Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells.
Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells.
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DOI：
10.1186/s12885-020-07398-9
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发表时间：
2020-10-23
期刊：
影响因子：
3.8
通讯作者：
Straubinger RM
中科院分区：
文献类型：
--
作者：
Niu J;Wang X;Qu J;Mager DE;Straubinger RM
对于大多数患者来说，胰腺癌对治疗的反应很差，需要新的治疗方法。标准治疗紫杉醇（PTX）与birinapant（BRP）（一种凋亡拮抗剂SMAC（第二种来源于caspase的激活剂）的二价模拟物）组合，对PANC-1人胰腺癌细胞发挥协同杀伤作用。为了研究这种协同药效学相互作用的潜在机制，将捕获PANC-1细胞生长，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，这些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。PTX单独（15 nM）引起剂量依赖性G2/M期阻滞和细胞多倍性。联合BRP/PTX（150/15 nM）使G2/M期细胞减少35%，多倍体细胞减少45%，凋亡增加20%。而单独的BRP或PTX在促凋亡蛋白pJNK中没有产生变化，并且在抗凋亡蛋白Bcl 2中略有增加，与媒介物对照相比，药物组合显著增加pJNK并降低Bcl 2。开发了一种多尺度、基于机制的数学模型，以研究birinapant/紫杉醇对参与细胞生长、死亡和细胞周期分布动力学的关键蛋白质的时间分布的综合影响。该模型与观察到的Bcl 2/BAX比率降低一致，表明BRP诱导的有丝分裂阻滞细胞的凋亡是BRP和PTX之间协同作用的主要贡献者。将蛋白质组学和细胞反应谱与多尺度药效学模型相结合，为评价联合化疗中基于药效学的药物相互作用提供了一个定量机制框架，并可能指导有前途的药物方案的开发。
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. 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. 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. 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.
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影响因子：
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作者：
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