协同作用的比尼帕他/紫杉醇在胰腺癌细胞中的药效动力学模型。
Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells.
机构信息
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
出版信息
BMC Cancer. 2020 Oct 23;20(1):1024. doi: 10.1186/s12885-020-07398-9.
BACKGROUND
For most patients, pancreatic adenocarcinoma responds poorly to treatment, and novel therapeutic approaches are needed. Standard-of-care paclitaxel (PTX), combined with birinapant (BRP), a bivalent mimetic of the apoptosis antagonist SMAC (second mitochondria-derived activator of caspases), exerts synergistic killing of PANC-1 human pancreatic adenocarcinoma cells.
METHODS
To investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, data capturing PANC-1 cell growth, apoptosis kinetics, and cell cycle distribution were integrated with high-quality IonStar-generated proteomic data capturing changes in the relative abundance of more than 3300 proteins as the cells responded to the two drugs, alone and combined.
RESULTS
PTX alone (15 nM) elicited dose-dependent G2/M-phase arrest and cellular polyploidy. Combined BRP/PTX (150/15 nM) reduced G2/M by 35% and polyploid cells by 45%, and increased apoptosis by 20%. Whereas BRP or PTX alone produced no change in the pro-apoptotic protein pJNK, and a slight increase in the anti-apoptotic protein Bcl2, the drug combination increased pJNK and decreased Bcl2 significantly compared to the vehicle control. A multi-scale, mechanism-based mathematical model was developed to investigate integrated birinapant/paclitaxel effects on temporal profiles of key proteins involved in kinetics of cell growth, death, and cell cycle distribution.
CONCLUSIONS
The model, consistent with the observed reduction in the Bcl2/BAX ratio, suggests that BRP-induced apoptosis of mitotically-arrested cells is a major contributor to the synergy between BRP and PTX. Coupling proteomic and cellular response profiles with multi-scale pharmacodynamic modeling provides a quantitative mechanistic framework for evaluating pharmacodynamically-based drug-drug interactions in combination chemotherapy, and could potentially guide the development of promising drug regimens.
背景
对于大多数患者来说，胰腺导管腺癌对治疗的反应较差，因此需要新的治疗方法。标准护理紫杉醇（PTX）与双价模拟物凋亡拮抗剂 SMAC（第二线粒体衍生的半胱天冬酶激活剂）的二聚体抑制剂 birinapant（BRP）联合使用，对 PANC-1 人胰腺导管腺癌细胞具有协同杀伤作用。
方法
为了研究这种协同药效学相互作用的潜在机制，我们将捕获 PANC-1 细胞生长、细胞凋亡动力学和细胞周期分布的数据与高质量 IonStar 生成的蛋白质组学数据相结合，该数据捕获了细胞对两种药物（单独和联合）反应时超过 3300 种蛋白质相对丰度的变化。
结果
单独使用 PTX（15 nM）可引起剂量依赖性的 G2/M 期阻滞和细胞多倍体形成。联合使用 BRP/PTX（150/15 nM）可使 G2/M 减少 35%，多倍体细胞减少 45%，并使细胞凋亡增加 20%。BRP 或 PTX 单独使用时，促凋亡蛋白 pJNK 没有变化，抗凋亡蛋白 Bcl2 略有增加，但与载体对照组相比，药物联合使用可显著增加 pJNK 并减少 Bcl2。开发了一个多尺度、基于机制的数学模型，以研究 birinapant/紫杉醇联合对参与细胞生长、死亡和细胞周期分布动力学的关键蛋白的时间曲线的综合影响。
结论
该模型与观察到的 Bcl2/BAX 比值降低一致，表明 BRP 诱导有丝分裂期阻滞细胞的凋亡是 BRP 和 PTX 协同作用的主要原因。将蛋白质组学和细胞反应谱与多尺度药效动力学模型相结合，为评估联合化疗中基于药效学的药物-药物相互作用提供了一个定量的机制框架，并可能为有前途的药物方案的开发提供指导。
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