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ReviewMicrotubule-targetedagents:WhenmitochondriabecomeessentialtochemotherapyA.
Rovinia,A.
Savrya,b,D.
Braguera,b,M.
Carréa,aINSERMUMR911,CentredeRechercheenOncologiebiologiqueetenOncopharmacologie,UniversitéAix-Marseille,FacultédePharmacie,27BoulevardJeanMoulin,13385MarseilleCedex5,FrancebAssistancePublique-HpitauxdeMarseille,FranceabstractarticleinfoArticlehistory:Received22July2010Receivedinrevisedform2January2011Accepted4January2011Availableonline7January2011Keywords:AnticancerdrugMicrotubuleMitochondriaApoptosisPharmacologyMicrotubule-TargetingAgents(MTAs)constituteaclassofdrugslargelyusedforcancertreatmentinadultsandchildren.
Incancercells,theysuppressmicrotubuledynamics,andinducecelldeathviathemitochondrialintrinsicpathway.
Todate,linksbetweenmitochondriaandmicrotubulenetworkdisturbanceinMTAsmechanismofactionarenotobvious.
Theaimofthepresentcontributionistoprovideelementsthatcouldanswertothequestion:howfararemitochondriaessentialtoanticancerchemotherapythattargetsthemicrotubulecytoskeletonWereviewthemainmolecularcandidatestolinkmicrotubulealterationwiththeapoptoticmitochondrialpathwaycontrol.
InvolvementofdirecttargetingofmitochondriainMTAefcacyisalsodiscussed.
Furthermore,welineupcurrentevidenceandemergingconceptsontheparticipationofbothmitochondriaandmicrotubuleinMTAneurotoxicsideeffects.
Todeciphertheinterconnectionsbetweenthemitochondrialandthemicrotubulenetworksmayhelptoimprovecancercellresponsetochemotherapy.
ThisarticleispartofaSpecialIssueentitled:BioenergeticsofCancer.
2011ElsevierB.
V.
Allrightsreserved.
1.
IntroductionImprovementofanticancertherapeuticstrategiesisoftenlimitedbyapoorknowledgeofmolecularmechanismsunderlyingcarcinogenesisandcellresponsetotreatment.
Althoughcarcinogenesisisaverycomplexprocess,itcanbedividedintotwocrucialsteps:1)appearanceofoncogenemutationsinagroupofcells,leadingto2)disorderlycellproliferation.
Thisuncontrolledcelldivision,joinedtoneo-angiogenesisinduction,isresponsiblefortumorformation,growthandspreading.
Asthemicrotubulenetworkishighlyinvolvedincellproliferation,itappearedtobeapreferentialtargetforcancertherapy.
Forthatmatter,greateffortshavebeendevotedtodiscoverdrugsthataffectmicrotubules.
Nowadays,theso-calledMicrotubule-TargetedAgents(MTAs)constituteaclassofanticancerdrugslargelyusedintheclinics.
Amongthem,taxanesandVincaalkaloidsarepowerfulinhibitorsofmicrotubuledynamicsandapoptosisinducers,usedtotreatsolidtumorsandmalignanthemopathies.
ThetherapeuticsuccessofMTAsaccountsforthedevelopmentofnewmicrotubule-targetingcom-poundsbypharmaceuticalcompanies,whichhasbeen–andisstill–intenseandfruitful.
Theaimofthepresentcontributionistoanswerthequestion:howfararemitochondriaessentialtoanticancerchemotherapythattargetsthemicrotubulecytoskeletonFirst,webrieysummarizedthecellulareffectsofMTAsonmicrotubuledynamics,andtheirfunctionalconsequences.
Then,asMTAanticancereffectivenesshasbeenrelatedtotheapoptoticmitochondrialpathway,welinedupthemainmolecularcandidatestolinkmicrotubulealterationwithapoptosiscontrol;andwediscussthedirecteffectsofMTAsonmitochondria.
WealsoreviewedcurrentevidenceandemergingconceptsofbothmitochondriaandmicrotubuleroleinMTAneurotoxicsideeffects.
Lastly,weconsideredMTAsastoolstostudytheinuenceofmicrotubuledynamicsonmitochondrialdynamics.
2.
MTAfamilyofmolecules,areferenceinanticancerchemotherapyMicrotubulesarecytoskeletalhollowlamentspresentinmosteukaryoticcellsthatresultfrompolymerizationofα/βtubulinpolymers.
Inmammaliancells,microtubulesarepolarizedstructuresnucleatedatthecentrosomewheretheminusendisanchored.
Theplusendgrowstothecellperipheryandconstantlyexploresthecytoplasm,makingmicrotubulehighlydynamicpolymers.
Indeed,afundamentalpropertyofmicrotubulesistoexhibitadynamicinstability,whichischaracterizedbyasuccessionofslowpolymerizationandrapiddepolymerizationphases.
Theswitchfrommicrotubulegrowthorpausetoshrinkageisknownas"catastrophe",andtheswitchfromshrinkagetogrowthorpauseisnamed"rescue"[1].
Thisdynamicbehaviorisofparticularimportanceintheregulationofmanycellularfunctionsbythemicrotubulecytoskeleton,asbeingthesupportforcelldivision,shapechanges,motilityandcelldifferentiationsuchasBiochimicaetBiophysicaActa1807(2011)679–688ThisarticleispartofaSpecialIssueentitled:BioenergeticsofCancer.
Correspondingauthor.
INSERMUMR911-CR02,FacultedePharmacie,27BdJeanMoulin,13385MarseilleCedex5,France.
Tel.
:+33491835626;fax:+33491835635.
E-mailaddress:manon.
carre@univmed.
fr(M.
Carré).
0005-2728/$–seefrontmatter2011ElsevierB.
V.
Allrightsreserved.
doi:10.
1016/j.
bbabio.
2011.
01.
001ContentslistsavailableatScienceDirectBiochimicaetBiophysicaActajournalhomepage:www.
elsevier.
com/locate/bbabioformationofneuronaloutgrowths.
Thus,farfrombeingconsideredasmerearchitecturalelements,microtubulesarekeydeterminantsofcellulareventsandfunctionalities.
Onlyafewmicrotubule-governedcellularprocessesrequireanoverallremodelingofthecytoskeletonnetwork,butalldependonatightlyregulatedmicrotubuledynamics.
Microtubule-TargetedAgents(MTAs)remainbenchmarkclinicaltreatmentsdisplayinghighcytotoxicefciencyandarestillwidelyusedagainstabroadspectrumofchildren'sandadult'stumors.
Theyrecentlyreceivedarevivalofinterestaspotentanti-angiogenicandvascular-disruptingagents[2].
Researchanddevelopmentarestillinprogresstodiscovermoreactiveandlesstoxiccompounds(forextensivereviews,see[3,4]).
Attemptstoimprovetheintracellulardrugconcentrationandamorespecictargetingoftumorcellsareespeciallyunderintenseinvestigations,andtheemergingeldofnanotechnologiesactivelyparticipatestothisquest[5].
TheMTAfamilyiscomposedofmorethan30compounds,historicallyclassiedindestabilizingandstabilizingagents,accordingtotheirbindingsiteontubulinormicrotubules[3,6].
Destabilizingagentsinhibitmicrotubulepolymerizationinvitro;theyincludetheVincaalkaloidssuchasvinblastineorvincristinethatbindtotheso-called"Vinca"tubulindomain,aswellasnocodazoleorcombretastatinsthatbindtothe"colchicine"tubulindomain.
Stabilizingagentsenhancetubulinpolymerizationandmicrotubulestabilization;theyincludetaxanes,suchaspaclitaxelordocetaxel,andEpothilones.
Althoughthedistinctionindestabilizingandstabilizingagentsisusefulforstructure–activitystudies,itisnomoreusedincellularandinvivostudiessincebothclasseshavebeenshowntocommonlydisturbmicrotubuledynamics,withoutchangingtheoverallmicrotubulemassinalargerangeofconcentrations[7].
Itisnowlargelyacceptedthatcytotoxic(i.
e.
pro-apoptotic)concentrationsofMTAssuppressmicrotubuledynamics.
[8–11].
Anextensivedecreaseinmicrotubuledynamicspreventsthenormalalignmentofchromosomes,activatesthespindleassemblycheckpoint,whichresultsinthecellblockadeinmitosis[12].
Itshouldherebenoticedthatamoderatedsuppressionofmicrotubuledynamics,whichdidnotallowtheaccumulationofcellsinmitosis,isalsoassociatedwithapoptosisinductionintumorcells[13–15].
Thus,itremainsunclearwhetherandhowthemitoticarrestiscoupledtotheactivationoftheapoptoticmachinery[16,17].
Elsewhere,microtubuledynamicssup-pressioncorrelateswithcelllocomotionalteration,asdescribedinbroblaststreatedwithpaclitaxelandnocodazole[18,19].
Surprisingly,theincreaseinmicrotubuledynamicsbylowconcentrationsofvinunineandpaclitaxelhasbeenalsoshowntoinhibitendothelialcellmigration,resultinginMTAanti-angiogenicactivities[20].
Thiseffectwascorrelatedwiththeinhibitionofinterphasemicrotubulefunctions,resultingininhibitionofadhesionsitedynamicsandformationoflong-livedstressbers[21].
Interestingly,whatevertheconcentrationstudied,MTAsdisorganizethenetworkofmicrotubule+endtrackingproteins(+TIPs).
Amongthem,theendbinding(EB)familyofproteinsspecicallyformscomet-likeaccumulationattheendsofgrowingmicrotubules.
Astheyensuremicrotubulegrowth,EBproteinsarecrucialregulatorofmicrotubuledynamics[22].
Taxanes,VincaalkaloidsandEpothilonescommonlydisruptEBproteindistributionincancer,endothelialandneuronalcells[21,23](andpersonaldata),whichmayaccountforMTAs'maineffectsoninterphaseandmitoticmicrotubuledynamics.
3.
AnticancereffectivenessofMTAs:mitochondriacomeintoplayMTAs,includingthenewestinclinicaltrials,haveshownahighabilitytoinduceapoptosis[24–28].
Thisprogrammedandtightlyregulatedcelldeathwasrstidentiedin1993,byBhallaetal.
[29],asthemechanismresponsiblefortheanti-tumorcytotoxiceffectsofpaclitaxelinhumanmyeloidleukemiacells[14].
Sincethen,theireffectiveness,evenintheclinics,hasbeenwellcorrelatedtoapoptosisextentinalltumorcells.
Itshouldbenotedthat,eventhoughMTAscaninducecelldeathinendothelialcells,itisdispensablefortheiranti-angiogenicandanti-vascularpropertiesatlowdoses[30,31].
ThissectionwillthusbefocusedonapoptoticactorsnecessarytoMTAanticanceractivityintumorthemselves,givingcluestounderstandhowcanmicrotubuledysfunctionbeanecessarystepinapoptosisinduction.
3.
1.
IntrinsicpathwayinductionbyMTAs:whattolearnforonco-pharmacologyFromthenumerousintracellularapoptoticsignals,twomajorroutescanbediscerned:themitochondrialpathway,knownastheintrinsicpathway,andthedeathreceptorpathway,so-calledextrinsicpathway.
AlthoughMTAshavebeenshowntomodifyexpressionlevelsofdeathreceptorsandtheirligands,theextrinsicpathwayisgenerallyexcludedfromMTA-inducedapoptosis[32–34].
MTAeffectivenessislargelyacceptedasaconsequenceofcaspaseactivationthroughtheintrinsicapoptoticpathway[35].
Ofnote,theanticanceractivityofnovelimprovedpharmacologicalfeaturesofMTAs,suchashydrophilicpaclitaxelderivativeorpaclitaxelloadedpoly(L-lacticacid)microparticles,isevaluatedbymeasuringtheirimpactonmitochondria[36,37].
Itpointsouthowtheseorganellesarecrucialintheappraisalofmicrotubule-targetedchemotherapysuccess.
3.
1.
1.
ThelethalcascadeMitochondrialmembranepermeabilizationisthecentralgateinturningon/offapoptosis,asitallowsthereleaseofalargepanelofpro-apoptoticproteins[38,39],thatactivatesdownstreamsignalingcascadesandleadstothenalexecutionofcelldeath.
AnearlyandtransienthyperpolarizationofthemitochondrionhasbeenreportedwithMTAs,whichis,intumorcells,followedbytheΔΨmcollapseandthereleaseofpro-apoptoticfactors[17,30].
Thesubsequentactivationofthecaspasecascadeisthenon-returnpointtocellbiochemicaldestructionandphenotypicchangesinMTA-inducedapoptosis[35,40–43].
Inresponsetopaclitaxel-orepothilone-treatment,themassivecytochromecreleasefrommitochondriatriggerstheformationofthemulti-factorcomplexapoptosome,whichleadstoanearlyincreaseincaspase-9activity.
Accordingly,thecaspase-9specicinhibitor(z-LEHD-fmk)effectivelyprotectscellsfromMTA-mediatedapoptosis[42–44].
OverexpressionofApaf-1,theadaptormoleculeoftheapoptosome,hasbeenshowntoenhancepaclitaxel-inducedapoptosis[45].
Insituationswhereactivationofcaspase-9isdisturbed,overexpressionofthedownstreameffectorcaspase-3restoressensitivitytoMTAsinresistantcancercells[46].
Smac/DiabloandOmi/Htra2peptidesarealsoreleasedfrommitochondriaduringtheirpermeabilization,andfavorcaspaseactivitybypreventingactionoftheinhibitorofapoptosisproteins(IAPs)[39,47].
InhibitionofIAPscan,invitro,modulatetheefcacyofantineoplasticagents.
Smac/DIABLOpeptideenhancedtheinductionofapoptosisandlongtermantiproliferativeeffectsofpaclitaxelinbreastcancercells[48,49].
CombinationofpaclitaxelwitharecombinantadenovirusencodingSmac/DIABLOalsoproducedgreaterlevelsofapoptosisinovariancarcinomacells[50].
Inaddition,ectopicSmac/DIABLOsensitizeddrug-resistantepithelialovariancancercellstopaclitaxel-inducedapoptosis[51].
Thus,anincreaseinSmac/DIABLOactivityseemstobeapromisingstrategytoimproveMTAtreatment,includingindrug-resistantcancer,butaclinicalapproachisstilllacking.
3.
1.
2.
Bcl-2familymembersMuchefforthasbeendirectedtowardelucidatingthemechanismofmitochondrialmembranepermeabilization,and,whilestilldiscussed,itisnowlargelyacceptedthatthisprocessisunderthecontroloftheBcl-2familymembers.
TheBcl-2familyiscomposedofupto30proteinsthatcanbedividedinto3groups:oneofBcl-2-likesurvivalfactorsandtwoothersofcelldeathpromotingfactorsnamedBax-likeandBH3-only[52].
Therelativelevelsofanti-andpro-apoptoticclansinmitochondrial680A.
Rovinietal.
/BiochimicaetBiophysicaActa1807(2011)679–688membranesarbitratecelllifeordeathdecision.
MTAsmodulatebothexpressionlevelsandactivityofpro-apoptoticmembersoftheBcl-2family.
Up-regulationoftheBad,PUMA,Baxand/orBakhasbeenobservedaftertreatmentwithpaclitaxel,epothiloneBaswellaswithVincaalkaloids[15,53–55].
Asexpected,Bcl-XS,BaxorBadover-expressionsensitizescancercellstopaclitaxelandvincristine[56–58].
Inaddition,MTAstriggerBaxactivationthroughitsconformationalchange[54,59]thatallowsN-terminaldomainexhibitionandBaxstableinsertionintotheoutermitochondrialmembrane[60,61].
MTAsalsoinitiateBimtranslocationfrommicrotubulestomitochondria,asdiscussedinthenextsection.
Lastly,thelatecleavageofBidintoafunctionalfragment(tBid)hasbeenproposedtobeasignalamplica-tionloopwhichcouldberequiredforanoptimalreleaseofmitochondrialfactorsfollowingMTAtreatment[62,63].
Inparallel,Bcl-2-likeanti-apoptoticproteinscanbepost-transla-tionallyinactivatedbyhyperphosphorylationinducedbyalargepanelofMTAs[15,64–68].
Ithasinitiallybeenthoughttobeamarkerofmitosisratherthananapoptosis-relatedsignal,butboththeextentandthedurationofthemitosis-associatedBcl-2hyperphosphorylationislikelytodistinguishapre-apoptoticcellfromonedestinedtodivide[69].
TreatmentswithMTAsalsodecreaseexpressionlevelsofBcl-XLandBcl-2toactivatetheintrinsicpathway[70–72].
Overexpressionoftheanti-apoptoticproteinsBcl-2andBcl-XLareinvolvedinresistanceofcancercellstomicrotubule-targetedchemotherapy[73–76].
Thus,Bcl-2and/orBcl-XLantisensestrategieshavebeendeveloped,andwererstreportedtomediateanincreaseindocetaxel-andpaclitaxel-sensitivityinvitroandinmicexenografts[33,77–79].
ABT-737,aBH3-mimeticthatantagonizesBcl-2,Bcl-XL,andBcl-w,increasedMTApro-apoptoticeffectsinavarietyoftumorcelllines,includingbreastcancercellswithacquiredresistancetopaclitaxel[80–82].
Similarly,A-385358,asmallmoleculewithrelativeselectivityforbindingtoBcl-XLpotentiatedtheactivityofpaclitaxelinnon-small-celllungcancercells,invitroandinvivo[83].
In2003,aphaseIIclinicaltrialofoblimersen(antisenseoligonucleotidestargetingBcl-2)incombinationwithdocetaxelvalidatedprogressionintophaseIIIforpatientswithadvancedhormonerefractoryprostatecancer.
However,Bcl-2inhibitiondidnotalwayssucceedinenhancingtreatmenteffectiveness[84–87].
Furthermore,itshouldbeusedwithcautionincombinationwithMTAssinceworksshowedthatBcl-2down-regulationisresponsibleforanunexpectedresistancetopaclitaxelandvinunineinovariancancercells[17,88].
Accordingly,Bcl-2overexpressioncanincreasenon-smallcelllungcancersensitivitytodocetaxel[89].
Similarly,prostatecancercellscanadapttoantisenseRNAtargetingBcl-xL,leadingtoaparadoxalresistancetodocetaxelandvinblatine[90].
Thisdualroleof"prosurvi-val"mitochondrialproteinspointsouttheneedforfurtherinvestigationtoelucidatetheirrealcontributioninMTAtreatmenteffectivenessandtheirpotentialastargetforclinicalantisensestrategies.
3.
2.
Proteinsreleasedfromthemicrotubuletomitochondria:atthedoorstepsofMTAeffectivenessWhilethemaineffectsofMTAsonboththeintrinsicapoptoticsignalingcascadeandthemicrotubulenetworkarenowquitewellunderstood,clearlinksarestilllackingbetweenthetwoevents.
Sinceapoptosisandproliferationarecloselyrelated[91],effectsofMTAsonproteinsthatcontrolbothphenomenahavebeenstudiedforyears.
Cellcycleisatightlyregulatedprocess,anditsdisturbancebyMTAsmayparticipateinthemitochondrialapoptoticpathwayinitiation.
Therefore,studiesonhowcellcyclecheckpointsmodulatetheintrinsicpathwayareofmajorinterest,andextensivelyreviewed[27].
Thepresentsectionwillbefocusedonproteincandidatesthatcouldbuildmolecularbridgesbetweenmicrotubulesandtheapoptoticmachinery.
Indeed,microtubulesserveasscaffoldsfordifferentsignalingmolecules,extendingthelistofbiologicalprocess-esregulatedbythemicrotubulenetworkincells.
Amongmicrotubule-linkedcomponents,regulatorsoftheapoptoticprocesssuchasp53andBimmaybereleasedfrommicrotubulestowardsmitochondria.
SincepolymerizinganddepolymerizingMTAsdisplaythecommonpropertyofsuppressingmicrotubuledynamics,itprobablyexplainswhytheinvolvementofthemicrotubule-transportedfactorsinapoptosisissimilaramongsttheseanticancerdrugs.
3.
2.
1.
p53,themultifacetedmoleculeDifferentlinesofevidenceindicatethatp53up-regulationandactivationarerequiredformaximalcellsensitivitytoTaxanes,VincaalkaloidsandEpothilones[15,54,71,92–96].
Theroleofp53inapoptosismediatedbymicrotubuledisturbanceisreinforcedbyrecentdatashowingthatoverexpressionofthemicrotubule-associatedproteinTaurenderedneuroblastomacellsresistanttoapoptosisbymechanismsinvolvingreductionofp53level[97].
MTAconcentrationseemstobecritical,aslowdosesofpaclitaxelincreasep53proteinlevels,whereashighdosesdonotaffectoreveninhibittheselevels[72,98,99].
Similarly,lowdosesofvinunineup-regulatep53,whilehighdosesincreasep53toalowerextent[17].
Theconcentration-dependentactivationofthistranscriptionfactormayresultfromitsmicrotubule-governedtrans-port.
Indeed,itsdynein-dependenttransporttothenucleusisthoughttobeaconsequenceofmicrotubuledynamicssuppressionbybothstabilizinganddepolymerizingagents[92,95,100,101].
Highconcentra-tionsofMTAsprobablyinducetooextensivedamagestomicrotubules,whichcannomoreserveastracksforp53trafcking.
Onceinthenucleus,p53transcriptionalpropertiesareactivated,leadingtomodulationingenetargetssuchasp53itselforp21and,moreinterestingly,membersoftheBcl-2family[36,102,103].
UnderMTAtreatment,p53inductionhasbeenshowntodown-regulateBcl-2andup-regulateBax[15,71,104,105].
Recently,weidentiedanovelbindingsiteofp53ontheBcl-2promoter,responsibleforthetranscriptionaldown-regulationofBcl-2byvinorelbineinbreastcarcinomacells[104].
TheBH3-onlymembersPUMAandNoxacanalsobeup-regulatedfollowingp53induction[54,106,107],buttheroleofMTA-mediateddisturbanceofmicrotubuledynamicsinthisprocessremainstobecharacterized.
Besidesitsabilitytomodulatethepro-apoptotic/anti-apoptoticratioinfavorofapoptosis,p53inducesapoptosisthroughatranscription-independentmechanism.
Inresponsetovariouspro-apoptoticstimuli,includingMTAs,p53rapidlymovestothemitochondriaincellularandmicemodels[15,93,108–111].
Onceatthemitochondrion,p53primarilyassociatedwiththeoutermitochondrialmembrane,butasmallsubfractionmaybelocatedwithinthemitochondrialmatrix[108,111–113].
Themitochondrialp53participatesintheapoptoticcascadebyinducingthemitochondrialoutermembranepermeabiliza-tionthroughdirectactivationofBax-likeandBH3-onlyproteins,andbyforminginhibitorycomplexeswithBcl-2-likemembers[106,114].
Thep53-targeteddrugpithrin-μ,whichblockstheinteractionofp53withBcl-XL[115],inhibitsapartofvinorelbine-inducedapoptosis[104],supportingaroleforthemitochondrialp53inMTApro-apoptoticproperties.
Whilesomekeystepshavebeeninvokedtoexplainhowp53translocationfrommicrotubulescanbetriggered[74,115],theexactroleofMTA-induceddamagesofmicrotubuledynamicsisstillanunexploredeld.
3.
2.
2.
BimgoesforawalktomitochondriaBH3-onlymemberoftheBcl-2family,Bimisinvolvedininhibitionofmetastasisformationandinthepro-apoptoticresponseoftumorcellstochemotherapy[116–121].
Bimexpressionlevelincreasesdramaticallyafterpaclitaxeltreatment[99,122]andgenesilencingexperimentsshowedthatitsup-regulationisacriticalregulatorofapoptosisincancercells[122–124].
WhileBimcanbelocalizedatmitochondriawithoutcelldeathstimuliinsomecellularmodels,numberofstudiesshowedthatitissequesteredbymicrotubulesviaitsinteractionwiththedyneinlightchainDLC1/LC8ofthemotorcomplexorviaadirectinteractionwithmicrotubules[125,126].
Interestingly,Bim-decientlymphocytesarelesssensitivetopaclitaxel-mediatedperturbationsof681A.
Rovinietal.
/BiochimicaetBiophysicaActa1807(2011)679–688themicrotubulenetwork,whichunderscorestheimportanceofBiminmediatingapoptosisinducedbyagentsthattargetmicrotubules[127].
Duringtreatmentwithpaclitaxel,Bimmayactasasensorofcytoskeletonintegrity,sinceitisunleashedfrommicrotubulesandtranslocatestomitochondria[123].
Insupporttothishypothesis,theplanttoxincalledpersinhasbeenshowntoinduceBimreleasebyactingasamicrotubule-stabilizingagentinbreastcancercells[128].
Similarly,theHIV-1TatproteinactivatedapoptosisinhostcellsbytriggeringBimtranslocationtomitochondriainresponsetomicrotubulestabilization[127].
WealsoshowedthatepothiloneBinducedBimaccumulationtomitochondria,leadingtoapoptosisinhumanneuroblastomacells[93].
Sincethen,workshaveconrmedthatMTAsfreedBimfrommicro-tubulesandenrichedmitochondriainthispro-apoptoticprotein[129,130].
BimsequestrationfromdyneinmaybereleasedthroughitsphosphorylationbyJNK,asdescribedwithUVtreatment[116,131].
SuchakinasecanbeactivatedbyMTAs[27].
However,itmayalsobearguedthatBimtranslocationtriggeredbyMTAsresultsfromdisturbanceofmicrotubuledynamicsorstructure.
Indeed,microtu-buledestabilizationbyGadd45aledtoBimreleasewithoutactivationofJNK[132].
Amongthedifferenthypotheses,theenhancedgenerationofmitochondrialreactiveoxygenspecies(ROS)byMTAs[35,41,133–136]hasbeenshowntoberesponsibleforBimaccumu-lationtomitochondriainneuroblastomacells[93].
Thus,themitochondrialcompartmentitselfcaninitiatethesignalingdialogwiththemicrotubulenetwork,whichresultsinapoptosisandthusparticipatesinMTAefcacy.
4.
DirecteffectsofMTAsonmitochondria:wheredowestandInparallelwiththeireffectsonthemicrotubulenetwork,MTAscanalsoactivatetheapoptoticpathwaythroughadirectactiononmitochondria.
IncubationofmitochondriaisolatedfromtumorcellswitheitherTaxanes,VincaalkaloidsorEpothilonesprovokescyto-chromecrelease[137].
Incontrast,otherclassesofanticancerdrugssuchas5FUordoxorubicinwerenotabletopermeabilizemembranesfromisolatedmitochondria[138](andpersonaldata).
MTAsinduceanearlyΔΨmcollapseandasubsequentlargeamplitudeswellingofisolatedmitochondria[88,136,138,139].
Themitochondrialmembranepermeabilizationisinhibitablebycyclosporine[138],consistentlywiththepermeabilitypore-dependentCa2+lossfromisolatedmitochondriainducedbypaclitaxelandnocodazole[139,140].
Paclitaxelhasalsobeenshowntosignicantlyincreasethecytochromeoxidase-mediatedROSproductionbypuriedmitochondria[136].
Interestingly,thepro-apoptoticeffectsofpaclitaxelcanbeenhancedbyimprovingitsspecicdeliverytomitochondriausingamitochondria-specicnanocarriersystem(DQAsomes)[141].
Then,itraisesthequestionofthepotentialtarget(s)ofMTAsinmitochondria.
Tubulin,thatwasfoundtobestronglyassociatedwithmitochondrialmembranesinbothpuriedorganellesandwholecells[139,142,143],wastherstcandidateproposedtoexplainthespeciceffectofMTAsonisolatedmitochondria.
ThemitochondrialtubulinsubfractionisenrichedinclassIIIβ-tubulin(TUBB3),but,incontrastwiththecytoskeletalform,itsoverexpressiondoesnotcorrelatewithcellresistancetoMTAs[144].
AnassociationhasbeenreportedbetweenthemitochondrialtubulinandVDAC[142,145],themajoroutermembraneporethatislikelyinvolvedinthereleaseofpro-apoptoticfactorsbyMTAsfromtheintermembranespacetocytosol.
ThecurrentknowledgeontheMTA-inducedintrinsicpathwayhasrejuvenatedthestudyfromEvtodienkoetal.
[146],whichsuggestedtheinvolvementofeithermitochondria-boundtubulinperseand/orcontactsbetweenmitochondriaandmicrotubulesinregulationofmitochondrialmembranepermeability[146].
Morethan10yearslater,theC-terminaltailoftubulinhasbeenproposedtomodulatetheVDACopeningandthemitochondrialrespirationrate[145].
Bcl-2hasalsobeenidentiedasapotentialtargetforpaclitaxelbyphagedisplayandachemicalapproach[147,148].
Recently,Ferlinietal.
revealedthat,inovariancancercells,paclitaxeldirectlytargetedBcl-2intheloopdomain[149].
Asaresult,paclitaxelchangedtheroleofBcl-2frominhibitortoenhancerofthemitochondrialmembranepermeabilization,facilitatingapoptosis.
Thisprocessmayexplainwhythedown-regulationofBcl-2isresponsibleforanunexpectedresistancetoMTAsindifferenttumorcelltypesandcancerpatients[17,66,88,89].
Finally,thetwohypotheseshavejoinedwhentheassociationbetweenthetubulinandBcl-2hasbeenrevealed,byco-immunoprecipitationfrommitochondriallysatesandwithpuriedproteins[17,88,150].
Suchacomplexthatgatherstubulin,Bcl-2andVDACcouldbebothadirecttargetforMTAsandaregulatorofthemitochondrialmembranepermeability.
Thus,whilethemitochondri-altargetsofMTAsareprobablynotalldened,itisreasonabletothinkthattheseanti-tumoragentsdisplaycrucialanti-mitochondrialpropertiesinvolvedintheirefcacy.
Therelevanceofthisphenomenonremainsdifculttoproveinwholecells,sincethedirecteffectsofMTAsonthemitochondrialnetworkareusuallyundistinguishablefromthoseresultingfrommicrotubulemodications.
Moreover,resultsshowingthatinterfer-enceofpaclitaxelwiththemitochondrialsignalingcascadeoccurredupstreamofmicrotubuleorganizationalteration[140]shouldbereevaluatedbymeasuringmicrotubuledynamics,ahighlymoresensitiveparameterthanmicrotubulearchitecture.
Nevertheless,weshowedthattheearlyproductionofROSfrommitochondriawasnecessarytoBimtranslocationtowardsmitochondria,whichinturntriggeredapoptosisinhumanneuroblastomacells[93].
ThesedatastronglysuggestthatsomeofthemostrapideffectsofMTAsontheintrinsicapoptoticpathwaymaybeinitiatedthroughadirectactiononmitochondrialintegrity.
TheinvolvementofMTA-mediatedROSgenerationfrommitochondrianeedstobereconsideredinprocessessuchasEBproteincometdisruptionbyMTAs(seesection2),whichisthoughttoresultfromtargetingofthemicrotubulesystem,butwhichhasbeenrecentlyshowntobetriggeredbyH2O2[151].
Then,itiseasytospeculatethatsomealterationsofthemicrotubuledynamicsinducedbyMTAscouldbe,atleastinpart,linkedtothedrugs'anti-mitochondrialproperties.
5.
Mitochondria–microtubulepair:MTAsstirupthetroubleinneuronalsystemChemotherapy-inducedperipheralneuropathy(CIPN)isthemaindoselimitingsideofalargepanelofMTAs[152,153].
Mostofthetime,peripheralneuropathyreversesifthetreatmentisstopped.
However,insomecases,recoveryfromsymptomsisincompleteandalongperiodofregenerationisrequiredtorestorefunction[154].
Thisneurotoxicsideeffectisstillanunsolvedclinicalissue,sothewaysthatcytoskeletonandorganellesinterplayandhowMTAsaltertheserelationshipsinneuronalmodelsareofhighimportance.
5.
1.
Animalmodelsofchemotherapy-inducedneuropathy:slippingfrommicrotubuletomitochondrialinvolvementDespiteintensiveeffortsinthedevelopmentofneuroprotectiveagents(recentlyreviewedin[155]),todate,therearenoapprovedtherapiesforpreventionortreatmentofneuropathiestriggeredbyMTAchemotherapy[152,153,156].
ThisispartlyduetothepoorunderstandingofmechanismsunderlyingMTA-inducedneurotoxic-ity,andthustoalackofavaluablemethodofstandardizationintheclinicalmeasurementofCIPN.
Asapostulate,ithasoftenbeendeclaredthatMTAssimilarlyaffectthemicrotubulenetworkincancerandneuronalcells,butevidencewasnotalwayssustained.
For20yearsnow,animalmodelsofCIPNhavebeendeveloped(listedin[157]),attemptingtoinvestigateMTAsmechanismofactionontheperipheralnervoussystem.
Mostofthesemodelsareessentially682A.
Rovinietal.
/BiochimicaetBiophysicaActa1807(2011)679–688focusedonthereportofpain-relatedbehaviorandonlyafewgoonfurtheronneurophysiologicalexperiments.
Whileratmodelsofvincristine-inducedperipheralneuropathydescribedabnormalmi-crotubuleassembliesanddensitiesasmaindamages[158,159],thesemicrotubuleproleswerenotobservedwithpaclitaxelinratmodels[160].
IthasthusbeenhypothesizedthatthemicrotubulenetworkwaslikelynottheonlytargetofMTAstobeinvolvedinneurondysfunctions.
Inparallel,thedecipheringofMTAactionprogressivelyslippedconsiderationsfrommicrotubulestomitochondria.
Invitrodatausingpaclitaxelreportedanterogradeandretrogradeaxonaltransportblockadeinratdorsalrootganglia(DRG)andhippocampalneurons.
Then,invivostudiesshowedasignicantincreaseintheincidenceofswollenmitochondriainaxonsafterpaclitaxeltreatment[160,161].
SimilardatawereobtainedwithinvitrocultureofDRG,inwhichtheinductionofatypicalmitochondriabypaclitaxelwasassociatedwithasignicantreductionoftheirfunctioningandthelossofmitochondrialmembranepotential[162].
Nevertheless,inthesestudies,thelinkbetweenmicrotubuledensityandinhibitionofneuronalorganelledistributionremainedcontroversialduetovariablepaclitaxelinjectionsmodesanddifferentadministeredconcentrationsoverthetime[163,164].
5.
2.
InhibitionofMTA'sneurotoxiceffects:domitochondrianeedtobeprotectedManyworksareattemptingtondclinicallyefcientneuropro-tectorsabletoenhanceneuronalcellsurvival.
Todate,severalneuroprotectiveagentslikethiols,neurotrophicfactorsandantiox-idantshavebeentestedinpreclinicalmodelsandclinicaltrialsfortheirabilitytopreventCIPN[165,166].
Althoughseveralofthesecompoundswereidentiedasneuroprotectivemoleculesofinterest,clinicaldataarestilldiscussed.
Mitochondrialdysfunctionandoxidativestressarewidelybelievedtounderliethepathogenesisofvariousneurodegenerativediseases[167].
Theinvestigationofneuroprotectiveantioxidantswasthusrationalizedasapromisingstrategytopreventoralleviatemitochondrialdamages.
Amongthem,efcacyofacetyl-LcarnitineandmorerecentlyalphalipoicacidtoexertneuroprotectiveeffectsagainstMTAs,invitro,wasassociatedwithareducedincidenceofswollenandvacuolatedmitochondriainratC-ber[161]aswellasinsensoryDRGneurons[162].
Moreover,alphalipoicacidpreventedtheearlylossofmembranepotentialdifferentialinmitochondriaexposedtopaclitaxel,thuspreventingneuronsfrommitochondrialenergeticfailureprobablythroughanti-oxidantactivities.
Anattractivestrategy,themitochondrialprotectionmightbelimitedinpreventingMTA-mediatedCIPNwhichinvolvesalterationofothertargetssuchasthemicrotubulecytoskeleton.
Inthiscontext,olesoxime(TRO19622)appearedasapromisingdrugcandidatetotreattheneurotoxicsideeffectsofmicrotubule-targetedchemotherapy[168].
ThisnewmoleculeprotectedneuronalcellsfromMTA-inducedneuriteshrinkagebyrestoringbothmicrotubuledynamics–throughEBproteincometsmaintainingatmicrotubuleends–andthemicrotubule-governedmitochondrialtrafcking[23].
Thus,compoundslikeolesoximethatareabletojointhesetwopropertieswouldholdpromisetobetterpreventandcurepatientssufferingfromneurodegenerativedisordersinwhichmicrotubule-associatedaxonaltransportisdefective.
TheirstudymayalsobringadditionalfundamentalinsightsintothemolecularmechanismsunderlyingneurotoxicpropertiesofMTAs.
6.
Inuenceofmicrotubuledynamicsperturbationonmitochondrialdynamics:aneweldofinvestigationShortlyaftertheirsuccessfuluseintheclinics,MTAshavebeenextensivelyemployedinfundamentalresearch.
Bymodulatingmicro-tubulearchitectureanddynamics,theyareappropriatepharmacolog-icaltoolstoprobethemitochondria–cytoskeletoninteractions.
6.
1.
HowcanMTAsmodulatethemitochondrialmotilityMTAeffectshavebeenespeciallystudiedinneuronalcells,inwhichmitochondriamovethroughouttheneuronalprocessestocontributetosynapticmaintenance.
Appropriatepositioningofthemitochondrialnetworkensuresorganellefunctionandisnecessarytocellsurvivalandfunctionality.
Assoonas1978,ChanKYandBuntAHusedvinblastinetoformparacrystalstructuresandtohighlighttheinterconnectedspatialorganizationofmicrotubulesandmitochon-driainsynaptosomesandaxonterminalsofratcerebralcortex[169].
Afewyearslater,axonalorganelletransporthasbeenshownnottobetotallysuppressedaftermicrotubuledisruption[170],andtobepartiallyinhibitedbytheintroductionofagentsthatspecicallydisruptactinmicrolaments[171–173].
Inparallel,thediscoveryandcharacterizationofmicrotubule-basedmotorskinesinanddyneinallowedtobetterenvisagetheaxonaltransportsystem.
Complemen-tarydata,intendingtodeciphertheimportanceofmicrotubule-governedtransportamongothercytoskeleta,usedamodelofneuronsgrownwithvinblastine.
Resultsshowedthatthewholemitochondrialcompartmentconcentratedintothecellbody,suggestingthatmicrotubuleswerenecessaryandsufcientforthetransportofmitochondriainaxons[174].
Consideringtheuncontestedroleofmicrotubulesastracksfortheintracellulartrafckingofmitochondria,itcanbearguedthatmitochondrialtransportdefectscouldresultfrommicrotubuledynam-icsalteration.
Insupporttothis,theparkinsoniantoxin(MPP+)hasbeenrecentlyshowntoinduceanearlyalterationofmicrotubuledynamicsandorientation,andasubsequentmitochondrialtransportimpairment[175].
Worksintumorcellsshowedthatpaclitaxelincreasedthespeedofmitochondrialmovement,whereascolchicineandnocodazoleretardedit[123,176],suggestingthatmicrotubulestabilizationcouldbenecessarytoorganelletrafcking.
Uptonow,themajorhypothesisexploredwasthechangesinmolecularmotorbindingtothemicrotubulerailways,throughtubulinpost-translationalmod-ications(PTMs).
Indeed,bindingofthemotorproteinkinesin-1,thatmostlyensuresanterogrademitochondrialtransportinaxons,isincreasedbymicrotubuledetyrosinationandacetylation[177,178].
ThesetwomajorPTMscorrelatewithmicrotubulestabilizationandareinducedbypaclitaxelandixabepiloneincancercells[179,180].
Thesedataweresupportedbyobservationsofpaclitaxelinhibitoryeffectsonfastretrogradetransportinratperipheralnerves[163,181].
However,resultsarestillcontroversialsincearecentworkshowedthatpaclitaxelabolishedkinesin-1translocationinpolarizedneuronsbyincreasingtheoveralllevelsoftubulinacetylation,detyrosinationandpolyglutamyla-tion[182].
Oneexplanationcouldbethat,whilemicrotubulestabiliza-tionisnecessaryforthemitochondrialtransport,itsover-stabilizationcompromisestheintracellulartrafcking.
Elsewhere,microtubuleassociatedprotein(MAPs)bindingtomicrotubulescanalsoinuencemotor-basedaxonaltransport,mainlybyaffectingtheattachmentanddetachmentcycleofthemotors.
Inneurons,tauandMAP4cancontroltheintracellulartrafckingbyreducingtheattachmentofkinesintomicrotubules[183,184].
MorerecentlySeitzetal.
showedadecreaseinrun-lengthforbothkinesinordyneinwhenMAP2candtauwereoverexpressedincells,combinedwithasignicantdecreaseinkinesinattachmentfrequencyontaxol-stabilizedmicrotubules[185].
Then,aspaclitaxelhasbeenshowntoincreaseMAP2afnityformicrotubule[186],itcouldthuseasilybethoughtthatpaclitaxelbyregulatingMAPsbindingcouldmodulateorganelletrafcking.
Lastly,thep150Gluedsubunitofdynactinisa+TIP(cfpart2)that,inassociationwithdynein,participatestoorganelleretrogradetransport.
Interestingly,p150GluedinteractionwithEB1atmicrotubuleplus-endsseemstobecentralinthedynein/dynactinfunction[187].
Thus,bysignicantlydisturbingEB1localization[21,23],MTAsmaycausethelossofbothmicrotubuledynamicsandmitochondrialtransport,whichtogethermightleadtocancercelldeath.
Sameobservationscouldbe683A.
Rovinietal.
/BiochimicaetBiophysicaActa1807(2011)679–688transposedtotheneuronalmodelasEBfamilymembersarecrucialforneuritegrowthandmaintenance,andaretoolsofchoicetopreciselymeasureplus-endmicrotubuledynamicsbylivemicroscopy[188].
Interestingly,neurotoxicconcentrationsofpaclitaxelhavebeenshowntoinduceadecreaseinthenumberandlengthofEB3comettailsinAplysianeurons[189].
Moreover,paclitaxelsignicantlydisturbedthemicrotubulepolarorientation,byreducingthepercentageofmicro-tubuleswithplusendsfacingtheaxontipandincreasingthosewithplusendsfacingthecellbody[189].
Allthesemicrotubulemodicationswereassociatedwithaseverelyimpairedmitochondrialtransport.
Inagreementwiththesedata,weshowedthatpaclitaxelandvincristinesuppressedEB1andEB3accumulationatmicrotubuleplus-ends,andsignicantlyreducedthemitochondrialmotilityinhumandifferentiat-edneuronalcells[23].
6.
2.
CanMTAsdisruptthession/fusionequilibriumRecently,withtheemergenceoftheneuropathologyeldofresearch,studieshaveourishedsuggestingthatmitochondrialdysfunctionsareearlyandcausaleventsinmanyneurodegenerativediseases[190]suchasamyotrophiclateralsclerosis,Alzheimer's,Huntington'sorParkinson'sdiseases.
Onepotentialcauseofmitochon-drialdysfunctionisthedisruptionofthehighlycontrolledequilibriumbetweenmitochondrialssionandfusion.
Excessivessionordefectsinfusionaltercellfunctionsandviabilitythroughimpairmentofmitochondrialmotility,decreaseenergyproduction,andincreaseoftheoxidativestress[191].
Examplesaregivenwithstudiesusingtaxolatconcentrationsresponsibleformicrotubulestrongstabilizationandleadingtodisruptionofmitochondrialssion/fusionbalance[192]aswellastheirabilitytofastlymoveanddistributetowardshighenergydemandsubcellularlocations[193].
Inthesestudies,MTAshavebeenemployedathighconcentrationsduringveryshorttimeofexposure(lessthan24h)toinducemicrotubulemodicationsandthustoanalyzemitochondrialdynamicityparameters.
Thereisnowacrucialneedinreconsideringtheconcentrationsemployed.
Indeed,lowerconcentrationsmaygivecomplementarycuestountanglemitochondriaandmicrotubuleinterconnectionsandmayhelptodecipherhowtheanti-microtubulepropertiesofMTAsleadtodisturbancesinmitochon-drialdynamics.
Intumorcells,suchmoderatedconcentrationsofMTAssignicantlyaltermicrotubuledynamicsandinducethemitochondrialnetworkfragmentation,asanearlyprocessassociatedwiththeirpro-apoptotic,anti-angiogenicandneurotoxicactivities[23].
AspreviouslyshownwithBH3-onlypeptides[194],ourrecentworkssuggestedthatthisprocesscouldresultfromBimaccumulationinmitochondrialmembranes(Savryetal,submitted),byamolecularmechanismthatshouldbeinvestigated.
7.
ConclusionToconclude,itclearlyappearsthatMTAsarebothanticancerdrugswithahighclinicalvalueandveryusefultoolstoanalyzetherolesplayedbythemicrotubulenetworkinphysio/pathologicalprocesses.
TodecipherthetangleofMTA-inducedapoptoticsignalsisatrickyexerciseand,todate,itisstilldifculttodeterminewhetherbiochemicaleventsthatleadtoapoptosisareactivateddownstreamorupstreaminhibitionofmicrotubuledynamicsandfunctions.
However,itbecomesclearthatcrucialmolecularlinksareestablishedbetweenthemicrotubulenetworkandtheapoptoticmachinery,toensurethesuccessofthecelldeathprogram.
Inthatsense,analysisofmechanismsresponsiblefortumorcellresistancetoMTAswouldalsoprovidekeyinformationaboutthecloseconnectionsbetweenmicrotubulesandtheapoptoticmachinery.
ThecoexistenceofmodicationsinthemicrotubulesystemandthemitochondrialsignalingcascadeincellsresistanttoMTAs[17,179,195]strengthenstheneedfornovelinsightsintointerconnectionsbetweenthetwocompartmentstohelpcircumventingthisclinicalproblem.
ItalsoconrmedthatthemitochondrionisstillapromisingtherapeutictargetthatcouldimprovecombinatorialtherapywithMTAsandprovidecrucialarmstohelptreatingcancers.
AcknowledgementsWethankDr.
StéphaneHonoréandDr.
VéroniqueBourgarel-Reyforhelpfulcommentsonthemanuscript.
ARreceivedafellowshipfromtheRégionProvenceAlpesCted'Azur(France)andASfromtheAssistancePubliquedesHopitauxdeMarseille.
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