Department of Chemistry, University of California, Davis, CA, USA.
J Healthc Eng. 2013;4(1):47-66. doi: 10.1260/2040-2295.4.1.47.
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.
仿生促凋亡剂（例如 BH3 类似物）已被证明可选择性地在癌细胞中激活内在死亡途径（类型 2 凋亡），这种机制可能是开发成功的抗癌疗法的关键。本工作报告了数学建模和计算机模拟，以探讨癌细胞凋亡的机制。结果表明，低概率 Bid-Bax 型反应与过表达的反应物分子的组合允许特异性杀伤癌细胞。Bax 的低概率激活也成为凋亡激活中固有细胞间变异性的基础。癌细胞群体中 Bcl-2 与 Bax 比值的变化也会进一步影响由于随机 Bid-Bax 反应产生的内在波动。凋亡抗性的这种异质性也可以为具有更高肿瘤形成潜力（癌症干细胞样细胞）的细胞起源提供一种机制。我们的研究结果对癌症治疗具有重要意义，例如在最小化癌症细胞死亡的随机波动方面。
