A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity 英文参考文献.docVIP

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A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity 英文参考文献.doc

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A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity 英文参考文献

ASwitchingMechanisminDoxorubicinBioactivation CanBeExploitedtoControlDoxorubicinToxicity NnennaA.Finn1,HarryW.Findley2,MelissaL.Kemp1* 1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, 2The Division of Pediatric Hematology/Oncology,EmoryUniversitySchoolofMedicine,Atlanta,Georgia Abstract Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changesinnetworkcomponentsismuchlessunderstood.Toinvestigatethepropertiesofthecoupledreduction/oxidation reactionsofthedoxorubicinbioactivationnetwork,weanalyzedmetabolicdifferencesbetweentwopatient-derivedacute lymphoblasticleukemia(ALL)celllinesexhibitingvarieddoxorubicinsensitivities.Wedevelopedcomputationalmodelsthat accuratelypredicteddoxorubicinbioactivationinbothALLcelllinesathighandlowdoxorubicinconcentrations.Oxygen- dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategiescanbeemployedtoeitherenhanceorimpededoxorubicincytotoxicityinALLcellsduetotheswitching that occursbetweenoxygen-dependentsuperoxidegenerationandNADPH-dependentdoxorubicinsemiquinoneformation. Citation:FinnNA,FindleyHW,KempML(2011)ASwitchingMechanisminDoxorubicinBioactivationCanBeExploitedtoControlDoxorubicinToxicity.PLoS ComputBiol7(9):e1002151.doi:10.1371/journal.pcbi.1002151 Editor:ThomasLengauer,Max-Planck-Institutfu¨rInformatik,Germany ReceivedApril7,2011;AcceptedJune21,201