ABSTRACT
Apoptosis is an important area of research because of its role in keeping a mature multicellular organism's number of cells constant, hence, ensuring that the organism does not have cell accumulation that may transform into cancer with additional hallmarks. Firstly, we have carried out sensitivity analysis on an existing mathematical mitochondria-dependent apoptosis model to find out which parameters have a role in causing monostable cell survival, which may, in turn, lead to malfunction in apoptosis. We have then generated three base parameter sets that represent healthy cells. These parameter sets were built by changing the sensitive parameters while preserving the bistability. For each base set, we varied the proapoptotic and antiapoptotic production rates, to yield new sets for the cells that have malfunctioning apoptosis. In a hypothetical cell model, we simulated caspase-3 activation by numerically integrating the governing ordinary differential equations of a mitochondria-dependent apoptosis model. These simulations were carried out for four potential treatments, namely: (1) proteasome inhibitor treatment, (2) Bcl-2 inhibitor treatment, (3) IAP inhibitor treatment, (4) Bid-like synthetic peptides treatment. The results suggest that the proteasome inhibitor treatment is the most effective treatment, though it may have severe side effects. For this treatment, the amount of proteasome inhibitor needed for caspase-3 activation may be different for hypothetical cells with a different pro- or anti-apoptotic protein defect. It is also found that caspase-3 can be activated by Bcl-2 inhibitor treatment only in those hypothetical malfunctioning cells with Bax deficiency but not in others. These results are in line with the view that molecular heterogeneity in individuals may be an important factor in determining the individuals' positive or negative responses to treatments.
Subject(s)
Apoptosis , Models, Theoretical , BH3 Interacting Domain Death Agonist Protein/chemistry , Biomarkers, Tumor/metabolism , Caspase 3/metabolism , Computer Simulation , Genotype , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Mitochondria/metabolism , Normal Distribution , Peptides/chemistry , Phenotype , Proteasome Inhibitors/chemistry , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitorsABSTRACT
Bistability in apoptosis, or programmed cell death, is crucial for the healthy functioning of multicellular organisms. The aim in this study is to show the presence of bistability in a mitochondria-dependent apoptosis model under nitric oxide effects using chemical reaction network theory. The model equations are a set of coupled ordinary differential equations arising from the assumed mass action kinetics. Whether these equations have a capacity for bistability (cell survival and apoptosis) is determined using a modular approach in which the model is decomposed into modules. Each module contains only a subset of the whole model and is analyzed separately. It is seen that bistability in a module is preserved throughout the whole model after adding the remaining reactions in the pathway on these modules. It is also found that inhibitor effect of some proteins and the appearance of a reacting protein in a later stage as a product is a desired feature but not sufficient for bistability (in the absence of cooperativity effects). On the whole model, two apoptotic and two cell survival states are obtained depending on the initial cell conditions. The results suggest that the antiapoptotic effects of nitric oxide species are responsible for the bistable character of the apoptotic pathway when cooperativity is not assumed in the apoptosome formation.
