Conversely, with the a hundred nM doxorubctreatment degree, there was a rapd ncrease qunone doxorubcaccumulatoat ten mn, but ths ncrease was followed by a shardecrease ntracellular qunone doxorubcwhch theappeared to equbrate to a steady state level that was mantaned for that rest within the treatment duraton.Addtonally, to the 100 nM doxorubctreatment regmen, the ntracellular qunone doxorubclevels the EU1 Res cells have been sgnfcantly lower thathose seethe EU3 Sens cells, representng a full swtch behavor compared to that seeat the ten mM doxorubctreatment degree.Wthout addtonal parameter inhibitor tgf beta receptor inhibitors fttng, the knetc smulatoof the lower doxorubctreatment condtowas capable to capture the decreased quantities of qunone doxorubcobserved the EU1 Res cells, compared on the EU3 Sens cells, likewise as the general shape on the ntracellular qunone doxorubcaccumulatocurve, provdng even further valdatoof the qualty within the cell lne specfc models for explanng the complex responses we observed expermentally.
The doxorubcnduced NADdepletothe EU1 Res cells was not sgnfcantly dfferent from that seethe EU3 Sens M344 cells.Whe model smulatons accurately predcted smar NADdepletotrends betweeEU1 Res and EU3 Sens cells, the underestmatoof NADdepletothe model smulatons was stl obvious on the 100 nM doxorubcconcentratocondton.Dfferences doxorubcnduced superoxde generatobetweethe EU1 Res and EU3 Sens cells were neglgble and knetc model smulatons of doxorubcnduced superoxde generatoaccurately captured ths behavor.The lack of sustaned accumulatoof qunone doxorubcboth the EU1 Res and EU3 Sens cells, pared wth the expermentally determned NADdepletoand superoxde generatoprofes with the a hundred nM doxorubctreatment cond ton, suggest that each the EU1 and EU3 cells undergo a shft the control of ther doxorubcmetabolsm profes being a end result of alterations the doxorubctreatment condtoappled.odel generatedhypotheses of altered NADand qunone doxorubcdynamcs are confrmed by pharmacologcal nterventodrug senstve cells Concentratodependent dfferences doxorubcboactva toexst betweethe EU1 Res plus the EU3 Sens cells.
Based othese dfferences, wehypotheszed that thriving nterventostrateges for alterng the behavor on the doxorubcboactvatonetwork wthALL cells would also be doxorubcconcentratodependent.To check thshypothess the EU3 Sens cell lne, we carried out a seres of pharmacologcal nterventostrateges, for both the ten mM along with the a hundred nM doxorubcconcentratocondton, that have been amed at decreasng the quantity of doxorubcreductve conversothat happens wththe

EU3 Sens cells.We opted to alter NADregeneratousng the pharmacologcal G6PD nhbtor, dehydroepandrosterone, simply because NADs nvolved the CPR and oxygedependent enzymatc reactons that play a purpose reductve conversoand redox cyclng of doxorubcn.