INSULIN-LIKE GROWTH FACTOR-TYPE 1 RECEPTOR INHIBITOR NVP-AEW541 ENHANCES RADIOSENSITIVITY OF PTEN WILD-TYPE BUT NOT PTEN-DEFICIENT HUMAN PROSTATE CANCER CELLS
INSULIN-LIKE GROWTH FACTOR-TYPE 1 RECEPTOR INHIBITOR NVP-AEW541 ENHANCES RADIOSENSITIVITY OF PTEN WILD-TYPE BUT NOT PTEN-DEFICIENT HUMAN PROSTATE CANCER CELLS
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DOI：
10.1016/j.ijrobp.2011.03.030
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发表时间：
2011-09-01
影响因子：
7
通讯作者：
Haustermans, Karin M.
中科院分区：
文献类型：
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作者：
Isebaert, Sofie F.;Swinnen, Johannes V.;Haustermans, Karin M.
目的：在过去的十年中，许多针对胰岛素样生长因子 1 型受体 (IGF-1R) 的单克隆抗体和小分子临床试验已经启动。尽管 IGF-1R 信号传导在放射抗性中发挥重要作用，但此类药物与放射治疗联合的研究仍然滞后。因此，本研究的目的是探讨小分子IGF-1R激酶抑制剂NVP-AEW541对前列腺癌细胞固有放射抗性的影响。 方法和材料：在三种人前列腺癌细胞系（PC3、DU145、22Rv1）中测定NVP-AEW541对细胞增殖、细胞活力、IGF-1R信号、放射敏感性、细胞周期分布和双链断裂修复的影响。此外，通过使用组成型活性 Akt 或失活激酶死亡 Akt 的转染实验探索了 PTEN 通路状态的重要性。结果：NVP-AEW541 在所有三种细胞系中均以时间和剂量依赖性方式抑制细胞增殖并降低细胞活力。在 PTEN 野生型细胞系 DU145 和 22Rv1 中观察到放射增敏作用，但在 PTEN 缺陷型 PC3 细胞系中未观察到放射增敏作用。 NVP-AEW541 诱导的放射增敏与磷酸 Akt 水平的下调和高水平的残留双链断裂同时发生。 PTEN 状态在放射增敏作用中的重要性通过使用组成型活性 Akt 或失活激酶死亡 Akt 的转染实验得到了证实。结论：NVP-AEW541 增强 PTEN 野生型中电离辐射的作用，但不增强 PTEN 缺陷的前列腺癌细胞中的电离辐射作用。根据肿瘤 PTEN 状态正确选择患者对于在临床试验中获得最佳结果至关重要，在这些临床试验中，正在探索放疗与这种 IGF-1R 抑制剂的组合。 (C) 2011 爱思唯尔公司
Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells.Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt.Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt.Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored. (C) 2011 Elsevier Inc.