Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer
Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer
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DOI：
10.1016/j.lungcan.2011.09.011
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发表时间：
2012-04-01
期刊：
影响因子：
5.3
通讯作者：
Miyoshi, Shinichiro
中科院分区：
文献类型：
--
作者：
Ueno, Tsuyoshi;Tsukuda, Kazunori;Miyoshi, Shinichiro
研究了新开发的Hsp90抑制剂NVP-AUY922 （AUY922）对非小细胞肺癌（NSCLC）的抗肿瘤活性。使用21个非小细胞肺癌细胞系，对其体细胞改变进行了表征。使用改良的MTS法分析细胞增殖。Western blotting检测客户蛋白的表达。流式细胞术分析细胞周期。AUY922对NSCLC细胞系的IC50值范围为5.2 ~ 860 nM（中位数为20.4 nM）。根据以往的数据，IC50小于50 nM的细胞被归类为敏感细胞，21个NSCLC细胞系中有19个被判定为敏感细胞。5种恶性胸膜间皮瘤（MPM）细胞系的IC50值显示，MPM细胞的IC50值（中位数为89.2 nM，范围为22.2 ~ 24,100 nM）显著高于NSCLC细胞（p = 0.015）。在药物敏感的细胞系中，在低药物浓度（50-100 nM）下，总蛋白和磷酸化的客户蛋白（EGFR， MET， HERZ和ART）均显著减少。对H1975和H838两个敏感细胞系进行细胞周期分析。AUY922处理后，亚g (0)-G(1)细胞群增加，PARP表达出现裂解，表明诱导了细胞凋亡。综上所述，AUY922对大多数NSCLC细胞系有效，不受已知分子改变类型的影响，有望成为治疗NSCLC的一种有前景的新药。2011爱思唯尔爱尔兰有限公司版权所有。
The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24, 100 nM) than the NSCLC cells (p = 0.015). There was significant depletion of both the total and phosphorylated client proteins - EGFR, MET, HERZ and ART - at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G(0)-G(1) cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.