抄録
Apoptosis can be triggered by extracellular death signals, deprivation of survival signals, and genetic or toxicological damage. There are two major pathways of caspase activation: (1) ligand-dependent or receptor-induced activation through death receptor and; (2) mitochondria-dependent activation via cytochrome c release. Here, we propose a mathematical model for mitochondria-dependent and independent apoptosis induced by cisplatin, an effective chemotherapeutic agent widely used for the treatment of cancer patients. Standard mass action models for the apoptotic pathways are formulated by using Michaelis-Menten kinetics when the total enzyme concentration is constant. Then, we modeled the signal transduction network of apoptotic reactions that are also modeled by ordinary differential equations. The present study provides a mechanistic mathematical model describing key elements of receptor-mediated and stress-induced caspase activation for apoptosis. To validate our model, we compared predictions with experimental observations. Our simulations successfully reproduced experimental results. Further, we could predict the sequential events of apoptotic signal response according to cisplatin concentration, demonstrating that our model predictions are consistent with available information and experimental data. Thus, the model could aid in better understanding apoptosis mechanism(s) and in identifying therapeutic approaches promoting or retarding apoptotic cell death.
