As it currently stands, our model only considers cytosolic doxorubicin bioactivation, and is hence inherently restricted. In addition, our in vivo doxorubicin bioactivation network consists of species which have been involved with many different other intracellular reactions which are independent of doxorubicin bioactivation, including NADPH. NADPH may be a metabolite that is definitely implemented ubiquitously in cells for any assortment of redox dependent reactions . In addition, NADPH-dependent thiol oxidationbased mechanisms may perhaps in reality contribute to doxorubicininduced cell injury in some cells , therefore delivering a website link involving intracellular thiol-disulfide standing and doxorubicininduced toxicity; a website link that was unaccounted for by our model method on account of the qualitative nature in the findings. The capability within the recent in vivo models to accurately make clear the experimental information and predict new conditions doesn’t at once preclude alternate mechanisms which may be at get the job done.
It is actually entirely achievable that mechanisms past the scope of these designs contribute to the cell-line variations in doxorubicin sensitivity which have been exhibited between the EU1-Res and EU3-Sens cells. We have now by now offered evidence that altered doxorubicin transport may not be a major cause of the differential doxorubicin-sensitivity that exists among selleck chemical reference the EU1-Res as well as the EU3-Sens cell lines . Even so, non-transport relevant mechanisms similar to altered doxorubicin detoxification, altered replication habits, or altered ROS metabolism could play a substantial role while in the doxorubicin toxicity profiles exhibited by these cells, and also the value of these alternate mechanisms could emerge on characterization of more cell lines.
Doxorubicin detoxification is imagined to be mediated by both one- and two-electron pathways of quinone reduction that depend on the activities of cellular reductases and glutathione Stransferases . Cell-to-cell variation selleck chemical find out this here in these enzymes could account for differences in cell sensitivity to doxorubicin treatment method. Additionally, considering most mammalian xenobiotic detoxification sytems depend on the addition of a glutathione moeity, through glutathione S transferases , variations in the glutathione redox potential of these cells could also contribute to the variations in doxorubicin-sensitivity which can be exhibited between the 2 cells.
Furthermore, if ROS metabolism is a essential aspect that determines the sensitivity of cancer cells to doxorubicin treatment, as was suggested from the proposed signaling actions from the ROS-generating module, then differences in glutathione redox probable and distinctions in other NADPH-consuming mechanisms could successfully advertise or hinder doxorubicin toxicity in these cells. Given that additional mechanisms of doxorubicin toxicity could possibly exist, the systematic analysis of those alternate mechanisms are important to assess their relative significance in vivo.