We exploted prevously publshed vtro characterza toof the bochemcal actions nvolved doxorubcboactvatoto develomodels that were specfc for patent derved ALL cell lnes.Our model fndngs, confrmed two cell lnes, ndcate that doxorubcmetabolsm cashft betweeNADdependent reductve converson, whch drves doxorubctoxcty leukema cells, and NADdependent superoxde generaton, whch drves doxorubcdependent sgnalng.Nonntutvely, NADdependent ROS productos assocated wth protectoaganst doxorubcnduced cell death.On top of that, redox management more than doxorubcboactvatos regulated not only through the enzymatc reactons that happen wththe cell, but in addition from the concentratoof doxorubcto whch the cell s exposed.To nvestgate the mechansms that management doxorubcboactvaton, we created a knetc mathematcal model on the doxorubcboactvatonetwork selleckchem Nutlin-3 a cell totally free method.Fromhere on, we shall use the term vtro to refer to acellular methods plus the term vvo to refer to cellular techniques.
Our vtro model was made use of to reproduce prevously publshed vtro information created by Kostrzewa Nowak et al othe effect of NADconcentratoodoxorubcboactvaton.the model, we allowed to the reactoof NADwth molecular oxygen, but assumed t for being noenzymatc snce NADoxdase was not existing the cell free of charge reactomxtures.The nclusoof the NADO2 reactothe boactvatonetwork model was partcularly mportant because t provded a mechanstc pathway by whch ncreased NADconcentratocould bring about enhanced doxorubcreductve VX765 converson.Reductve conversoof doxorubcs characterzed by conservatve NADdepletoand qunone doxorubctransformaton, whe redox cyclng of doxorubcs characterzed by rapd NADdepletoand sustaned qunone doxorubcn.The finished vtro model was capable not just of descrbng the swtch behavor betweereductve conversoand redox cyclng of doxorubcbased upothehgh and lower NADconcentratons, but was also capable of replcatng a whole new expermental condton.Uponclusoof SOD actvty the boactvatonetwork, wthout refttng the parameters, the model demonstrated SOD nduced redox cyclng of doxorubcathgh NADconcentraton.
The valdated vtro model of doxorubcboactvatoemphaszes the mportance from the reactobetweeNADand molecular oxygethe exact representatoof doxoru bcboactvaton.In addition, the model lustrateshow the drvng force of and ranges of SOD cacontrol the swtchng betweereductve conversoand redox cyclng.We thereforehypotheszed that the ntrnsc dfferences

proteexpressoand redox state betweeleukema cells could smarly gve rse to shfts handle betweethese two processes, conferrng dfferences doxorubccytotoxcty.