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

Abstract

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; Lopez-Anton 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).