title: Low probability activation of Bax/Bak can induce selective killing of cancer cells by generating heterogeneity in apoptosis.
abstract: Biomimetic pro-apoptotic agents (e.g., BH3 mimetics) have been shown to activate the intrinsic death pathway (Type 2 apoptosis) selectively in cancer cells, a mechanism that can be key to developing successful anti-cancer therapy. This work reports mathematical modeling and computer simulations to explore the mechanisms for cancer cell apoptosis. The results indicate that a combination of low probability Bid-Bax type reaction along with overexpressed reactant molecules allows specific killing of cancer cells. Low-probability activation of Bax also emerges as a basis for inherent cell-to-cell variability in apoptotic activation. Variations in Bcl-2 to Bax ratio within a cancer cell population can further affect intrinsic fluctuations generated due to the stochastic Bid-Bax reaction. Such heterogeneity in apoptosis resistance can also provide a mechanism for the origin of cells with higher tumorigenic potential (cancer stem-like cells). The implications of our results for cancer therapy, such as in minimizing stochastic fluctuations in cancer cell death, are discussed.
authors.affiliation: Department of Chemistry, University of California, Davis, CA, USA. scdas@ucdavis.edu
authors.forename: Subhadip
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Somkanya C
authors.initials: SC
authors.lastname: Das
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D040761:Biomimetic Materials / Q000627:therapeutic use; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000627:therapeutic use*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein