A discrete Petri net model for cephalostatin-induced apoptosis in leukemic cells

Understanding the mechanisms involved in apoptosis has been an area of extensive study due to its critical role in the development and homeostasis of multi-cellular organisms. Our special interest lies in understanding the apoptosis of tumor cells which is mediated by novel potential drugs. Cephalostatin 1 is a marine compound that can induce apoptosis in leukemic cells in a dose- and time-dependent manner even at nano-molar concentrations using a recently discovered pathway that excludes the receptor-mediated pathway and which includes both the mitochondrial and endoplasmic reticulum pathways (Dirsch et al., Cancer Res 63:8869–8876, 2003; López-Antón et al., J Biol Chem 28:33078–33086, 2006). In this paper, the methods and tools of Petri net theory are used to construct, analyze, and validate a discrete Petri net model for cephalostatin 1-induced apoptosis. Based on experimental results and literature search, we constructed a discrete Petri net consisting of 43 places and 59 transitions. Standard Petri net analysis techniques such as structural and invariant analyses and a recently developed modularity analysis technique using maximal abstract dependent transition sets (ADT sets) were employed. Results of these analyses revealed model consistency with known biological behavior. The sub-modules represented by the ADT sets were compared with the functional modules of apoptosis identified by Alberghina and Colangelo (BMC Neurosci 7(Suppl 1):S2, 2006).