📒 Deoliveira 2016
A biophysical systems approach to identifying the pathways of acute and chronic doxorubicin mitochondrial cardiotoxicity1
- Doxorubicin (DOX) presents dose dependent, cumulative and irreversible cardiotoxicity that can lead to cardiomyopathy and ultimately congestive heart failure, strongly associated to mitochondrial dysfunction
- inhibit the electron transport chain (ETC) by binding to cardiolipin
- redox cycling.
- topoisomerase II poison and can form DNA adducts , which can damage the DNA and inhibit gene transcription and DNA replication
- can form vicious cycles -> chronic irreversible toxicity
Method and Results
- based on ETC-ROS and ME-R model with some modifications (please see suplement data)
- TCA cycle, transporters, ROS production and scavenging systems and a detailed ETC representation
- All simulations in this work consider that the mitochondria are in the presence of substrate and ADP (state 3)
- DOX binds onto cardiolipin in the IMM, IC50 values in the literature, with fitted Hill coefficients
- In the complex I, as a multiplier to IF site ROS generation.
- 7% increase in the superoxide concentration for 1mg/kg of DOX in rats (37mg/m2 in human, 5 to 30μM in mitochondria). 7% increase for 30μM of DOX in this model.
Damage to mtDNA
- mass action model for mtDNA damage and repair. mtDNA level is normalized (scaled).
- expression of all proteins and enzymes encoded in mtDNA was considered to be scaled by the mtDNA concentration
- mtDNA damage by [•OH] (hydroxyl radical, derived from other ROS) and DOX directly
- constant concentration of the drug and performing a simulation until the model reached a steady state.
- For low drug concentrations, the ATP concentration and the membrane potential were only barely reduced
- For high drug concentrations, mitochondrial function gradually deteriorate until a threshold is reached and the mitochondria completely collapse, with a complete loss of membrane potential and ATP concentration, a sharp increase in the ROS concentrations and a reduction in the O2 consumption to residual levels
- Theshold: 210 μM
- dynamic simulations: fast absorbtion (5 mins) and slow elimination (24 hrs)
- For low doses, mitochondrial function is only marginally affected, but at high doses, some significant variations can be observed. Mitochondrial function deteriorates as the dose increases
- these effects are always temporary and all quantities return to their baseline values after the drug is fully eliminated from the system
- Added mtDNA model. stable region 0.75-0.73. unstable < 0.73 (viscious cycle)
- weekly doses of 1mg/kg of DOX, 30μM in the model.
- direct mtDNA damage by DOX is the main pathway that triggers this vicious cycle, being responsible for over 75% of the mtDNA content reduction during the acute stages of DOX intoxication.
- Iron chelators to mitigate mtDNA damage and the loss of mtDNA content associated with DOX.
- The simulations reproduced the setup of this in vivo experiment with rats
- extending the chelating treatment to two of three times the duration of the DOX treatment might considerably increase the cardioprotection
- Redox cycling is the main contributor to acute increases in ROS concentrations at clinically relevant concentrations
- ETC inhibition also showed negligible effects at clinically relevant concentrations, but more prominent @ lethal dose
- redox cycling and ETC inhibition alone are not capable of generating any long term alterations in mitochondria function; mtDNA damage is necessary.
- direct mtDNA damage by DOX is responsible for over 75% of the mtDNA content reduction during the acute stages of intoxication. ROS sustained the vicious cycle.
- cardioprotective agent that has shown efficacy (partial protection)
- extending the iron chelating therapy to time periods longer than the DOX treatment can enhance this protective property
- The repair systems of mtDNA are complex and still poorly understood
- additional 15,000 simulations were performed, exhaustively exploring the space of potential parameter combinations
- support the conclusion that direct damage to mtDNA by DOX is the main toxicity pathway responsible for triggering the vicious cycle
- the expression of mtDNA encoded proteins was considered to be proportional to the mtDNA content
- there could be delays between the mtDNA damage and the reduction in the density of mtDNA encoded proteins
- do not take into account oxidative damage to any other structures or proteins
De Oliveira BL, Niederer S. A biophysical systems approach to identifying the pathways of acute and chronic doxorubicin mitochondrial cardiotoxicity. PLoS Comput. Biol. 2016;12(11):e1005214. doi:10.1371/journal.pcbi.1005214. ↩︎