Hsp90 Inhibitors NVP-AUY922 and NVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cells along with a Cell Type-Specific Cytotoxicity
Hsp90 Inhibitors NVP-AUY922 and NVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cells along with a Cell Type-Specific Cytotoxicity
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DOI：
10.1593/tlo.12211
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发表时间：
2012-10-01
影响因子：
5
通讯作者：
Djuzenova, Cholpon S.
中科院分区：
文献类型：
--
作者：
Niewidok, Natalia;Wack, Linda-Jacqueline;Djuzenova, Cholpon S.
靶向热休克蛋白 90 (Hsp90) 为增强肿瘤细胞对电离辐射 (IR) 的敏感性提供了一种有前景的治疗方法。为了探讨安排药物速释给药的影响，在本研究中，我们分析了肺癌 A549 和胶质母细胞瘤 SNB19 细胞对同时药物速释治疗和长期药物给药的反应。在单独IR、单独药物或联合药物IR治疗后的不同时间间隔，通过Hsp90及其客户的集落计数和表达谱、以及几种细胞凋亡标记物和细胞周期相关蛋白，以及IR药物诱导的细胞周期停滞、DNA损伤和修复来评估细胞反应。短暂暴露于任一 Hsp90 抑制剂 30 分钟不会影响两种肿瘤细胞系的放射敏感性。增加 IR 后药物治疗的持续时间逐渐增强 SNB19 细胞对 IR 的敏感性。相反，A549细胞对药物-IR组合的反应很大程度上取决于两种药物的细胞毒性作用，而无需放射增敏。联合药物-IR 治疗在两种肿瘤细胞系中诱导的 DNA 损伤比单独治疗更严重，并且还延长了 SNB19 细胞中 DNA 损伤修复的动力学。除了大的细胞周期紊乱之外，药物IR治疗还导致两种细胞系中抗凋亡蛋白Akt和Raf-1的消耗，以及NVP-AUY922情况下A549细胞中生存素的减少。数据表明，同时抑制 Hsp90 和照射可能会诱导细胞类型特异性放射增敏以及针对肿瘤细胞的细胞毒性。
Targeting heat shock protein 90 (Hsp90) provides a promising therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation (IR). To explore the impact of scheduling drug-IR administration, in the present study, we analyzed the response of lung carcinoma A549 and glioblastoma SNB19 cells to simultaneous drug-IR treatment followed by a long-term drug administration. Cellular response was evaluated at different time intervals after IR-alone, drug-alone, or combined drug-IR treatments by colony counts and expression profiles of Hsp90 and its clients, along with several apoptotic markers and cell cycle-related proteins, as well as by IR-drug-induced cell cycle arrest, DNA damage, and repair. A short 30-minute exposure to either Hsp90 inhibitor did not affect the radiosensitivity of both tumor cell lines. Increasing the duration of post-IR-drug treatment progressively enhanced the sensitivity of SNB19 cells to IR. In contrast, the response of A549 cells to drug-IR combination was largely determined by the cytotoxic effects of both drugs without radiosensitization. Combined drug-IR treatment induced more severe DNA damage in both tumor cell lines than each treatment alone and also protracted the kinetics of DNA damage repair in SNB19 cells. In addition to large cell cycle disturbances, drug-IR treatment also caused depletion of the antiapoptotic proteins Akt and Raf-1 in both cell lines, along with a decrease of survivin in A549 cells in case of NVP-AUY922. The data show that simultaneous Hsp90 inhibition and irradiation may induce cell type-specific radiosensitization as well as cytotoxicity against tumor cells.