Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity-pharmacodynamic drug-drug interaction modeling
Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity-pharmacodynamic drug-drug interaction modeling
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DOI：
10.1158/1078-0432.ccr-06-2468
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发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Jusko, William J.
中科院分区：
文献类型：
--
作者：
Wetzler, Meir;Earp, Justin C.;Jusko, William J.
目的：组成型信号转导子和转录激活子3（STAT 3）活性在50%的急性髓性白血病病例中观察到，并与不良治疗结果相关，三氧化二砷（ATO）下调。热休克蛋白（HSP）90是一种参与信号转导途径的分子伴侣。我们假设HSP 90抑制剂将增强ATO对组成型STAT 3活性和细胞杀伤的作用。一个问题是ATO和HSP 90抑制剂的作用将导致HSP 70的上调，HSP 70是一种已知抑制细胞凋亡的蛋白质。实验设计：我们使用了半机械药效学模型来表征ATO和HSP 90抑制剂对组成性STAT 3活性、HSP 70表达和细胞死亡的浓度-效应关系。ATO与3种HSP 90抑制剂的药效学相互作用显示，尽管ATO与3种HSP 90抑制剂同时协同上调HSP 70，但ATO与3种HSP 90抑制剂在抑制组成性STAT 3活性和诱导细胞死亡方面具有协同作用。这些初步结果为研究ATO与HSP 90抑制剂联合治疗具有组成性STAT 3活性的急性髓细胞白血病提供了基础。
Purpose: Constitutive signal transducer and activator of transcription 3 (STAT3) activity, observed in similar to 50% of acute myelogenous leukemia cases and associated with adverse treatment outcome, is down-regulated by arsenic trioxide (ATO). Heat shock protein (HSP) 90 is a molecular chaperone involved in signal transduction pathways. We hypothesized that HSP90 inhibitors will potentiate ATO effect on constitutive STAT3 activity and cell killing. One concern was that the effect of ATO and HSP90 inhibitors will result in up-regulation of HSP70, a protein known to inhibit apoptosis.Experimental Design: We have used a semimechanistic pharmacodynamic model to characterize concentration-effect relationships of ATO and HSP90 inhibitors on constitutive STAT3 activity, HSP70 expression, and cell death in a cell line model.Results: Pharmacodynamic interaction of ATO and three HSP90 inhibitors showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70.Conclusions: These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity.