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1、Perspectivepubs.acs.org/jmcRoleofReactiveOxygenSpecies(ROS)inTherapeuticsandDrugResistanceinCancerandBacteriaAllimuthuT.Dharmaraja*DepartmentofGeneticsandGenomeSciencesandComprehensiveCancerCenter,SchoolofMedicine,CaseWesternReserveUniversity,Cleveland,Ohio44106
2、,UnitedStatesABSTRACT:Evadingpersistentdrugresistanceincancerandbacteriaisquintessentialtorestorehealthinhumans,andimpelsinterventionstrategies.Adistinctpropertyofthecancerphenotypeisenhancedglucosemetabolismandoxidativestress.Reactiveoxygenspecies(ROS)aremetabo
3、licbyproductsofaerobicrespirationandareresponsibleformaintainingredoxhomeostasisincells.Redoxbalanceandoxidativestressareorchestratedbyantioxidantenzymes,reducedthiolsandNADP(H)cofactors,whichiscriticalforcancercellssurvivalandprogression.Similarly,Escherichiaco
4、li(E.coli)andlife-threateninginfectiouspathogenssuchasStaphylococcusaureus(SA)andMycobacteriumtuberculosis(Mtb)areappreciablysensitivetochangesintheintracellularoxidativeenvironment.Thus,smallmoleculesthatmodulateantioxidantlevelsand/orenhanceintracellularROScou
5、lddisturbthecellularoxidativeenvironmentandinducecelldeath,andhencecouldserveasnoveltherapeutics.PresentedhereareacollectionofapproachesthatinvolveROSmodulationincellsasastrategytotargetcancerandbacteria.■Next,hydroxylradical(OH•),oneofthehighlyreactiveINTRODUCT
6、IONROS,isgeneratedbyametal(Fe(II)orCu(I))mediatedChemicalgeneticsisoneofthesuccessfulstrategieswidelyexploredfortheidentificationofdrugcandidatesandtheirreductionofH2O2throughtheFentonreaction(Schemes1mechanismofactionincells.1Phenotypicscreeningofdrugand2).Hydro
7、xylradicaldirectlyreactswithDNA,whichisoftenirreversible,causingoxidativedamageandeventuallycandidatesexploitsthegeneticdifferencesincancerouscells5,7leadingtomutationsintheDNAsequence.ThereactivesitesandhasidentifiedmanysuccessfulFDAapproveddrugs,inDNAarethesugar
8、backboneandnucleobases.Inribose,C-includingafatinib,imatinib,andtrastuzumab,andothers,such4′tertiaryradicalisgeneratedandsubsequentuncontrolledasneratinib,thatareinad
