opening科比凯拉

Chapter18DNARepairandResistancetoCancerTherapyAntónioS.
Rodrigues,BrunoCostaGomes,CéliaMartins,MartaGromicho,NunoG.
Oliveira,PatríciaS.
GuerreiroandJoséRueffAdditionalinformationisavailableattheendofthechapterhttp://dx.
doi.
org/10.
5772/539521.
IntroductionHumansareconstantlyexposedtodiversechemicalandphysicalagentsthathavethepotentialtodamageDNA,suchasreactiveoxygenspecies(ROS),ionizingradiation(IR),UVlight,andvariousenvironmental,dietaryorpollutantchemicalagents.
Theintegrityandsurvivalofacelliscriticallydependentongenomestability,andcellspossessmulti‐plepathwaystorepairtheseDNAlesions.
Thesepathwaysarediverseandtargetdiffer‐enttypesoflesions.
ThecriticalroleplayedbyDNArepairinthemaintenanceofgenomestabilityishighlightedbythefactthatmanyenzymesinvolvedhavebeenconservedthroughevolution[1-4].
VeryrarelygermlinemutationsoccurinseveraloftheDNArepairgenesandarethecauseofcancerpredisposingsyndromes,suchasXerodermapigmentosum(XP),[5],Fanconianemia(FA)andataxiatelangiectasia(AT)andareassociatedwithinherentchromosomeinstability[2].
Oneofthemostwell-knownexamplesofadefectinDNArepairleadingtocanceristheassociationofgerm-lineBRCA1/2mutationswithbreast,ovarianandperitonealmalignan‐cies[6].
TheserarehumanDNArepairsyndromeshavebeeninvaluableinprovidingmech‐anisticexplanationsfortheinvolvementofDNArepairsystemincancer.
Theyhavealsobeeninstrumentalinthetranslationofthesefindingstotheclinic.
Ontheotherhand,recentstudieshaveshownthatdefectiveDNAdamagerepairispresentinvirtuallyallsporadictumours[7].
MutationsinDNArepairgenescouldbeei‐therresponsiblefortheoccurrenceoftumoursorcouldariseduetorandomaccumula‐tionofmutationsduringcyclingofcancercells.
ThepresenceofincorrectDNArepairintumourcellspredisposesthemtoaccumulateevenmoregeneticalterations.
Forexample,colorectalandendometrialcancerswithdefectiveDNAmismatchrepair(MMR)dueto2013Rodriguesetal.
;licenseeInTech.
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0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
mutationsintheMLH1andMSH2genesexhibitincreasedratesofacquisitionofsinglenucleotidechangesandsmallinsertions/deletions[8].
Thus,thepresenceofa"mutatorphenotype"[9]couldincreasetheevolutionaryacquisitionofalterationsthatultimatelycouldleadtoenhanceddrugresistance.
AfurtherreminderontheimportanceofDNArepairistheobservationthatmutationsinspecificgenescanleadnottoanincreaseincancerbuttoacceleratedagingsyndromes[7].
AnexampleofthisisCockayne'ssyndrome(CS),whichcausessevereprogeroidsyndromes[10].
Mutationsinthegenesthatencodetwoproteinsinanucleotideexcisionrepair(NER)sub-pathwaycalledtranscriptioncoupledrepair(TCR)causeglobalprematurecelldeaththroughapoptosis.
InthiscaseapoptosisensuresthatDNAmutationsarenottransmittedtodaughtercells,albeitattheexpenseofcellviability,andhighlightstheimportanceofmain‐tainingDNAintegrity.
Onemajorproblemincancertherapyisthefactthatofthe7.
6millioncancerdeathsthatoc‐cureveryyearworldwide(2008data;http://www.
who.
int/cancer/en/),manyareduetofail‐ureofcancertherapyassociatedwithacquiredandintrinsicresistancemechanisms.
Thesemechanismsofresistancecanbeclassifiedindifferentways,butthemostcharacterizedarealteredcellulardrugtransport,increasedsurvivalordecreasedcelldeath,alteredDNAre‐pair,andalterationsindrugtargets[11,12].
OverthelastyearstheimportanceofDNAre‐pairpathwaysinresistancetochemotherapyhasbeenincreasinglyrecognized,buttranslationtotheclinicisstillscarce.
SincemanyclassicalcancertherapiestargetDNA,theinfluenceofDNArepairsystemsinresponsetoDNAdamagewhichprimarilyresultfromchemotherapyandradiotherapyiscriticaltocellsurvival.
TheuseofinhibitorsofDNAre‐pairorDNAdamagesignallingpathwaysprovidesaninterestingopportunitytotargetthegeneticdifferencesthatexistbetweennormalandtumourtissue[13,14].
TherationaleunderlyingtheuseofDNAdamagingagentsintherapeuticstrategiesistokillcancercellswhilesparingnormaltissues,duetoincreasedcellcyclingofcancercells.
Un‐fortunatelyhighlycyclingnormalcells(e.
g.
bonemarrow,hairfolliclesandgastrointestinalepithelia)arealsotargetedbyDNAdamagingtherapeuticagents,givingrisetothesecon‐daryeffectsnormallyseenaftercancertherapy(e.
g.
diarrhoea,mouthulcers,hairloss,anae‐miaandsusceptibilitytoinfections).
Nevertheless,DNA-damagingchemotherapeuticagentsareeffectiveandprolongsurvivalofcancerpatients[15].
Chemotherapeuticagentscommonlyusedincancertreatmentproduceaplethoraoflesionsthatcanbetargetsforcel‐lularresponses.
Forexample,DNAdoublestrandbreaks(DSBs),single-strandbreaks(SSBs),andoxidizedbasesareinducedbyionizingradiation(IR),anthracyclines,platinumcompoundsandtaxanes.
AnthracyclinesaretopoisomeraseIIinhibitorsandDNAinterca‐latingagents,whichwhenusedcanleadtoDSBs.
Platinumcompoundsarebifunctionalal‐kylatingagentsthatinducepredominantlyintra-andinterstrandcrosslinks(ICLs)andtaxanesaremitoticinhibitors.
Alltheselesionsinducecellularresponsesthatcoveramulti‐tudeofpathways,includingDNArepairpathways,DNAtolerancemechanisms,coordina‐tionnetworksthatlinkrepairandcellcycleprogression,aswellasapoptoticandothercelldeathpathwayswhenDNAdamageisirreparable[16-19].
NewResearchDirectionsinDNARepair490TheDNArepairpathwaysthatrespondtotheselesionsinclude:directrepairofalkylad‐ductsbyO6-alkylguanineDNAalkyltransferase(MGMT);repairofbasedamageandSSBsbybaseexcisionrepair(BER);repairofbulkyDNAadductsbynucleotideexcisionrepair(NER);repairofcross-linksbyDNAinterstrandcross-linkrepairandrepairofmismatchesandinsertion/deletionloopsbyDNAmismatchrepair(MMR);repairofDSBsbyhomolo‐gousrecombination(HR)andnon-homologousendjoining(NHEJ).
DetaileddescriptionofthebiochemicalpathwaysofDNArepairisbeyondthescopeofthischapterasseveralre‐viewsonthesubjecthavebeenpublished[1,17,20-23].
TheobservationthatavarietyoftumoursfrequentlypresentderegulatedexpressionofDNArepairgenes(e.
g.
MGMT,PARP1)rapidlyleadtothenotionthatDNArepairpath‐wayscouldbetargetedincancertreatmentandleadtopersonalizedtherapy[24,25].
Tu‐mourswithspecificDNArepairdefectscouldbecompletelydependentonback-upDNArepairpathwaysfortheirsurvival.
Thisdependencecouldbeexploitedtherapeuticallytoin‐ducecelldeathandapoptosisintumourcells[26,27].
Thegeneticstateinwhichsimultane‐ousinactivationof2genes(orpathways)islethal,whilelossofoneortheotheraloneisviableiscalledsyntheticlethality(alsoknownasconditionalgenetics).
Therationaleforin‐ducingsyntheticlethalityincanceristhatcertaincancercellslackonepathwaytorepairtheirDNA(e.
g.
HR)buthavealternativepathways(baseexcisionorsingle-strandrepair)thatallowthemtosurvive.
InhibitionofthesealternativepathwayswouldthenimpairDNArepairandinducecelldeath[26,27].
Thereforeitpredictsthatgenotoxicagentslead‐ingtoaparticulartypeofDNAdamagewillkillcancercellswithgeneticdeficitsinrepairofthattypeofdamage.
Recently,thisspecificanticancerstrategyhasbeenthefocusofintenseinvestigations[28,29].
InthecaseofthehereditaryBRCA1/2-deficientbreastandovariancancersyndromes,men‐tionedearlier,thisstrategyhasbeentranslatedintotheclinic,intheformofPARPinhibi‐tors.
TheseBRCA1/2-tumoursaredefectiveintherepairofDSBsbyHR.
WhenareplicationforkinoneofthesetumoursencountersaDNASSB,itconvertsthatintoaDSB,butthepresenceofaDSBpreventsprogressionofthereplicationapparatus.
SinceBRCA1/2arebothrequiredforDSBrepair,thetumourcellswiththosemutatedgeneswilldependonrepairofSSBstopreventDSBsfromoccurring.
TheDNArepairproteinPARP1isrequiredforrepairofSSBs,andsmallmolecularinhibitorsofPARP1willpreventrepairofSSBs,morespecifi‐callyincellsthataredeficientinBRCA1/2.
SincenormalcellshavetheabilitytorepairtheDSBsgeneratedatthereplicationfork,becausetheyhaveatleastonenormalalleleofBRCA1/2,theuseofPARPinhibitorshasthepotentialoftargetingonlytumourcells.
Thisproofofconceptprovenclinically,wherethePARP1inhibitorolaparibimprovesthepro‐gression-freesurvivaloffamilialbreastcancer[30].
Followingthisleadseveralsmallmole‐culeDNArepairinhibitorsarebeingdevelopedworldwide.
However,notallBRCA1/2defectivetumoursrespondequallywelltothistypeoftherapy.
Thus,inthepastyearsevidencehasaccumulatedthatdrugresistanceisalsolinkedtoalter‐ationsinthesepathways[31-33].
Thus,tumourcellsmayalsoacquireresistancebyinvokingbiochemicalmechanismsthatreducedrugactionorbyacquiringadditionalalterationsinDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952491DNAdamageresponsepathways[34].
Therefore,thefocushasalsobeendirectedonDNArepairpathwaysthatcouldberesponsibleforcancerdrugresistance.
Resistancetochemotherapylimitstheeffectivenessofanti-cancerdrugtreatment.
Tumoursmaybeintrinsicallydrug-resistantordevelopresistancetochemotherapyduringtreatment.
Acquiredresistanceisaparticularproblem,astumoursnotonlybecomeresistanttothedrugsoriginallyusedtotreatthem,butmayalsobecomecross-resistanttootherdrugswithdifferentmechanismsofaction.
Resistancetochemotherapyisbelievedtocausetreatmentfailureinover90%ofpatientswithmetastaticcancer[35].
Thus,drugresistanceisclearlyamajorclinicalproblem.
Theattempttodevelopmoretargetedtherapeuticshasbeenamajorobjectiveincancerre‐searchinlastyears,andmoreandmoremoleculartargetsarebeingidentified(e.
g.
tyrosinekinaseinhibitors,monoclonalantibodiestargetingmembranereceptorkinases).
Someofthesetargetedtherapiesareinclinicaluse,whileothersarebeingevaluatedinclinicaltrialstovalidatetheirefficacy.
Morerecently,thequestfortargetedtherapieshasalsofocusedonDNArepairpathways.
Unfortunately,resistancetothesetherapiesisalsolikelytoappear,ashasoccurredwithothertargetedtherapies,suchasthetyrosinekinaseinhibitorsofthefusionBCR-ABL1gene,responsibleformostcasesofchronicmyeloidleukaemia(e.
g.
imati‐nib,dasatinib,nilotinib).
TheapplicationofDNArepairinhibitorsintheclinichasalsoshowntobefraughtwithdifficulty,sincetheyalsotargetDNArepairpathwaysinnormalcells.
TheearlyclinicaltrialwithMGMTinhibitorsincombinationwithtemozolomide(TMZ)wasstoppedearlybecausethecombinedtreatmentsharmedbonemarrowaswellascancertissue,whereastheclinicalsuccessofPARPinhibitorstranspiredsincePARPisnotcriticaltocellsurvival.
Hence,unlikepastvisionsofa"magicbullet"towardscancer,futureresearchoncancertherapyshouldmorereasonablyenvisagecancertherapyasa"neverendingstory",inwhichnoveltargetedtherapeuticsareconstantlybeingovercomebytheevolutionaryprocessespresentincancerouscells[36].
2.
TargetingDNArepairpathwaysAsmentioned,DNArepairpathwaysincludethedirectreversaloflesions,essentiallyde-alkylationofalkylatedbasesbyMGMT,NER,BER,MMRandthedoublestrandbreakre‐pairbyHRandNHEJ.
Alterationsinallthesepathwayshavebeenobservedindrugresistanttumourcells;however,theclinicalsignificanceofthealterationsisnotcompletelyunderstood.
Numerousgenesinvolvedineachofthesepathwayshavebeenshowntobeup-ordown-regulatedindiversetypesoftumoursandconstituteapotentialsourceofbio‐markerstoevaluatedrugresistancetocancerchemotherapeutics[25,32,33].
3.
MGMTanddrugresistanceAlkylatingagentsarewidelyusedtotreatcancers,andoneofthemajorDNAlesionsformedoccursessentiallybythealkylationofDNAattheO6-positionofguanine,whichNewResearchDirectionsinDNARepair492subsequentlycangenerateDNAbreaksandcelldeath.
TMZ,streptozotocin,procarbazineanddacarbazineareexamplesofcancerchemotherapeuticsthatmethylateDNA[37].
Directrepairofalkylatedguanineresiduesproceedsthroughtheremovalofthealkylmoi‐etybyMGMT.
MGMTisaconservedproteinfromprokaryotesthrougheukaryotes.
TheMGMTproteinremovesthealkylgroupfromO6-alkylguaninebydirecttransfertoacys‐teineresidueinitsactivesitetowhichthealkylgroupbecomescovalentlyattached,result‐ingintheinactivationoftheprotein.
TheMGMTproteinissubsequentlyubiquitinatedanddegradedbytheproteasome[38,39].
TheO6-alkylguanineadductaccountsforabout10%oftotalalkylations,butdisplaysastrongmutagenicandcytotoxicpotential,becauseO6-alkyl‐guaninesexhibitdistortedbasepairingcharacteristicsinpairingwiththymine,thereby,re‐sultinginG:CtoA:TtransitionsuponDNAreplication[40].
HencetheuniqueDNArepairmechanismwhichdependsonthesuicidaldegradationoftheMGMTprotein.
TumourexpressionofMGMTvariesandcorrelateswiththerapeuticresponsetoalkylatingagents.
NumerousstudieshavefoundastrongcorrelationbetweenMGMTactivityanddrugresistanceinprimarytumoursandestablishedhumantumourcelllines[16,41,42].
Highlevelsofexpressionhavealsobeennotedinmelanoma[43],pancreaticcarcinoma[16]besidesglioblastomas[44].
ResistancetoalkylatingagentssuchasTMZhasbeenlinkedtoover-expressionofMGMT[43].
ThereforeMGMTlevelsarebeingstudiedasbiomarkersofintrinsicchemosensitivitytoalkylatingagents,suchasTMZorBCNU(carmustine).
Conversely,reducedMGMTactivityinculturedtumourcellsandhumantumoursisof‐tentheresultofepigeneticsilencingbypromotermethylationofCpGislands,whichleadstotheformationofinactivechromatinthatlimitstranscription,andthereforehigh‐erchemosensitivitytoalkylation.
Hegietal.
reportedthatof206patientswithglioblasto‐mathatweretreatedwithTMZandradiotherapy,thosewithamethylatedMGMTpromoter(45%)hadasignificantlybettersurvival[45].
Hence,MGMTpromotermethyla‐tionstatusisemergingasaprognosticfactorfortumourtherapyandiscurrentlybeingassessedforselectingglioblastomachemosensitivitytowardsTMZ[46-48].
Themecha‐nismsunderlyingincreasedMGMTpromotermethylationarecomplexandnotcomplete‐lyknown,althoughitisoneofthemoststudiedDNArepairgenes[38].
InnormalcellsMGMTpromotermethylationisuncommon,butoccursfrequentlyintumours.
Approxi‐mately25%oftumoursofmanydifferenttypes,includingnon-small-cellcarcinomaofthelung,lymphoma,headandneckcancers,andupto40%ofgliomaandcolorectaltu‐mourswerefoundtopresentCpGislandpromotermethylation[49].
SincehighMGMTexpressionresultsindrugresistancetoalkylatingagents,onestrategytoovercomeresistanceandimproveefficacyistousepseudosubstratesofMGMT,suchasO6-benzylguanine(O6-BG)orO6-(4-bromothenyl)guanine(O6-BTGorlomeguatriborPaTrin-2)whichinactivatetheenzymeandenhancecelldeath[50].
O6-BGisaspecific,potent,andnontoxicinhibitorandleadstosensitizationofcancercellstocisplatin,chloroethylatingandmethylatingagents[51,52].
ClinicaltrialsareunderwaytotestcombinationsofO6-BGwithcarmustineorTMZforthetreatmentofglioma,anaplasticglioma,lymphoma,myeloma,co‐loncancer,melanomaandsarcoma,amongothers[53].
O6-BTGpresentshigherbioavailabil‐itythanO6-BG,butalsopresentshigherhaematologicaltoxicitywhenco-administeredwithDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952493TMZcomparedtoTMZalone.
Thereforefulluseofthisinhibitormaybemoredistant[54,55].
HaematologicaltoxicitywasalsoobservedwithO6-BTGco-administeredwithdacarba‐zineinpatientswithadvancedmelanomaandothersolidtumours[56].
ThecombinationofO6-BTGandTMZwasalsoevaluatedinaphaseIclinicaltrialforadvancedsolidtumours[57],andinapilotstudyforrefractoryacuteleukaemia[58].
AphaseIclinicaltrialwasalsoconductedassociatingO6-BTGwithIrinotecanforcolorectalcancer[59].
AphaseIIclinicaltrialofO6-BTGplusTMZforstageIVmetastaticcolorectalcancerisalreadycompleted.
Thetrialwasconsideredcompletedaftertherecruitmentof19patientsduetotheabsenceofre‐sponsesandalsobecauseevidencesfromotherstudiessuggestthattheO6-BTGdosingregi‐menwasinappropriate[55].
ThesestudiesshowedaconsistentdepletionofMGMTandprovidednon-toxicdosesofO6-BGorO6-BTGtobeusedinfurtherstudies.
Thehaematolog‐icaltoxicityobservedwiththecombinationofMGMTinhibitorsandchemotherapeuticagentsmightbeattributedtoaneffectivedepletionofMGMTinoff-targetcells[60].
Addi‐tionally,theadministrationofasub-optimaldoseoftheMGMTinhibitor,atherapeuticdos‐ingschedulethatallowstherecoveryoftheMGMTactivityorthechoiceofaninadequatetreatmentforthetypeofcancercouldexplainthelackofeffectsinclinicaltrials.
Inviewofthis,tumour-targeteddeliveryofMGMTinhibitorsbythedevelopmentofspecificformula‐tionsorlocaladministration[61]couldbeadoptedtoimprovethetherapeuticefficacyofthechemotherapeuticdrugsandtotranslateintotheclinictheresultsobtainedinpreclinicalstudies.
Nonetheless,itisnotclearifclinicalapplicationofMGMTinhibitorsisaviablether‐apyinallsettings.
4.
TargetingMMRincancerdrugresistanceMMRisinvolvedinthedetectionandrepairofbase-basemispairsduringDNAreplication,smallinsertion/deletionmutationsatrepetitivemicrosatelliteregionsandalsointheregula‐tionofhomologousrecombination[62].
MMRproteinsarealsoinvolvedintherepairofDNAdamagecausedbyROSandalkylatingagents.
MMRproteinsinteractwithcompo‐nentsofotherrepairpathways,includingNER,BER,andHR,thussignallingwithotherpathwaysinresponsetoDNAdamage.
TheMMRsystemconsistsofvariousproteins.
MSH2heterodimerizeswithMSH6orMSH3toformMutSαorMutSβ,respectively,bothofwhichareATPasesthatplayacriticalroleinmismatchrecognitionandinitiationofrepair.
ThisinducesaconformationalchangeinMutS,resultinginaclampthattranslocatesonDNAinaATPdependentmanner,recruitstheMutLcomplex,whichinhumansisaheterodimerconsistingoftheMLH1andPMS2proteins,anddisplacesDNApolymeraseandPCNA,thereafterrecruitinganexonuclease(EXO1)thatdegradesthenewlysynthesizedDNAstrand[63].
OtherMMRgenes(MLH1,MLH3,PMS1,andPMS2)areinvolvedinMMR.
MLH1alsoheterodimerizeswithPMS2,PMS1,orMLH3toformMutLα,MutLβ,orMutLγ,respectively[63].
Polymeraseδ(polδ)thenpolymerizestheDNAstretchandDNALigaseIperformsligation.
MMRdeficiencyleadstoawiderangeoftumourtypes.
GermlinedeficiencyinMMRac‐countsfortheLynchsyndrome(hereditarynon-polyposiscolorectalcancer-HNPCC),inNewResearchDirectionsinDNARepair494whichalargeincreaseinfrequencyofinsertionanddeletionmutationsinsimplerepeat(mi‐crosatellite)sequences,aphenomenonknownasmicrosatelliteinstability(MSI),isobserved[64].
DNAmismatchrepairdeficiencyinsporadictumoursisseenincolonic,gastric,endo‐metrial,andothersolidtumours.
MSIisalsoassociatedwithawidevarietyofnon-HNPCCandnon-colonictumours,includingendometrial,ovarian,gastric,cervical,breast,skin,lung,prostate,andbladdertumoursaswellasglioma,leukaemia,andlymphoma[65].
DefectsinMMRarealsoassociatedwithresistancetocertainchemotherapeuticagents[66].
ResistancetoalkylatingagentssuchasTMZandprocarbazineoccurswithinactivationofMMRintumourcells[63].
MMR-deficientcellsarerelativelyresistanttomethylatingagents(upto100fold),whereascellswithafunctioningMMRsystementereitherG2arrestorapoptosis,dependingontheseverityoftheDNAdamage[67].
DownregulationofproteinsoftheMMRpathwayisassociatedwithresistancetoclinicallyimportantdrugsincludingplatinum-containingcompounds,anthracyclines,alkylatingagents,antimetabolitesandepi‐podophyllotoxins[68].
Forexample,MSH2proteindeficiencybyenhancingMSH2degradationleadstosubstantialreductioninDNAmismatchrepairandincreasedresistancetothiopurines.
Somaticdele‐tionsofgenesregulatingMSH2degradationresultinundetectablelevelsofMSH2proteininleukaemiacells,MMRdeficiencyanddrugresistance[69].
Anotheragent,etoposide,isatopoisomeraseIIalpha(TOP2A)inhibitor,whichisusedinthetreatmentofbreastcancer.
AlterationsintheexpressionofdrugtargetsorDNArepairgenesareamongtheimportantresistancemechanismsagainstTOP2Ainhibitors.
DecreaseintheexpressionlevelsofTOP2A,andtheMMRgenesMSH2andMLH1mayplaysignifi‐cantrolesinthedevelopmentofchemotherapeuticresistancetoetoposideinbreastcancer.
Thesegenesmaybeconsideredforfurtherdevelopmentofnewstrategiestoovercomere‐sistanceagainsttopoisomeraseIIinhibitors[70].
MMRisalsoinvolvedinrepairofcross-linkingagentssuchasplatinumbasedchemothera‐peutics.
Increasedtolerancetoplatinum-inducedDNAdamagecanoccurthroughlossoffunctionoftheMMRpathway.
DuringMMR,cisplatin-inducedDNAadductsarerecog‐nizedbytheMMRpathway,butarenotrepaired,givingrisetosuccessiverepaircycles,ul‐timatelytriggeringapoptosis.
ThusinMMRdeficientcells,celldeathisnotasefficient,promotingtolerancetoplatinumagents[71].
MMR-deficientcellsarealsomoretolerantto6-thioguaninetreatment,usedtotreatleukae‐mias,thanMMR-proficientcells.
Theanti-metabolite6-thioguanineisincorporatedintoDNA,whereitcanbemethylatedbyS-adenosylmethionineto6-methylthioguanine(Me6-thioguanine),whichhassimilarmiscodingpropertiesasmethylguanine[68].
Nevertheless,althoughmanypreclinicalstudiessuggestMMR-deficientcellsareresistanttoalkylatingagents,fewclinicalstudieshavebeenpublishedregardingMMRdeficiencyandresponsetoalkylatingagents.
Onthecontrary,forexample,Maxwelletal.
,[72]foundthatMMRdeficiencydoesnotseemtoberesponsibleformediatingTMZresistanceinadultma‐lignantglioma.
CoupledwiththelackofsubstantialdatalinkingpolymorphismswithintheMMRgenesandresistancetochemotherapyorradiotherapy,publishedworksuggeststhatDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952495theMMRpathwayhaslowpriorityinthequestfornewcancertherapies.
However,ongo‐ingresearchontheroleofmicroRNAsandcancerdrugresistancecouldincreaseinterestinthispathway.
PublishedworkhassuggestedthatforexamplemiR-21targetsMSH2andconsequentlyinducesresistanceto5-Fluorouracil(5-FU)incolorectalcancer[73](seethesectionofmicroRNAsanddrugresistance).
5.
TargetingBERincancerdrugresistanceBERisthemainpathwayforremovingsmall,non-helix-distortingbaselesionsfromthege‐nome.
Thus,BERtargetspredominantlybaselesionsthatariseduetooxidative,alkylation,deamination,anddepurination/depyrimidinationdamage.
Someexamplesofchemothera‐peuticagentsthatgeneratelesionsthataretargetedbyBERincludeTMZ,melphalan,dacar‐bazine/procarbazine,andstreptozotocin[33].
SomechemotherapeuticagentsalsogenerateROSasa"by-product"suchasplatinum-baseddrugs(i.
e.
oxaliplatinandcisplatin),anthra‐cyclines,(i.
e.
epirubicin,daunorubicin,doxorubicin)andpaclitaxel[31,33].
ROSinduceDNAlesionsthatarealsorepairedbytheBERpathway.
Additionally,IRproducesanum‐berofDNAlesionsthatarerepairedbytheBERpathway.
EndogenousproductionofROSalsogivesrisetoseverallesions,whicharevariableinnumberandconsequence.
Forin‐stancethehighlymutagenic8-hydroxyguanine(8-oxoG)isformedinlargequantitiesasaconsequenceofthehighoxidationpotentialofthisbase,andhasamiscodingeffect,duetoDNApolymeraseactivitywhichinsertsadenineoppositeto8-oxoG,resultinginG:CtoA:Ttransitionmutations.
TheBERpathwayisinitiatedbyoneofmanyDNAglycosylases,whichrecognizeandcata‐lyzetheremovalofdifferentdamagedbases.
AfterrecognitionofthedamagedbasebytheappropriateDNAglycosylase,itcatalyzesthecleavageofanN-glycosidicbond,thusre‐movingthedamagedbaseandcreatinganapurinicorapyrimidinicsite(APsite).
TheDNAbackboneiscleavedbyeitheraDNAAPendonucleaseoraDNAAPlyase,activitypresentinsomeglycosylases.
Thiscreatesasingle-strandedDNAnick5'totheAPsite.
ThenewlycreatednickisprocessedbytheAPendonuclease,creatingasingle-nucleotidegapintheDNA.
AtthispointBERcanproceedthroughashort-patchBER,wherepolymeraseβ(polβ)introducesasinglenucleotidepasttheabasicsiteandLigaseIIIαsealstheDNAnick,orthroughalong-patchBER,wherePolymeraseδ/εintroducestwotoeightnucleotidespasttheabasicsite.
TheresultingoverhangDNAisexcisedbyFEN1endonucleaseandthenicksealedbyDNAligaseI[74].
Inadditiontotheseenzymes,anumberofaccessoryproteinsareinvolvedinBER,includingtheX-raycross-complementationgroup1protein(XRCC1),PARP1,theproliferatingcellnuclearantigen(PCNA),andtheheterotrimertermed9-1-1,whichfunctioninscaffoldsforthecoreBERenzymes[75].
PreclinicalevidenceshaveimpliedtheBERpathwayintherepairofDNAlesionsinducedbyantimetabolites,monofunctionalalkylatingdrugs,radiotherapyandradiomimeticagents.
Moreover,BERmodulationmayalsosensitizecancercellstotheeffectofchemother‐apeuticdrugsthatareabletogenerateROS[31,33].
Therefore,targetingBERwithinhibitorsNewResearchDirectionsinDNARepair496ofthemultifunctionalAPEndonuclease1andDNApolβisanattractivefieldtothedevel‐opmentofnoveltherapeuticcompounds.
SomestudieshavefoundderegulationofBERgenesintumours.
Forexamplepolβhasbeenshowntobeoverexpressedinavarietyoftumourcells[76].
N-methylpurineDNAglycosy‐lase(MPG)overexpression,togetherwithinhibitionofBER,sensitizesgliomacellstotheal‐kylatingagentTMZinaDNApolβ-dependentmanner,suggestingthattheexpressionlevelofbothMPGandpolβmightbeusedtopredicttheeffectivenessofBERinhibitionandPARP-mediatedpotentiationofTMZincancertreatment[77].
Werecentlyobservedanin‐creaseinexpressionoftheBERgenesMDB4andNTHL1inImatinibresistantK562leukae‐miacells,andknockdownoftheirexpressioninresistantcellsusingsiRNAdecreasedcellsurvivalaftertreatmentwithdoxorubicin[78].
Nevertheless,theinvolvementofderegulat‐edBERcomponentsinchemotherapyresistanceisnotcompletelyevidentatpresent,exceptforPARP,andtheAPendonucleases.
Thefollowingtextshalldescribeongoingresearchtar‐getingthesecomponentsoftheBERpathway.
ThemajorAPendonucleaseinmammaliancellsisapurinic/apyrimidinicendonuclease1/redox-factor-1(APE1/Ref-1,alsocalledAPEX1),andhasbeenfoundtobeelevatedinanumberofcancerssuchasovarian[79],prostate[80],osteosarcoma[81]andtesticularcan‐cer[82].
Over-expressionofAPE1invitroledtoincreasedprotectionagainstbleomycin[82].
ThuselevatedlevelsofAPE1incancercellshavebeenpostulatedtobeareasonforchemo‐therapeuticresistance[81,83,84].
InhibitionofAPE1hasbeenshowntoincreasecellkillingandapoptosisandalsotosensitizecancercellstochemotherapeuticagents,andthusAPE1isconsideredasamoleculartargetintherapeutics[85,86].
APE1endonucleaseactivityisindirectlyinhibitedbyblockedAPsitesthatresultfromthebindingofthesmallmoleculemethoxyamine(MX)totheDNA.
WiththeAPE1'ssubstrateunavailable,BERcannotproceedandthecytotoxicabasicsitesaccumulateinthecell,eventuallyleadingtocelldeath.
ThepromisingresultsfrominvitroandinvivoexperimentsshowingMXsensitizationtothecytotoxiceffectofTMZ[87-90],carmustine[91],pemetrexed[92]and5-iodo-2'-deoxyuridine(IdUrd)aswellasapotentiationofIdUrd-mediatedradiosensitization[93,94],inmultiplesolidtumoursmodels,providedtheproof-of-concepttoconductclinicaltrialswithMXasadjuvanttherapyofanticanceragents.
APhaseIclinicaltrialofpemetrexedandoralmethoxyaminehydrochloride(TRC102)inpatientswithadvancedrefractorycancerisalreadycompleted[95].
Accord‐ingtotheauthors,thisdrugiswelltoleratedafterdailyoraladministrationandpotenti‐atestheactivityofchemotherapy.
Safety,pharmacokineticandpharmacodynamicprofileofMXwasalsoevaluatedincombinationwithTMZinaPhaseIclinicaltrialforpa‐tientswithadvancedsolidtumours[96].
Currently,twoclinicaltrials(PhaseI)arere‐cruitingpatientstostudythesideeffectsandthebestdoseofMXtobeadministeredincombinationwithTMZandfludarabinephosphateinpatientswithadvancedsolidtu‐moursandrelapsedorrefractoryhematologicmalignancies,respectively.
InviewoftheemergingrolesofAPE1,manyeffortshavebeenmadetodevelopsmallmole‐culeinhibitorsthatcanbetranslatedtotheclinic.
Insilicobasedapproacheswithdesignofpharmacophoremodels[97,98]andhigh-throughputscreeningofseveralcommerciallyDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952497availablelibrariesofcompoundshavebeenperformedtoidentifyapharmacologicallyac‐tiveinhibitorforAPE1[86,99-102].
LucanthoneactsasadirectinhibitorofAPE1butalsointeractswithothercellulartargetsandtheassociatedtoxicityhinderstheirtherapeuticuse[103,104].
CRT0044876wasidentifiedbyafluorescence-basedhigh-throughputassayandshowedpromisingresultsininvitrostudies[105].
However,someauthorswerenotabletoreproducethereportedeffectsofthiscompound[85].
HypersensitivityofDNApolβ-nullcellstomethylmethanesulfonate(MMS),aDNA-meth‐ylatingagent,displayedanotherpotentialtargetinBER[106].
Severalsmall-moleculeinhibi‐torsofDNApolβhavebeenidentifiedandmanyofthesecompoundsarenaturalproducts,suchaskoetjapicacid(KJA),atriterpenoid.
PamoicacidwasoneofthefirstsyntheticsmallmoleculeinhibitorsofDNApolβtobecharacterizedandismoreactivethantheformercompound[107].
Nevertheless,theactuallyknowninhibitorsofDNApolβhavelowpoten‐cyandspecificitythatmakethemweakcandidatestodrugdevelopment(foracomprehen‐sivereviewsee[108]).
InviewofthepreclinicaldatathatsuggestanimportantroleofDNAPolβintherepairofchemotherapeutic-inducedDNAdamage,thedesignofeffectiveDNAPolβinhibitorsisanattractiveresearcharea.
InwhatconcernsPARP1,thisenzymeisaDNAdamagesensorthatbindstoDNAbreakstoactivatetherepairpathways.
PARP1isnotdirectlyinvolvedintherepairofthelesionsbutisessentialtosignalthedamageandtocoordinatethefunctionsofsever‐alBERandDSBrepairproteins.
PARPinhibitorshavebeenthoroughlydevelopedandseveralreviewspaperspublishedunderthistopic.
ForarecentcomprehensivereviewonPARPinhibitorsseeJavleetal[109].
PARPinhibitorswerefirstevaluatedinclinicaltri‐alsaschemosensitizers.
AfterAG014699combinationwithTMZ[110],otherPARPinhibi‐tors,specificallyINO-1001,ABT-888andAZD2281werealsotestedasadjuvanttherapyofmultipleanticanceragentssuchasgemcitabine,carboplatin,TMZorchemotherapeuticcombinations(e.
g.
cisplatinplusgemcitabine)[111].
Currently,severalPARPinhibitorsarebeingevaluatedinclinicaltrials,eitherincombinationwithchemotherapeuticdrugsorinmonotherapy[28,109,112-117].
Someofthesechemicalsshowedanenhancementofthetoxicityinnormaltissuesthatre‐quireddoseadjustmentsandoptimizationofthetherapeuticschedule.
Interestingly,pre‐clinicalandclinicaldatarevealedthatPARPinhibitorsassingleagentscouldbelesstoxictothenormalcellsandaremoreeffectiveinkillingBRCA1-andBRCA2-mutatedcancercellssincethesecellsaredefectiveinHR,thebackuppathwayresponsiblefortherepairofDSBsgeneratedafterPARPchemicalinhibition.
Similarly,mutationsinotherproteinsrelatedtotheDNAdamageresponse,suchasATMandPTENhavealsobeenassociatedtodefectsinDSBrepairandmaybeinvolvedinanincreasedsensitivitytoPARPinhibitors[118-120].
ThesefindingsledtoanovelpotentialtherapeuticindicationoftheDNArepairinhibitorsassingleagentsincancertherapywhichiscurrentlybeingevaluatedinclinicaltrials[121].
ThissyntheticlethalapproachwasalsoreportedinaninvitrostudywithAPE1inhibitorsinBRCAandATMdeficientcells[116,122].
Recently,negativeresultsfromthefirstphaseIIIclinicaltrialinbreastcancerpatientswithacombinationofiniparib(BSI-201)andgemcitabine/carboplatinwerereported[123].
TheNewResearchDirectionsinDNARepair498mechanismofactionofthisinhibitorisnotfullyunderstood,anissuethatshouldbefurtherclarified.
Nonetheless,promisingpositiveoutcomeshavealreadybeensuggestedwithotherPARPinhibitors[124,125].
AfurtherunderstandingofthecomplexPARPinteractome,thediscoveryofPARP1specificsmallmoleculeinhibitorsandanaccurateselectionofthebestcandidatestothetreatmentisstillneededtoimprovethequalityofinformationobtainedfrompreclinicalandclinicaltrialsandtopromotethedevelopmentofcurrentlyknownPARPinhibitorsaswelltodiscovernovelcompounds.
6.
TargetingNERindrugresistanceNERrepairsDNAlesionswhichalterthehelicalstructureoftheDNAmoleculeandin‐terferewithDNAreplicationandtranscription,suchasbulkyadductsandcross-linkingagents[2].
Briefly,NERconsistsoftherecognitionofDNAdamageanddemarcationofthespecificareaaffected,followedbytheformationofacomplextounwindthedam‐agedportionandexcisea24-32oligonucleotidesectionthatcontainsthelesion.
Finally,theexcisednucleotidesareresynthesizedandligated.
TwoNERsub-pathwaysexistwithpartlydistinctsubstratespecificity:globalgenomenucleotideexcisionrepair(GGR)sur‐veystheentiregenomefordistortinglesionsandtranscription-coupledrepair(TCR)fo‐cusesspecificallyinthetranscribedstrandofexpressedgenes,bytargetingdamagethatblockselongatingRNApolymerases.
Intotalmorethan30proteinsparticipateinNER[126].
ThegenesinvolvedinGGRareDNAdamagerecognitionbyXPC-HR23Bcom‐plex,lesiondemarcationandverificationbyaTFIIHcomplex,assemblyofapre-incisioncomplex(RPA,XPAandXPG),DNAopeningbyXPBandXPDhelicases,dualincisionbyERCC1-XPFandXPGendonucleases,releaseoftheexcisedoligomer,repairsynthesistofillintheresultinggap,andligationbyligaseI.
DefectsintheproteinsinvolvedinNERresultinthreeautosomalrecessivedisordersXP,CS,andTTD.
ThemostrelevantclassofchemotherapeuticsassociatedwithNERistheplatinum-basedgroupofagents.
Platinum-basedchemotherapyhasbeenusedforthetreatmentofawidevarietyofsolidtumoursincludinglung,headandneck,ovarian,cervical,andtes‐ticularcancerformanyyears[127].
TheseagentsinteractwithDNAtoformpredomi‐nantlyintra-strandcross-linkDNAadductsthattriggeraseriesofintracellulareventsthatultimatelyresultincelldeath.
Themoststudiedplatinumbasedcancertherapeuticsarecisplatinandthelesstoxiccarboplatinandoxaliplatin,buttherehasbeenaresur‐genceinthedevelopmentofplatinumbaseddrugs,andmoreplatinumbasedchemo‐therapeuticsareinclinicaltrials[128].
Thebasicmechanismofactionofcisplatin(andcarboplatin)involvescovalentbindingtopurineDNAbases:platinumbindingtotheN7positionoftheimidazoleringofthepu‐rinebasesofDNA—guanine(G)andadenine(A)—toformeithermonofunctionalorbifunctionaladducts.
Inthecaseofcisplatin,mostoccuronthesameDNAstrandandinvolvebasesadjacenttooneanother,andarethereforeknownasintra-strandadductsorcrosslinks,namelyGpG1,2intra-strand(60–65%ofalladducts)andApG1,2intra-DNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952499strand(20–25%)whichprimarilyleadstocellularapoptosis[128].
TheseDNAlesionsarerepairedbytheNERpathway.
Cisplatinhasbeenusedsuccessfullyastherapytotreatmetastatictesticularcancerwith>90%curerate.
ThehighsensitivityoftesticulartumourcellsisattributedtoreducedDNA-re‐paircapacityinresponsetoplatinum–DNAadducts[129].
ExtractsfromtesticularcancercellshadlowconstitutiveNERcapacityand,inparticular,lowlevelsoftheproteinXPA[130].
FurtherstudieshaveshownlowlevelsofXPAandotherNERproteins(XPFandERCC1),intesticularcancers.
ThissuggestedthatreducingNERcapacityinacancerholdsthepotentialtosensitizethecancertocisplatin.
ParallelstudiesrevealedthatincreasedDNArepaircapacitywasacommonfunctionincancersthatwereinherentlyresistanttocis‐platinorthatacquiredresistancefollowingtreatment[130].
Clinicalstudiesinovariancancerpatientshavecorrelatedincreasedexcisionrepaircross-complementationgroup1–(ERCC1)mRNAlevelswithclinicalresistancetoplatinumbasedchemotherapy[131,132].
Inmetastaticcolorectalcancerpatients,higherERCC1ex‐pressionlevelswereconsideredaspredictiveforlowersurvivalrateswhentreatedwithox‐aliplatinincombinationwith5-fluorouracil,suggestingthatenhancedDNArepairdecreasestheefficacyofplatinum-basedtreatment[133].
Inanotherstudyasubgroupof761patientswithmetastaticlungcancertreatedwithaplatinumbasedcompoundwereretro‐spectivelyevaluatedbyimmunohistochemicalanalysisofERCC1.
Thisstudyshowedastat‐isticallysignificantsurvivalbenefitinpatientswithlowlevelsofERCC1whohadreceivedplatinumbasedchemotherapy,comparedtopatientswithlowlevelsofERCC1whodidnotreceivechemotherapyandpatientswithhighlevelsofERCC1whoreceivedcisplatinche‐motherapy[134].
Also,lowERCC1expressioncorrelatedwithprolongedsurvivalaftercis‐platinplusgemcitabinechemotherapyinnon-smallcelllungcancer(NSCLC)[135].
Hence,itishypothesizedthathighexpressionoftheERCC1genemightbeapositiveprog‐nosticfactor,andcouldpredictdecreasedsensitivitytoplatinum-basedchemotherapy.
Ex‐pressionofERCC1hasbeenusedtostratifypatientstreatedwithplatinumbasedchemotherapeuticswithsomesuccess,andalsotopredictimprovedsurvivalinplatinumtreatedpatients[136].
Nonetheless,resultsfromthepublisheddataareinconsistent.
Tode‐riveamorepreciseestimationoftherelationshipbetweenERCC1andtheprognosisandpredictiveresponsetochemotherapyofNSCLC,ameta-analysiswasperformedandresultsindicatedthathighERCC1expressionmightindeedbeafavourableprognosticandadrugresistancepredictivefactorforNSCLC[137].
Otherstudieswithdifferenttumour/chemotherapyassociationshaveshownthatERCC1mRNAexpressionintumoursmaybeapredictivemarkerofsurvivalforIrinotecan-resist‐antmetastaticcolorectalcancerreceiving5-FUandOxaliplatincombinationchemotherapy[133].
InthisstudypatientswhosetumourshadlowERCC1mRNAexpressionhadasignifi‐cantlylongermediansurvivalthanthosewithhighERCC1expression.
OthergenesinvolvedinNERhavebeenshowntoinfluencedrugresistance.
Forexample,increasedexpressionofexcisionrepaircross-complementationgroup4(ERCC4orXPF)wasobservedinhydroxycamptothecin(HCPT)treatedbladdercancertissuecomparedtoun‐NewResearchDirectionsinDNARepair500treatedsamples.
ComplementaryinvitrostudiesshowedthatenhancedERCC4expressiondecreasedthesensitivityofbladderT24cellsand5637cellstoHCPT,whereasaftergenesi‐lencingofERCC4thechemotherapeuticresistanceofbladdercancercellstoHCPTwassig‐nificantlydecreased[138].
SincetheNERpathwayiscrucialfortherepairofbulkyadductsandcross-linkingagentsinnormalcells,thedevelopmentandapplicationofNERinhibitorsinclinicalsettingsisscarce,althoughpreclinicaldatashowthatthemanipulationofthispathwaycouldbearelevantstrategyincancerchemotherapy.
Forexample,preclinicalstudieshavedemonstratedthatthechemotherapeuticactionoftheplatinumagentoxaliplatinisimprovedwhencombinedwithcetuximab,achimericIgG1monoclonalantibodytargetingtheepidermalgrowthfac‐torreceptor.
ThisantibodyhasbeenshowntoreducetheexpressionofERCC4andERCC1.
Aconcomitantincreaseintheaccumulationofplatinumandapurinic/apyrimidinicsitesonDNAduringoxaliplatintreatmentwasobserved,thusleadingtoanincreaseinapoptosis[139,140].
Theseinterestingresultsaresuggestivethattargetingotherpathwaysthatregu‐lateexpressionofDNArepairgenescouldbeapromisingstrategy.
7.
HRanddrugresistanceHRrepairsDSBs,whichoccurthroughexposuretovariouschemotherapeuticagents,in‐cludingIR,topoisomeraseinhibitorsandDNAcrosslinkingagents(e.
g.
mitomycin,campto‐thecins,etoposide,doxorubicin,daunorubicinandbleomycin).
HRisalsorecruitedtorestartstalledreplicationforksandtorepairICL,therepairofwhichalsoinvolvestheFAproteincomplex.
HRensurestheaccuraterepairofDSBsbyusingahomologousundamagedDNAstrandfromanintactsisterchromatidasatemplateforDNApolymerasetoextendpastthebreak,andisthusrestrictedtolateSandG2ofthecellcycle.
ComponentsofHRincludetheRADgroupofproteins(includingRAD50,RAD51,RAD52,andRAD54),RPA,XRCC2,XRCC3,andtheBRCAproteins.
Briefly,HRoccursthroughpre-synapsis,preparationofarecombinationproficientDNAend;synapsis,formationofajointmoleculebetweenthere‐combinationproficientDNAendandadouble-strandedhomologoustemplateDNA;post-synapsisandresolution,repairofDNAstrandsandseparationoftherecombinedDNAmolecules[19].
DSBscanalsoberepairedbyNHEJthatdonotutilizesignificanthomologyatthebrokenends.
InNHEJ,DSBsarerecognizedbytheKuproteinthatthenbindsandac‐tivatestheproteinkinaseDNA-PKcs,leadingtorecruitmentandactivationofend-process‐ingenzymes,polymerasesandDNAligaseIV.
WhereasHRisrestrictedtolateSandG2,NHEJfunctionsinallphasesofthecellcycleandligatesbrokenDNAendswithouttheneedofanundamagedtemplate.
FollowingDNAlesionsinitialcheckpointsignallingisperformedbythekinasesATRandATM,twophosphatidylinositol3-kinasefamilymembers.
Activationofthesekinasesleadstoactivationoftheeffectorkinases,checkpointkinases1and2(Chk1andChk2;serine/threoninekinases).
TheactivatedeffectorkinasesarethenabletotransientlydelaycellcycleprogressionthroughtheG1,S,ortheG2phasessothatDNAcanbeefficientlyrepaired.
TheDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952501ATM/Chk2pathwaypredominantlyregulatestheG1checkpointandtheATR/Chk1path‐waytheSandG2checkpoints.
However,thereiscross-talkbetweenthepathwaysimplyingaroleforbothATRandATMpathwaysinallcellcyclecheckpoints.
Inadditiontodirectlyregulatingthecellcycle,thepathwaysalsoaffectDNArepair,transcription,chromatinreg‐ulation,andcelldeath.
Manydetailsofthesepathwaysarenotfullyknown.
OneconsequenceofDSBsisthelocalizedalterationofchromatinadjacenttoDSBsinordertofacilitaterecruitmentofrepairproteins.
Forexamples,ATMnotonlyphosphorylatesDNArepairproteinsrecruitedtoDNAendsbutalsothehistonevariantH2AXinnucleo‐somesadjacenttoDSBs,whichisalsophosphorylatedbyDNA-dependentproteinkinase(DNA-PK),anotherproteinkinaseactivatedbyDSBs.
PhosphorylatedH2AX(knownasγ-H2AX)aroundDSBsfacilitatestherecruitmentofanumberofDNArepairproteinsandchromatinmodulatingfactors.
Thepresenceoflargepatchesofγ-H2AXaroundaDSBhasmadeitsdetectionbyfluorescenttaggedantibodiesabiomarkerforDSBs[141,142].
ThereisaccumulatingevidencefortheexistenceofHRdefectsnotonlyinfamilialcancersbutalsoinsporadiccancers.
Mutationsorepigeneticalterationshavebeenobservedinsev‐eralgenesknowntobeinvolvedinHRregulationandrepair,suchasBRCA1andBRCA2.
FunctionalanalysisofhumancancertissuesandcancercelllineshasrevealedHRdeficien‐cy,chromatid-typechromosomalaberrations,severeICLhypersensitivity,andimpairedfor‐mationofdamage-inducedRAD51foci.
Forexample,althoughgeneticmutationsinBRCA1orBRCA2areonlyrarelyfoundinsporadictumors,incontrasttofamilialbreastandovari‐ancancers,epigeneticgeneinactivationoftheBRCA1promoterisafairlycommoneventinsporadicbreastcancers,withaberrantmethylationbeingdetectedin11to14%ofcases[143].
Non-triple-negativesporadicbreastcancersmayalsoharborHRdefects.
Ithasbeensuggestedthat~20%ofthesecancersaredefectiveinHRasmeasuredbyanimpairedabilitytomountRAD51fociinresponsetochemotherapy[144].
Thereisemergingevidencethatapproximatelyuptoonefifthofnon-familialbreastcancersharbourHRdefectsthatmaybeusefultargetsfortherapy.
TheBRCA1andBRCA2proteinsareinvolvedinHR,inassociationwithFAproteins,form‐ingacomplexDNAdamageresponsenetwork[145].
BRCA1expressionlevelshavebeendemonstratedtobeabiomarkerofsurvivalfollowingcisplatin-basedchemotherapyforNSCLCandovariancancer,suggestingthatthisgenecouldbeinvolvedinresponsetoplati‐numtherapy[146,147].
InvitrostudiesindicatethatlossofBRCA1orBRCA2increasessen‐sitivitytoagentsthatcauseDSBssuchasbleomycinand/orICLsincludingplatinumagents.
Conversely,lossofBRCA1orBRCA2mayincreaseresistancetomicrotubuleinterferingagentssuchastaxanesandvincristine[148,149].
Incontrast,BRCA1mayincreasesensitivitytospindlepoisonsbyactivatingthemitoticspindlecheckpointandsignallingthroughaproapoptoticpathway.
ThisdualroleofincreasingapoptosisandthereforesensitivitytospindlepoisonsandalsopromotingDNArepairandcellsurvivalaftertreatmentwithDNA-damagingdrugsmayinfluencetheresponseofbreastandovariancancercellstotreatment[150].
Chemotherapyinbreastandovariancancersisattainedbytreatmentwithplatinumbasedcompoundsandanthracyclinesandalsotaxanes,allofwhichinducebothNewResearchDirectionsinDNARepair502SSBsandDSBs.
EffortsareunderwaytouseBCRA1asapredictivemarkerforchemothera‐pycustomizationandresponse[151].
Regardingothertypesofcancer,BRCA1promoterhypermethylationisalsofoundinap‐proximately5-30%ofsporadicovariancancers.
Also,mutationsinBRCA1andBRCA2haverecentlybeenfoundinupto20%ofunselectedovariancancers[152].
Thus,theseHRdefi‐cientcancersareviabletargetsforsyntheticlethalityapproacheswithPARPinhibitors.
De‐fectsintheFA/BRCApathwayaswellasATMdefectshavebeendescribedinavarietyofothermalignancies,suchasprostaticadenocarcinoma,colorectalcancer,leukaemia,lym‐phoma,andmedulloblastoma[153,154].
However,itremainstobeseenwhetherthesede‐fectscanbetargetedeffectivelyintheclinic.
Single-agentchemotherapywithanitrogenmustard,usuallyChlorambucil,isthestandardinitialtherapyforChroniclymphocyticleukaemia(CLL)andatleast60–80%ofpatientsre‐spondbuteventuallyallpatientsbecomeresistanttotheseagents.
XRCC3proteinlevelsandDNA-damageinducedRAD51focicorrelateswithchlorambucildrugresistanceinlympho‐cytesfromCLLpatientsandwithmelphalanandcisplatinresistanceinepithelialtumorcelllines,indicatingthatincreasedHRcanbeinvolvedindrugresistancetotheseagents[155].
AnothercomponentoftheHRpathway,RAD51,hasbeenfoundtobeincreasedinex‐pressioninawiderangeofhumantumors,mostlikelycontributingtodrugresistanceofthesetumors.
Over-expressionofRAD51indifferentcelltypesleadstoincreasedhomol‐ogousrecombinationandincreasedresistancetoDNAdamagingagentstodisruptionofthecellcycleandapoptoticcelldeath.
RAD51expressionisincreasedinp53-negativecells,andsinceTP53isoftenmutatedintumorcells,thereisatendencyforRAD51tobeoverexpressedintumorcells,leadingtoincreasedresistancetoDNAdamageanddrugsusedinchemotherapies[156].
Chronicmyeloidleukaemia(CML)celllinesexpressingthefusionproteinBCR-ABL1uti‐lizeanalternativenon-homologousend-joiningpathway(ALTNHEJ)torepairDSBs.
TheexpressionlevelsofPARP1andDNAligaseIIIαservedasbiomarkerstoidentifyasubgroupofCMLpatientswhomaybecandidatesfortherapiesthattargettheALTNHEJpathwaywhentreatmentwithTKIshasfailed[157].
Tamoxifen-andaromatase-re‐sistantderivativesofMCF7cellsandEstrogenReceptor-/ProgesteroneReceptor-(ER-/PR-)cellshavehighersteady-statelevelsofDNAligaseIIIαandincreasedlevelsofPARP1,anotherALTNHEJcomponent.
Notably,therapy-resistantderivativesofMCF7cellsandER-/PR-cellsexhibitedsignificantlyincreasedsensitivitytoacombinationofPARPandDNAligaseIIIinhibitorsthatincreasedthenumberofDSBs.
Thus,ALTNHEJmaybeanoveltherapeutictargetinbreastcancersthatareresistanttofrontlinetherapiesandchangesinNHEJproteinlevelsmayserveasbiomarkerstoidentifytumorsthatarecan‐didatesforthistherapeuticapproach[158].
AnotherinterestingapproachinthisfieldistotargetcomponentsoftheDNAdamageresponse,namelyDNAdamagesignallingandcell-cyclecheckpoints[34].
Themembersofthephosphatidylinositol(PI)3-kinase-like(PIKK)familyperformcrucialrolesintheactivationofDSBrepairpathways,namelyinHRandNHEJ.
ATM,aPIKKfamilymem‐DNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952503ber,isaDSBsignallingproteinmainlyimplicatedinthephosphorylationofeffectorpro‐teinsfromHR.
ATMhasbeenalsoinvolvedintheregulationofNHEJ.
KU55933,2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-oneisaspecificandpotentsmall-moleculeinhibitorofATMidentifiedbyscreeningofacombinatoriallibrary.
Preclinicalstudieshaveshownanincreaseinthecytotoxicityofmultiplechemotherapeuticdrugsasdoxor‐ubicin,etoposide,camptothecinandionizingradiation[159,160]whiletheUV-inducedcellulareffectswerenotmodified.
Morerecently,KU60019,animprovedanalogueofKU55933,wasdeveloped.
Besidesitsradiosensitizingproperties,invitrostudiesrevealedthatKU60019mayalsoimpairthemigrationandinvasionoftumorcellsbyinhibitingATM-mediatedAKTphosphorylation[161].
DNA-PKisalsoatargettothedevelopmentofchemo-andradiosensitizers[162].
Infact,theidentificationofspecificsmallmoleculemodulatorsofDNA-PK[163-165],namelyNU7441andNU7026,wasshowntopotentiatetheeffectsofionizingradiationaswellaschemother‐apeuticagentsinhumantumorcelllinesandininvivoxenograftmodels.
AnotherexampleisthedevelopmentofAZD7762,whichpotentlyinhibitsChk1andChk2,abrogatesDNAdamage-inducedSandG2checkpoints,enhancestheefficacyofgemcita‐bineandtopotecan,andmodulatesdownstreamcheckpointpathwayproteins[166].
Thisagenthasbeenevaluatedinclinicaltrials,howeverduetoaninadequateresponsethedrughasbeendiscontinuedin2011(http://www.
astrazenecaclinicaltrials.
com).
8.
MicroRNAsandchemotherapyresistanceMicroRNAs(miRs)aresmallnon-codingRNAs(19to25nucleotides)thatregulategeneexpressionbybindingto3'untranslatedregion(UTR)ofseveralmRNAs,thusblockingtranslation.
Recently,itwasalsoshownthatmiRscanactbybindingtoopenreadingframesor5'UTRofmRNAs,asrevisedbyIorioandCroce[167].
DuetosmallsizeandincompletecomplementaritytomRNA,onemiRcanhaveawidespreadeffectonthetranscriptomeofacell,actingasahallmarkofseveraldiseases,includingcancer.
Nu‐merousstudieshavebeenperformedregardingbiogenesisandfunctionofmiRs,beingrevisedelsewhere[168-170].
InvitroandinvivostudieshavesuggestedthatmiRNAsmightbeusefulasdiagnosticandprognosticmarkers,andrecentdatasuggestthatmiR‐NAprofilingcanbeusedfortumortyping.
AlthoughitiswellestablishedthatmiRshaveanimportantroleincancer,thecomplexityoftheiractionremainstobeunderstoodandquestionsregardingtheiruseascancertherapyneedfurtherinvestigation.
ThestrongpleiotropyofmiRsinderegulatingnormalcellularhomeostasisduetomisexpression,hasledinvestigatorstobelievethattheyarevaluabletar‐getsforcancertherapyandconsequentlyfordrugresistance.
Twomajorapproachesforus‐ingmiRsastherapeuticscanbedescribed.
First,miRscanbeusedassinglemoleculesorcombinedinordertotargetoneormultipletranscripts.
Inthisapproach,amiRorasetofmiRsareantagonizedormimickedtoaltermiRlevelsandconsequentlychangetheproteinNewResearchDirectionsinDNARepair504outcomeinacancercell.
Second,miRscanactasmodulatorsofcellsensitivityforcancertherapy[167,171].
Thissecondapproachwillbeourfocus.
ManystudiesregardingmiRsexpressionpatternsincancercellshavebeenperformed.
ThesestudiesnotonlyallowinvestigatorstodeterminenovelbiomarkersforabetterandeasilyprognosticationofseveraltypesofcancerbutalsothefunctionalroleofthesamemiRs.
ThesecangiveustheknowledgeifthelossorgainofmiRfunctioninter‐fereswiththeoriginalbalanceofproteinlevelswhichmaybeimportant,butnotonly,indrugresponseandconsequentlyleadtodrugresistance.
SincemiRsexpressionseemstobetissue,gradeandstagespecific,theectopicexpressionorrepressionofmiRsinconjugationwithcancertherapyseemspromising.
Forthatreason,recentstudiesthatevaluatemiRexpressionprofilesofsensitiveandresistantcelllineshavebeenmadeinordertofindthekeymiRsignaturesrelatedtodrugresponse,whichnotonlypromotefurtheranalysisofthemechanismsofcancerdrugresistance,butalsoallowthediscov‐eryofnewdrugtargetsandindividualizedmedicine.
AlthoughthestudyofthetherapeuticpotentialofmiRsisstillrecent,severalstudieshavebeenpublishedandcompiled.
Forexample,Tianetal.
[172]andKutanzietal.
[173],publish‐edcompilationsofseveralstudiesreportinginfluenceofmiRsinmechanismsofdrugresist‐anceandhowtheycanmodulatedrugresponseinbreastcancer.
WithregardtomiRsandmodulationofdrugresistancethroughregulationofDNAdamageandrepairgenes,studiesarescarce.
ItisknownthatmiRshaveanimportantroleinDNAdamageresponse,whichincludesDNArepair[174,175].
OneexamplehowmiRscaninflu‐encedrugresistancethroughDNArepairisdemonstratedbyValerieetal.
[73].
TheauthorsshowedthatmiR-21targetsMSH2andconsequentlyinducesresistanceto5-FUincolorectalcancer.
SincemiR-21hasapleiotropiceffect,itispossiblethatitcouldregulateothergenesassociatedwithdrugresistance.
However,theimpactofMSH2seemstobeofextremeim‐portanceonacquired5-FUresistancesincewhenknockedoutcellsforMSH2aretransfectedwithmiR-21,cell-cyclearrestorapoptosisisnotaltered.
Theseresultsshowthattheinhibi‐tionofmiR-21actionmightrepresentanimportanttreatmenttoovercome5-FUresistance.
AcorrelationbetweenmiR-21andMSH2inbreastcancerwasalsofound[176].
Itisrecog‐nizedthatTGF-βisapromoterofmiR-21processingthroughtheinteractionwiththeSMADandDROSHAcomplex.
Ontheotherhand,MSH2isaproventargetofmiR-21.
Thus,TGF-βinhibitsMSH2geneexpressionandconsequentlyincreasesdrugresistance.
Indeed,tofindoutifTGF-βcontributestodrugresistancethroughMSH2,theauthorstestedtheresponseofbreastcancerMDA-MB-231celllinetocisplatin,methylmethanesulfonate(MMS)anddoxorubicininthepresenceandabsenceofTGF-β.
ExposuretoTGF-βfor24hincreasedcellviabilityupontreatmentwiththeseDNAdamagingagentsandknockdownofMSH2in‐ducedresistancetobothcisplatinanddoxorubicin.
Incontrast,transfectionoftheanti-miR-21enhancedtheeffectofcisplatininMDA-MB-231cells.
AnotherexampleofmiRinfluenceinDNArepairandconsequentdrugresponseismiR-182thattargetsBRCA1.
MoskwaandcolleaguesshowedthatectopicexpressionofmiR-182re‐pressesBRCA1proteinexpressionandsensitizesbreastcancercellstoPARPinhibitors[177].
However,PARPinhibitorsaremostlyusedinpatientswithBRCA1inheritedmuta‐DNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952505tions.
Therefore,thequestionifPARPinhibitorsareusefultherapeuticdrugsinsporadicbreastcancerrises.
Theoretically,ifadministratedwithBRCA1repressorssuchasmiR-182,PARPinhibitorscanhavethesameeffectasininheritedbreastcancer.
Furtherstudiesneedtobedoneinordertoclarifythisissue.
Asdescribedpreviously,MGMThasDNArepairactivityinsofarasitcanremovemutagen‐icO6-alkylguanineinducedbyalkylatingagents.
AlthoughTMZhasbeenwidelyusedinglioblastomamultiforme(GBM),manypatientsbecomeorareresistanttothischemothera‐pyagent,sinceMGMTcanrepairtheDNAdamageinducedbyTMZ.
Epigeneticregulationmechanisms,suchasmethylationoftheMGMTgenepromotercansensitizecancercellstoalkylatingchemotherapeuticdrugs.
GlioblastomapatientswithpositivemethylationstatusofMGMTgenepromoterhavebeenreportedtopresentabetterresponsetoTMZtreatment[44],buttheseresultshavenotbeenconfirmedbyotherstudies,andthereforeresultsareambiguous[178].
Indeed,somepatientswithunmethylatedstatusofMGMTpromotergenealsohavegoodresponsetoTMZ,whichpointsouttootherregulatorymechanismsofMGMTexpression[179].
Thus,miRsappearasgoodalternativeregulationcandidatesofMGMTexpressionlevels.
RecentevidencealsosuggeststhatthemiR-181familymightbeassociatedtodrugresponse[180].
Theauthorsfoundthatglioblastomapatientswithlowex‐pressionofmiR-181bandmiR-181chaveabetterresponsetoTMZ.
Onthecontrary,miR-181dseemstopost-transcriptionallyregulateMGMTsincebothdirectlyinteractandin‐verselycorrelateinrelationtoexpressionlevels[181].
ThisfactisimportantbecauseitcouldbeapredictivebiomarkerforchemotherapyresponseinGBM.
LakomyandcollaboratorsfoundthathighexpressionofmiR-195andmiR-196bissignificantlyassociatedwithlongersurvivalofGBMpatientsandmiR-21andmiR-181cwithhighriskGBMpatients[182].
HowevernoneofthesemiRswereassociatedwithMGMTgenepromoterstatus.
AltogetherthepotentialforuseofmiRsincancertherapyishigh,soarethechallenges,sinceeachmiRcantargetuptohundredsofmRNAtargets.
Therapidelucidationoftheroletheyplayincancersuggestthattranslationofthisknowledgewillrapidlyreachtheclinic.
9.
PhytochemicalsasalternativetherapiesagainstdrugresistanceAsdiscussedpreviously,frequentlynoveltherapeuticsthatshowpromisingresultsinpre‐clinicalassaysrevealunacceptabletoxicityinclinicaltrials.
Sincecancercellsfrequentlypresentderegulationofmultiplecellularpathways,targetingmultiplepathwaysseemsmorepromisingthanusingsingleagentsthattargetsinglepathways.
Inrecentyearsnaturaldietarycompoundssuchascurcumin,resveratrolandsoyisoflavonessuchasgenistein,havereceivedattentionduetothefactthattheyfrequentlytargetmultiplecellsignallingpathways,includingthecellcycle,apoptosis,proliferation,survival,invasion,angiogenesis,metastasisandinflammation.
Thustheiruseinchemopreventionhasgainedattention[183,184].
Additionally,sincemostofthecancerdrugsdevelopedhavebeendeliberatelydirectedtowardspecificmoleculartargetsthatareinvolvedinonewayoranotherinenablingpartic‐ularcellularfunctions,inresponsetomonotherapycancercellsmayreducetheirdepend‐NewResearchDirectionsinDNARepair506enceonaparticularproficiency(e.
g.
asinglerepairpathway),becomingmoredependentonanother,thuscontributingtoacquiredrugresistance.
Thus,asanalternativeapproach,se‐lectiveco-targetingofmultiplecoreandemerginghallmarkproficienciesinmechanism-guidedcombinationscouldresultinmoreeffectiveanddurabletherapiesforhumancancer[185].
Phytochemicalscanbehighlypleiotropic,modulatingnumeroustargets,includingtheactivationoftranscriptionfactors,receptors,kinases,cytokines,enzymes,andgrowthfac‐tors[186].
Thereforecurrenteffortsarehighlyengagedindiscoveringnaturalplant-basedchemicalsthatcouldassistinthefightagainstdrugresistance.
ForexamplesoyisoflavonesinhibitedAPE1expressioninprostatecancercellsinatime-anddose-dependentmanner,whereasIRup-regulatedexpressionofthisBERgene,inre‐sponsetoDNAdamage[187-190].
PretreatmentofcancercellswithsoyisoflavonesinhibitedtheincreaseinexpressionofAPE1,andenhancedtheefficacyofchemotherapyandradiationtherapyofmultiplecancersmodelsinvitroandinvivo,possiblythroughdown-regulationofthisDNArepairgene[188].
Anotherphytochemical,resveratrol,wasal‐soshowntoinhibitAPE1endonucleaseactivityandrendermelanomacellsmoresensitivetotreatmentwiththealkylatingagentdacarbazine[191].
Thusbothresveratrolandisofla‐vonessuchasgenisteincanhavetherapeuticpotentialasanAPEinhibitor.
Aseriesofana‐logsofresveratrolhavebeengeneratedinrecentyears,whichexhibitincreasedpotencyand/orarangeofselectiveactivitiescomparedtotheparentalcompoundresveratrol,andpossiblyimprovedpharmacokineticproperties[192].
Aclinicaltrialofresveratrolincoloncancerhasrecentlybeencompleted(http://www.
clinicaltrials.
gov).
ResveratrolcanalsoincreaseBRCA1andBRCA2expression,althoughnoeffectisseenattheproteinlevel[193].
AnincreaseinBRAC1expressioncanleadtoincreasedarrestofcellsintheG2phase,thusmakingthemmuchmoresensitivetoconventionaltherapy.
Onecommonche‐motherapeuticdrugisdoxorubicin,whichpredominantlyinducesDNAdamageinG2phasecells[194].
Resveratrol,curcuminandthenaturallyoccurringflavolignandeoxypodophyllo‐toxin[195]caninduceG2/Mcellcyclearrest,andaltertheexpressionofcellcycleregulatoryproteins,thusallowingdoxorubicintoinducelesionsandasaconsequenceenhancetheapop‐toticeffect[186,196,197].
LeCorreetal.
,alsodemonstratedthatresveratrolhasaneffectontheexpressionofgenesimplicatedintheregulationofBRCA1proteinfunctionsandinmultiplenuclearprocessesmodulatedbyBRCA1inhumanbreastcancerandfibrocysticbreastcells[198].
OneofthemechanismsbywhichresveratrolcanenhanceBRAC1expressionisbyassoci‐ationwithBRCA1,repressingthearomatichydrocarbonreceptor(AhR).
AhRbindsmanynat‐uraldietarybioactivecompoundsthereforecombinationdietswithAhRantagonistsmayoffertheadvantageofhighercancerpreventionefficacies[199].
InHR-deficienttumours,patientswithheterozygousmutationsintheHRgenesBRCA1andBRCA2developbreastandovariantumourswithfunctionallossofHRactivity,anddeficiencyinthispathwaymaydictatethesensitivityoftumourstocertainDNA-damagingagentsandthismaybeanotherpossibleap‐proachtotestnaturalcompoundstoovercomeresistance,andoncemoreenhancecombinato‐rystrategiestooptimizetreatmentoutcome[32].
Recentlyanextractofneemleaveswascharacterizedandasignificantup-regulationofgenesassociatedwithmetabolism,inflammationandangiogenesis,suchasHMOX1andDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952507AKRwasobserved.
Howevergenesassociatedwithcellcycle,DNAreplication,recombina‐tion,andrepairfunctionsweredown-regulated[200].
Onestudyanalysed531compoundsderivedfromplantsandfoundnocorrelationwithgenesinvolvedinNER(ERCC1,XPA,XPC,DDB2,ERCC4,ERCC5)orBER(MPG,APE1,OGG1,XRCC1,LIG3,POLB).
Itispossiblethatnaturalcompoundsmaytargetdifferentmolecularpathwaysfromthoseofstandardanti-tumordrugs,henceifDNArepairisinvolvedinthedevelopmentofresistancetoestab‐lishedanticancerdrugs,naturalcompoundsmaybeattractivesourcesofnoveldrugssuita‐bletotreatdrugresistanttumours,withtheadvantageofhavingreducedsideeffects[201].
Likewise,mostplantderivativescanactasantioxidantsandsomeofthemcanincreasehu‐manMGMTexpression(e.
g.
curcumin,silymarin,sulforaphaneandresveratrol)beyonditssteady-statelevels,havingaroleincancerchemoprevention[202].
Additionally,bothBRCA1andMGMTgenesaresusceptibletohypermethylation,andgreenteapolyphenolsandbioflavonoidshavebeenshowntoreversetheeffectsofDNAhypermethylation[203].
Theseresultssuggestthatsomedietarycompoundsmayhaveapotentialdemethylat‐ingeffect,andcouldbepromisingadjuvantstochemotherapyindrugresistantsettings.
Anotherissueincancerchemotherapyistheuseofmonotherapyvscombinedtherapy,andseveralstudieshavebeenperformedregardingpossiblecombinatorychemotherapywithnat‐uralcompounds(lessaggressivethanthemajorityofchemotherapeuticdrugs),albeitinpre‐clinicalsettings,e.
g.
silibininextract[204],ixabepilone[205]andcurcumin[206].
Someoftheseagentsarebeingevaluatedinclinicaltrials.
Silibininstronglysynergizedthegrowth-inhibito‐ryeffectofdoxorubicininprostatecarcinomacells,whichwasassociatedwithastrongG2-Marrestfollowedbyapoptosis[204].
Ixabepilone,ananalogueofthenaturalproductepothiloneB,isalreadyindicatedforthetreatmentoflocallyadvancedormetastaticbreastcancerintheUS.
InaphaseIIItrialinwomenwithlocallyadvancedormetastaticbreastcancerthatwerepretreatedwith,orresistantto,anthracyclines(e.
g.
doxorubicin)andresistanttotaxanes,pro‐gression-freesurvivalwassignificantlylongerinixabepilonepluscapecitabinerecipientscom‐paredwithrecipientsofcapecitabinemonotherapy[205].
Combinationtherapyusingcurcuminwithgemcitabine-basedchemotherapy,inaphaseI/IIstudy,inpatientswithpancre‐aticcancerwarrantsfurtherinvestigationintoitsefficacy[206].
Finally,aninterestingrecentdevelopmentconcernstheobservationthatmiRscouldberegu‐latedbynaturalagents,leadingtotheinhibitionofcancercellgrowth,epithelialtomesenchy‐maltransition(EMT),drugresistance,andmetastasis[207].
Formostepithelialtumors,progressiontowardmalignancyisaccompaniedbyalossofepithelialdifferentiationandashifttowardmesenchymalphenotype[185].
DuringtheacquisitionofEMTcharacteristics,cancercellslosetheexpressionofproteinsthatpromotecell-cellcontact,suchasE-cadherinandγ-catenin,andgaintheexpressionofmesenchymalmarkers,suchasvimentin,fibronectin,andN-cadherin,leadingtoenhancedcancercellmigrationandinvasion.
Ithasbeenshownthatdown-regulationorthelossintheexpressionofthemiR-200familyisassociatedwithEMT.
Gemcitabine-resistantpancreaticcellshavingEMTcharacteristicsshowedlowexpres‐sionofthemiR-200familyandmiR-200islostininvasivebreastcancercelllineswithmesen‐chymalphenotype.
HencetheinterestingobservationthatisoflavonecouldinducemiR-200expressioningemcitabine-resistantpancreaticcells,resultinginalteredcellularmorphologyNewResearchDirectionsinDNARepair508frommesenchymal-to-epithelialappearanceandinducedE-cadherindistributionthatismoresimilartoepithelial-likecells.
Likewise,let-7hasbeenfoundtoregulatecellproliferationanddifferentiation,andinhibittheexpressionofmultipleoncogenes,includingrasandmyc,andagainitwasobservedthatisoflavonecouldsignificantlyup-regulatetheexpressionoflet-7family,suggestingthatthisphytochemicalcouldreverseEMTcharacteristicsinpartduetotheup-regulationoflet-7[207].
Otherreportshaveshownthatcurcumin,isoflavone,indole-3-car‐binol(I3C),3,3′-diindolylmethane(DIM),()-epigallocatechin-3-gallate(EGCG)orresveratrol,canaltermiRNAexpressionprofiles,leadingtotheinhibitionofcancergrowth,inductionofapoptosis,reversalofEMTphenotype,andincreasingdrugsensitivity[208].
ItremainstobeseenifphytochemicalscanaffectmiRsthatregulateDNArepairpathways,butsinceanygivenmiRcantargetseveraltranscripts,thisregulationishighlylikely.
Over‐all,naturalcompounds,mayhaveanimportantroleinchemopreventionandincombinedtherapy,andmaypreventresistancetochemotherapy[188,189,208-210].
10.
ConclusionandfuturedirectionsAsdiscussedinthischapter,theultimatetargetofchemotherapyandradiotherapyisthecancercell,anduseofDNAdamagingagentsisjustifiablesincemostofthesecellsarehigh‐lycyclingcells.
ThetargetingofDNArepairpathwaysisbutoneofthemanystrategiesde‐velopedinthefightagainstcancer.
CancercellsfrequentlypossessalteredDNArepaircapacities,andthiscanbeputtouseintheclinic.
ThusthequestforspecifictherapiesthattargetDNArepairhasproducedmanypotentiallyusefulagents(Table1).
Usingsuchagentscantheoreticallyincreasetheefficacyofexistingchemotherapyand/orradiotherapy.
Nevertheless,thesamedifficultiesencounteredbyallotheralternativestrategiesarealsoarisingwhenwedisruptDNArepairprocesses.
ThesuccessoftheseagentsultimatelywilldependonourbasicknowledgeofthevariousDNArepairprocessespresentinagivencelltypeortissue.
NotallDNArepairpathwaysarepresentinalltissues,asevidencedbythefactthatmutationsinspecificpathwaysgiverisepreferentiallytocertaintumourtypesandnotothers.
Secondly,thesuccesswillalsode‐pendonthespecificgenomicandgeneticlandscapeofeachtumour,implyingthatdifferentcombinationsofinhibitorsandchemicalagentsshallhavetobetailoredtoeachtumour.
Wearestillfarfromachievingthisgoal,butgreatstrideshavebeentakeninthepastyears.
Thirdly,weshallhavetoredirectthestrategytodiscovera"cureforcancer"andinsteadfollowstrategiesthatallowustoaccompanytheinevitableandinexorableevolutionofthecancercellandconsistentlyfindandimplementmoreandmoretargetedtherapies,evenifthesestrategiesleadustoreturntoabandonedtherapies.
Theresurgenceofdrugholidays,inwhichatherapyisabandonedtemporarilytobetakenupafteracertainperiod,notun‐likewhatcanbeadoptedwithantibiotics,isonesuchstrategy.
Inthiscasetheabsenceofaselectivepressureimposedbyaspecificagentmayleadcancercellstoloseresistancetothisagent,makingthemagainvulnerabletothesameagent.
Thisstrategyhasbeenfollowedincertaincancersandcouldbeadaptedinothers,withtheadvantageofofferingreducedtimeonchemotherapy,reducedcumulativetoxiceffects,andimprovedqualityoflife[211,212].
DNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
5772/53952509TargetDrugConditionortumorCombinationtherapyagent(s)Phaseofclinicaltrialplanned,ongoingorrecentlycompleted*ReferenceMGMTO6-BenzylguanineMultipleMyelomaandPlasmaCellNeoplasmGlioblastoma,GliosarcomaMelanomaColorectalCancerCarmustineTemodarCarmustineCarmustinePhaseIIcompletedPhaseIIcompletedPhaseIIcompletedPhaseIIcompletedwww.
cancer.
govPARP1AZD-2281/KU59436(Olaparib)TripleNegativeBreastCancerTripleNegativeMetastaticBreastCancerKnownBRCAOvarianCancerorKnownBRCA/TripleNeg.
BreastCancerCisplatinPaclitaxelPhaseI/IIactivePhaseI/IIcompletedwww.
astrazeneca.
comAG014699/PF-01367338(Rucaparib)SolidtumorsMelanomaTemozolomideVariousagentsPhaseIcompletedPhaseIIongoingwww.
pfizer.
comINO-1001MelanomaTemozolomidePhaseIterminatedwww.
inotekcorp.
comBSI-201/(Iniparib)UterineCarcinosarcomaCarboplatin,Paclitaxel,PhaseIIactivewww.
biparsciences.
comwww.
sanofi.
comBreastCancerGemcitabine/CarboplatinPhaseIIcompletedPhaseIIIactiveABT-888/(Veliparib)BreastcancerCarboplatinTemozolomidePhaseIIactivewww.
abbott.
comProstateCancerTemozolomidePhaseIactiveMelanomaTemozolomidePhaseIIactiveVariouscancersVariousagentsPhaseI/IIactiveMK4827SolidBRCAOvarianSingleagentVariousagentsPhaseIongoingwww.
merck.
comCEP-9722SolidtumoursTMZVariousagentsPhaseIwww.
cephalon.
comwww.
tevapharm.
comGPI1016/E7016SolidtumoursTMZVariousagentsPhaseIwww.
eisai.
comLT673HematologicalcancersSolidtumoursVariousagentsPhaseIongoingwww.
bmrn.
comNMS-P118Preclinical;highlyselectiveagainstPARP-5(tankyrase)www.
nervianoms.
comBERMethoxyamine/TRC-102AdvancedrefractorysolidcancersHematologicalcancersPemetrexedTMZFludarabinePhaseIactivePhaseIongoingwww.
traconpharma.
comATMKinaseKU55933Preclinicalwww.
astrazeneca.
comCHK1AZD7762www.
astrazeneca.
comPF-00477736www.
pfizer.
comXL844www.
exelixis.
comFACurcuminGastrointestinalcancersPhaseIINewResearchDirectionsinDNARepair510TargetDrugConditionortumorCombinationtherapyagent(s)Phaseofclinicaltrialplanned,ongoingorrecentlycompleted*ReferencePathwayc-ABLImatinibVarioussolidtumoursPhaseIIIwww.
novartis.
comEGFRErlotinibNSCLCMonotherapyorcombinationPhaseII/IIIwww.
gene.
comGefinitibwww.
astrazeneca.
com*Asof10September2012,http://clinicaltrials.
govTable1.
Targetedtherapeuticsindevelopment,inclinicaluseorinclinicaltrials*.
ThisleadstothefinalandperhapsmostchallengingprobleminthedevelopmentofagentsthatmodulateDNArepair,whichistoxicitytonormalcells,inparticulartothehematopoieticsystemandthegastrointestinalepithelia.
Variousstrategiesarebeingfol‐lowedtominimizetoxicity,whichincludetheintermittentadministrationduringthera‐py,mentionedabove,alternatingwithothertherapies,usinghighlylocalizedradiotherapytogetherwithinhibitorstominimizecollateraldamage,andusinginhibitorsassingleagents[213,214].
Altogether,thecombineduseofthevariousweaponsatourdisposalinacoordinated,comprehensivefashioncouldeffectivelyleadtoimprovedpa‐tienttreatment.
AcknowledgementsThisworkwassupportedbygrantsPTDC/SAUGMG/71720/2006fromFundaodeCiênciaeTecnologia(FCT),andPEst-OE/SAU/UI0009/2011-12fromFCT.
M.
G.
wassupportedbyCIENCIA2008(FCT).
CIGMHissupportedbyFCT.
B.
G.
(SFRH/BD/64131/2009),P.
G.
(SFRH/BD/70293/2010)andC.
M.
(SFRH/BD/81097/2011)aresupportedbyPh.
D.
grantsfromFCT.
AuthordetailsAntónioS.
Rodrigues1*,BrunoCostaGomes1,CéliaMartins1,MartaGromicho1,NunoG.
Oliveira2,PatríciaS.
Guerreiro2andJoséRueff1*Addressallcorrespondenceto:sebastiao.
rodrigues@fcm.
unl.
pt1CIGMH–DepartmentofGenetics,FacultyofMedicalSciences,UniversidadeNovadeLis‐boa,Lisboa,Portugal2ResearchInstituteforMedicinesandPharmaceuticalSciences(iMed.
UL),UL,FacultyofPharmacy,UniversidadedeLisboa,Lisboa,PortugalDNARepairandResistancetoCancerTherapyhttp://dx.
doi.
org/10.
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