Abukwaik Roba, Vera-Siguenza Elias, Tennant Daniel A, Spill Fabian
Mathematics Department, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Saudi Arabia; School of Mathematics, University of Birmingham, B15 2TS, United Kingdom.
School of Mathematics, University of Birmingham, B15 2TS, United Kingdom; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom.
J Theor Biol. 2023 Sep 7;572:111562. doi: 10.1016/j.jtbi.2023.111562. Epub 2023 Jun 20.
Chemotherapeutic drugs are used to treat almost all types of cancer, but the intended response, i.e., elimination, is often incomplete, with a subset of cancer cells resisting treatment. Two critical factors play a role in chemoresistance: the p53 tumour suppressor gene and the X-linked inhibitor of apoptosis (XIAP). These proteins have been shown to act synergistically to elicit cellular responses upon DNA damage induced by chemotherapy, yet, the mechanism is poorly understood. This study introduces a mathematical model characterising the apoptosis pathway activation by p53 before and after mitochondrial outer membrane permeabilisation upon treatment with the chemotherapy Doxorubicin (Dox). "In-silico" simulations show that the p53 dynamics change dose-dependently. Under medium to high doses of Dox, p53 concentration ultimately stabilises to a high level regardless of XIAP concentrations. However, caspase-3 activation may be triggered or not depending on the XIAP induction rate, ultimately determining whether the cell will perish or resist. Consequently, the model predicts that failure to activate apoptosis in some cancer cells expressing wild-type p53 might be due to heterogeneity between cells in upregulating the XIAP protein, rather than due to the p53 protein concentration. Our model suggests that the interplay of the p53 dynamics and the XIAP induction rate is critical to determine the cancer cells' therapeutic response.
化疗药物用于治疗几乎所有类型的癌症，但预期的反应，即消除癌细胞，往往并不完全，总有一部分癌细胞会抵抗治疗。化疗耐药性中有两个关键因素起作用：p53肿瘤抑制基因和X连锁凋亡抑制蛋白（XIAP）。这些蛋白质已被证明在化疗诱导的DNA损伤后协同发挥作用，引发细胞反应，然而，其机制尚不清楚。本研究引入了一个数学模型，该模型描述了在用化疗药物阿霉素（Dox）处理后线粒体外膜通透性改变前后p53对凋亡途径的激活作用。“计算机模拟”显示，p53的动态变化呈剂量依赖性。在中高剂量的阿霉素作用下，无论XIAP浓度如何，p53浓度最终都会稳定在高水平。然而，半胱天冬酶-3的激活可能会被触发，也可能不会，这最终取决于XIAP的诱导率，从而决定细胞是死亡还是抵抗。因此，该模型预测，一些表达野生型p53的癌细胞未能激活凋亡，可能是由于细胞上调XIAP蛋白的异质性，而非p53蛋白浓度所致。我们的模型表明，p53动态变化与XIAP诱导率之间的相互作用对于确定癌细胞的治疗反应至关重要。
