Low Probability Activation of Bax/Bak Can Induce Selective Killing of Cancer Cells by Generating Heterogeneity in Apoptosis

Raychaudhuri, Subhadip; Das, Somkanya C.

doi:https://doi.org/10.1260/2040-2295.4.1.47

Journal of Healthcare Engineering

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Research Article | Open Access

Volume 4 | Article ID 512891 | https://doi.org/10.1260/2040-2295.4.1.47

Low Probability Activation of Bax/Bak Can Induce Selective Killing of Cancer Cells by Generating Heterogeneity in Apoptosis

Subhadip Raychaudhuri¹and Somkanya C. Das^2,3

Received01 Jul 2012

Accepted01 Nov 2012

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.

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