The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Minimal systems analysis of mitochondria-dependent apoptosis induced by cisplatin

  • Hong, Ji-Young (BioLead Inc., 609 Korea Mediventure Center) ;
  • Hara, Kenjirou (Iwata Chemical CO., LTD.) ;
  • Kim, Jun-Woo (Department of Mechanical and Biomedical Engineering, Kangwon National University) ;
  • Sato, Eisuke F. (Department of Biochemistry, Suzuka University of Medical Science) ;
  • Shim, Eun Bo (Department of Mechanical and Biomedical Engineering, Kangwon National University) ;
  • Cho, Kwang-Hyun (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2016.01.19
  • Accepted : 2016.04.18
  • Published : 2016.07.01
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Abstract

Recently, it was reported that the role of mitochondria-reactive oxygen species (ROS) generating pathway in cisplatin-induced apoptosis is remarkable. Since a variety of molecules are involved in the pathway, a comprehensive approach to delineate the biological interactions of the molecules is required. However, quantitative modeling of the mitochondria-ROS generating pathway based on experiment and systemic analysis using the model have not been attempted so far. Thus, we conducted experiments to measure the concentration changes of critical molecules associated with mitochondrial apoptosis in both human mesothelioma H2052 and their ${\rho}^0$ cells lacking mitochondrial DNA (mtDNA). Based on the experiments, a novel mathematical model that can represent the essential dynamics of the mitochondrial apoptotic pathway induced by cisplatin was developed. The kinetic parameter values of the mathematical model were estimated from the experimental data. Then, we have investigated the dynamical properties of this model and predicted the apoptosis levels for various concentrations of cisplatin beyond the range of experiments. From parametric perturbation analysis, we further found that apoptosis will reach its saturation level beyond a certain critical cisplatin concentration.

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