemechanismofendoperoxidecleavagebyeitherfreeredox-activehemeorfreeferrousiron,andthedownstreammoleculareventsthatfollowcleavage[36,40–48].Theseproposalsdifferintermsofthenatureofthecleavageandtheidentityofthereactiveintermediatesproducedbydrugactivation.Ingeneralterms,however,theyexplaintheparasite-speci?cdrugactivationthroughwhichreactivespeciesareproduced,leadingtocellulardamageandparasitekilling.Recentevidencesuggeststhatfreeredox-activehememayplayapredominantroleindrugactivation[49,50].A2008studyprovidedinvitrodatathatindicatedthatferroushememaybeastrongeractivatorofartemisininthanotheriron-containingspecies,includ-inghemin,freeferrousiron,andundigestedhemoglobin[49].Similarobservationsweremadeinliveparasites,inwhichartemisininactivationwasblockedbyinhibitinghemoglobindigestionbutnotbythechelationoffreeferrousiron[47].Thus,theprocessofhemoglobindigestionininfectederythrocytes,whichisrequiredforparasitegrowth,isthekeytothespeci?cityofartemisininactivation[38].Interestingly,instudiesusingyeastcellsasaproxyformalariaparasites[51,52],itwasfoundthatmitochondriaweredirectlyinvolvedinboththeactivationandactionofartemisinin,thusfur-therlinkingartemisininactiontoreactiveoxidativespecies(ROS)productionandoxidativedamage.Itisalsoplausiblethatmultipleredundantactivationpathwaysmayexistindifferentenviron-mentsorlocalities,wheretheconditionsandmagnitudeofactiva-tioncandiffer[53].Lookingahead,itwillbecrucialtoconsiderthepivotalroleofdrugactivationintheactivityofartemisininandtofurtherelucidateitsmechanismsunderdifferentconditions.3.2.DownstreammechanismThecrucialstepinelucidatingadrug’sMOAistoidentifyitscel-lulartargets.Intheconventionalunderstandingofdrugdesignandmechanisms,adrugmodi?esoneormorespeci?ccellulartargets,suchasproteins,inordertoeffectdownstreamchanges.However,J.Wangetal./Engineering5(2019)32–3935theexceedinglyfast-actingandpotentnatureofartemisininactiv-ity,takentogetherwithitsabilitytoalkylatetargets,maybeduetoquiteadifferentmechanism.Firstofall,hemereleasesfromhemoglobindigestionfunctionsthatliebeyonddrugactivation,aspreviouslyoutlined.Excesshemeisconvertedininfectederythrocytestohematin,whichistoxictotheparasiteviaoxidativedamageanddirectlysisofcellmembranes[54].Malarialparasiteshavethereforeevolvedadetoxifyingmech-anismthatconvertshematintothenontoxicandinertcrystallizedhemozoinviaabiocrystallizationprocess[55].Activatedartemisi-ninhasbeenreportedtopreventtheformationofhemozoinbyalkylatingheme;therefore,itfunctionsinasimilarcapacitytootherantimalarialdrugsthatactonhemozoinformation,suchasCQ[45,56–58].Thus,freehemefromhemoglobindigestionservesasboththeactivatorandthetargetofartemisinin[45].GiventhatactivatedartemisininisthoughttogenerateROS,itisunsurprisingthatartemisininhasalsobeenreportedtodirectlyalkylateproteintargets[59,60].Thetranslationallycontrolledtumorprotein(TCTP)andthePlasmodiumsarco/endoplasmicretic-ulumCa2+-ATPasePfATP6wereamongthe?rsttargetsofinterestthatwereidenti?edasinteractingpartnersofartemisinin[61–63].ConsiderationoftheroleofsingletargetsintheactivityofartemisininhasnowevolvedintoMOAsthatmaydependonmultipletargets,aslaterstudieshaveshown[64–67].Usingunbiasedproteomicsmethods,ithasbeenobservedthatartemisinintargetingmaybepromiscuousratherthanmonotarget-speci?c.Inthe?rststudythatsystematicallyreportedartemisininbindingtargets,over100proteinswereidenti?edinliveparasitestrains[47].AnindependentstudycarriedoutbyIsmailetal.[68]ledtoconsistent?ndings.Theseresultssupportapromiscuousmecha-nismofartemisinintargetinginwhichactivatedartemisininalkylatesanddamagesmanycellularproteins,therebydisruptingmultiplekeybiologicalfunctionsandresultingintoxicityandlethalityinparasites[47,48,50].Interestingly,PfATP6andotherkeytransporterssuchasPfCRTandPfmdr1areconsistentlylabeledinthesetypesofexperiments.These?ndingsareconsistentwithPfATP6beinganimportanttargetforartemisinins[47,68].Asanindependentlineofevidence,themappedbindingsitesofartemi-sinintoTCTPfurthersupportaheme-activatedpromiscuousmechanisminwhichmodi?cationsitesareproximity-basedandessentiallyrandom[50].Ourcurrentknowledgeofartemisininpaintsapictureofadrugwithauniqueandelegantmechanism.Artemisininanditsderiva-tivesareprodrugsthatabsolutelyrequireendoperoxidegroupcleavagefordrugactivationandsubsequentanti-parasiteactivity.Artemisininactivationisdependentonaheme-richenvironment,whichisspeci?ctoinfectederythrocytesaswellasbeinganunavoidableoutcomeofparasitemetabolism.Theheme-richenvi-ronmentitselfisthenexploitedbytheactivateddrugtoachieveef?cientparasitekilling.Thismechanismessentiallylinksinfectionandparasitegrowthtodrugactivation,thusensuringboththeout-standingspeci?cityandthetolerabilityofartemisinintherapy.Atthesametime,activatedartemisininindiscriminatelydamagesproximalproteinsandcellularstructures.Ratherthantargetingasingleproteinorcellularfunction,likethemajorityofconventionaldrugs(includingmostantimalarials),artemisininactslikealess-discriminative‘‘bomb”thatdetonatesuponactivationtocausewidespreaddamage.Thespeci?cityofartemisininmaythereforebeseentobebasedonitsactivationratherthanonitstargets.Theseuniquepropertiesofartemisininmakeitalmosttheidealweaponagainstmalaria,especiallyincombinationwithotherdrugsthatactviadistinctmechanismsandcomplementthepharmacologicalpro?leofartemisinin.Anobviousadvantageofapromiscuouslytargetingdrugisalsoworthnotinghere:Thedevel-opmentofdrugresistanceismuchmoredif?cultwhenmutationinoneorafewspeci?ctargetsisnotsuf?cienttoseriouslyimpactdrugactivity.Thisadvantagecouldwellexplainwhyartemisininhasremainedgenerallyef?caciousdespiteitsubiquitoususeoverdecades.Nevertheless,recenttrendshavesignaledtheincidenceandriseofmalariathatisbeingclearedmoreslowlybyACTs,especiallyintheAsianendemicregions[69].Thistopichasbeencomprehen-sivelycoveredfromvariousanglesbyrecentreviewsandcommen-taries[69–75].Regardlessofthecontroversiesabouttheexactde?nitionof‘‘artemisininresistance”inthe?eld,thethreatisundoubtedlyreal,giventheplacethatartemisininoccupiesinthecontrolofmalaria[76,77].Toresolvethisburningissue,twomajorchallengesmustbeovercome:①AfullunderstandingoftheMOAofartemisininmustbeachieved;and②thegeneticandphysiologicalfeaturesofthenewlyemergedartemisinin-resistantstrainsmustbede?ned.EventhoughtheMOAofartemisininhasbeenlargelydemysti?edinthepastfewyears,themolecularcharacterizationofartemisinin-resistantmalariaisfarfromclear.Continuedeffortsarerequiredtoachieveacompletepictureofhowartemisininresistancerelatestoitsmodeofaction.Basedonthisnewknowledge,newtherapeuticstrategiescanthenbedevelopedandtested.4.RepurposingartemisininArtemisinintherapyischaracterizedbyitsoutstandingtolera-bilityandrelativeaffordability.Thiscombinationofprovensafetyandaccessibilitymakeartemisininadrugofexceptionalinterestforrepurposingstudies.Indeed,interestinnon-malarialapplicationsofartemisininhasincreasedsteadilyovertimesinceartemisininwas?rstmadeknowntotheworld[78].Whilemalariaremainstheonlydiseaseforwhichartemisininisanapprovedtreatment,thepotentialapplicationsofartemisinininanti-cancer,anti-in?ammatory,anti-parasitic(outsideofmalaria)andanti-viralroles,amongothers,havebeenexploredinearnestovertheyears[78–82].Here,webrie?ycommentonsomepromisingresearchinartemisininrepurposing,especiallyinthe?eldofcancertreatment,asawindowintofuturedrugdevelopment.Theef?cacyofartemisininincancercultureswas?rstreportedin1993,andhassincebeenexpandedonandextensivelycharac-terized[83–85].Itisnowwell-reportedthatartemisininanditsderivativesdisplayselectivecytotoxicityagainstarangeofcancertypesinbothinvitroandinvivostudies[86].Foraysintoclinicaltestinghavebeengenerallypromising,iflimitedinnumberandscale[87–89].Morethantwodecadesofresearchonthebasisofartemisininactionincancerhasuncoveredaplethoraofimpli-catedtargetsandmechanisms.Artemisininhasbeenreportedtoinducemitochondrialapoptosisandotherformsofcelldeathsuchasnecroptosis,inhibitcancerangiogenesisandmetastasis,andarrestthecancercellcycle[90–97].Theseoutcomesarereportedlymediatedbyacombinationofoxidativedamage,DNAdamage,alterationofgeneexpression,andinteractionswithawidearrayofsignalingpathwaysincludingmammaliantargetofrapamycin(mTOR),NF-jB,mitogen-activatedprotein(MAP)kinases,andWnt/b-catenin,amongmanyothers[82,98–102].Thesepathwaysandmechanismshavebeenextensivelyreviewedinrecentpublications[79–82].Whilepathwayvalidationisanimportantaspectofmechanisticstudy,itisalsonecessarytoconsiderthebigpictureintermsofunifyingdrugactivationanddownstreamactivityinamannersimilartowhatwasdoneinmalariastudies.Asisthecasewithmalarialparasites,theactivationmechanismofartemisininincan-cercellsislikelytobeheavilylinkedtoitsspeci?cityofaction.Thus,theroleoffreeferrousironversusfreeredox-activehemeisonceagainbeingputunderscrutiny,especiallyconsideringthatironisintimatelylinkedtoartemisinin-inducedcytotoxicityincancer[103,104].Recentstudieshaveonceagainshedlighton36J.Wangetal./Engineering5(2019)32–39theroleofhemeinartemisininactivationincancercells,therebydrawingparallelswiththecaseinmalaria.Inparticular,arangeofmethodologieshavebeenusedtodemonstratethatmodulationofhemesynthesisandavailabilityclearlycorrelateswithcytotox-icity[105–108].Itisalsoimportanttonotethatcancercellshavebeenreportedtopossessenhancedlevelsofhememetabolismandsynthesis,andthatthiscouldunderpinthecancerspeci?cityofartemisinininasimilarmannertothecaseinmalaria[109–111].Speci?ctargetingofartemisinintomitochondria(thesiteofmammaliancellhemesynthesis)orenhancementofhemelevelsbytreatmentwiththehemeprecursoraminolevulinicacid(ALA)bothimprovedanti-canceractivity[112–114].Aheme-centricmechanismofactivationandaniron-dependentmechanismofdownstreamcytotoxicitycouldpossiblybeapointofreconciliationbetweentherolesofthosetwospeciesintheanti-canceractivityofartemisinin[115].Furtherworktofullyunderstandthebasisofartemisininspeci?cityincancerwillbecriticalforfuturetherapeu-ticapplications.Atthesametime,itisnecessarytoconsidertheappropriatedirectionwhenmovingforwardintermsofvalidatingartemisininMOAsincancer.Considerthecaseinmalaria,whereartemisininisproposedtoindiscriminatelyattackadjacenttargetsuponactiva-tion.Ifartemisininisactivatedinasimilarmannerincancercells,itisplausiblethatthesamepromiscuousmulti-targetmechanismwouldtakeplace.Thiswouldexplaintheremarkablerangeofcel-lulareffectsandimplicatedpathwaysthathavealreadybeenreported,asmultipletargetsandfunctionalpathwaysarelikelytobesimultaneouslyaffectedbysuchamechanism.Indeed,recentunbiasedstudiesofartemisinincancertargetsusingproteomicsapproacheshaverevealedasimilarmulti-targetMOAbyartemisi-ninincancercells[48,113,114].Themechanismofcytotoxicityitselfisalsoamatterofgreatinterest,especiallywithregardtonon-apoptoticformsofcelldeath.Recentworkhascloselylinkedartemisinin-inducedcytotoxicitytooxidativedamageandlysoso-malfunction,withafocusontheroleofironincontributingtotheiron-dependentformofcelldeathknownasferroptosis[116–118].Inparticular,lysosome-mediateddegradationoffer-ritinunderautophagyconditions(termedferritinophagy)releasesfreeferrousiron,whichinturncontributestobothferroptosisandiron-mediatedgenerationofROS[93,119].Autophagyitselfisacellularprocessthatisreportedlyactivatedbyartemisinin,buthasambiguouseffectsoncancercellsurvivalandthecytotoxicityofartemisinin[115,119].Itisclearthattherelationshipbetweenautophagy,lysosomalactivity,freeferrousiron,andiron-dependentferroptoticcelldeathfollowingartemisininexposurerepresentsamajorareaofuncertaintyintheanti-cancermecha-nismofartemisinin.However,effortsinunveilingnovel,cancer-speci?ctargetsandmechanismsaresteadilyongoingandcontinuetocontributetoagrandviewofartemisininasananti-cancerdrug.Artemisinin-mediatedeffectsoncancerstemcells,immunomodu-lation,cancermetastasis,cancermetabolismincludingtheregula-tionofglycolysis,andaplethoraofsignalingpathwaysincludingsignaltransducerandactivatoroftranscription3(STAT3),NF-jB,mTOR,andCREBPsignalingareamongrecentreports,andindicatenoveldirectionsforfurthervalidation[115,120,121].Inparticular,thepotentialabilityofartemisinintoserveasanimmunomodula-torincancerbyregulatingregulatoryTcell(Treg)activityandtheproductionofpro-cancer-survivalimmunosuppressivecytokinessuchasprostaglandinE2(PGE2)isnoteworthy,giventhecomplexroleofimmunomodulatorydrugsincancertherapy[122–125].Finally,effortstoimprovetheformulationanddeliveryofartemisinin-baseddrugshaveshownpromiseindeliveringenhancedef?cacyandreducedsusceptibilitytodrugresistance.Theseresultsincludenovelsyntheticdimers,trimers,anddrugconjugates(especiallytransferrin-conjugatedsystems),inadditiontocombinationtherapies;theyrepresentanexcitingongoingareaofresearchthathasbeenreviewedcomprehensivelyinrecentpublications[126–135].Inadditiontothepossibleapplicationsofartemisininincancertreatment,activeresearchistakingplaceonitspotentialrolesinaddressingarangeofotherdiseases.Inparticular,anti-in?ammatoryeffectsagainstautoimmunediseasesandallergicasthma,amongotherconditions,havebeenreportedinarangeofdiseasemodels[78].Someoftheseresultscorrelatewithobserva-tionsofimmunosuppressioninpatientsundergoingartemisinintherapyformalaria[136].Stronganti-viraleffectsofartemisininhavealsobeenreportedinherpesandinhepatitisBandCviruses,andotherparasiticdiseasesincludingschistosomiasishavealsobeenshowntorespondtoartemisinintreatment[137–141].Recent?ndingshaveevenidenti?edaremarkable—ifcontroversial—roleofartemisininindiabetesthroughinducingtransdifferentiationofpancreaticacellstogeneratebcells[142,143].TheMOAforthesealternativeapplicationsisfrequentlydiscussedintermsofthecanonicalmodelofROSgenerationandoxidativedamageinductionuponendoperoxidecleavage;however,non-canonical(includingendoperoxide-independent)mechanismshavealsobeenproposed,especiallyinthecaseofimmunomodulation[78,144].Itwillbeessentialtopursueaclearviewofhowdrugmechanismsandfunc-tionsmaydifferundervaryingapplicationsandconditions,whileconsideringtheimportanceoftheconditionsofdrugactivation.Itisalsoworthnotingthatrepurposingresearchmightbebestcarriedoutinpatientsandregionsthatarenotburdenedwithoratriskofmalaria,inordertoavoidpossibleinterferenceorcomplications.Everycaremustbetakentoensurethatthefullpotentialofartemisinincanberealizedwithoutcompromisingitscurrentapplications.5.ConclusionTheartemisininsareaclassofremarkabledrugsthathaverede-?nedthelandscapeofantimalarialtherapy.Acombinationofout-standingpotency,safety,andaccessibilityhasputartemisininattheforefrontoftheongoingbattleagainstthemalariascourge,whereithasalreadyimpactedmillionsoflives.Sinceitsdiscovery,aconcertedeffortbytheglobalcommunityhasassembledapic-tureofadrugwithauniquesetofpropertiesthatmakesitalmosttheidealantimalarialdrug.Activeresearchinother?eldshasalsorevealedabroadspectrumofpromisingapplicationsforartemisi-ninoutsideofmalaria.Webelievethatitisonlylogicaltoseektomaximizetheutilityofthisdruginarangeofcapacities.Inthecontextofmalaria,doingsomeanstocontinuetoclarifythemech-anismsofactivationandactionofartemisinin,whileworkingtofurtherimproveitspharmacologicalpropertiesbothaloneandincombination[145].Combinedwitha?rmgraspoftheprinciplesofartemisininactivity,thiscouldbethekeytoclearingtheuncer-taintiesofartemisininresistance.Sucheffortswouldensurethatthedrugcancontinuetoperforminasimilarorevengreatercapacitywithintherolethatithasservedforsolong.Lookingahead,repurposingstudiesdrivenbyarobustunderstandingofdifferentialMOAsindifferentdiseasesandsystemswillalsobeinstrumentalinde?ningthefutureofartemisinin.Ultimately,itisoursincerehopethatthisgiftfromChinesemedicinecancon-tinuetoservethepursuitofhealthforpeopleallaroundtheworld,formanyyearstocome.AcknowledgementsThisworkwassupported,inwholeorinpart,bytheprojectsoftheNationalNaturalScienceFoundationofChina(81641002and81473548);MajorNationalScienceandTechnologyProgramofChinaforInnovativeDrug(2017ZX09101002-001-001-05and
青蒿素 - 一种从中药中发现的神奇药物 - 图文
