Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line
Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line
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DOI：
10.3892/ijo.2014.2439
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发表时间：
2014-07-01
影响因子：
5.2
通讯作者：
Yamaguchi, Ken
中科院分区：
文献类型：
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作者：
Ashizawa, Tadashi;Akiyama, Yasuto;Yamaguchi, Ken
多形性胶质母细胞瘤(GBM)是恶性程度最高、侵袭性最强的肿瘤之一，预后极差，中位生存期不足2年。一旦复发，几乎没有治疗方法来控制胶质母细胞瘤的生长。特别是对替莫唑胺(TMZ)耐药(TMZ-R)的GBM非常难以治疗，人们迫切期待一种克服耐药性的新方法。此前，我们报道了一种新的STAT3二聚化小分子抑制剂STX-0119，用于癌症治疗。在本研究中，通过基于定量的基因表达分析、体外实验和动物实验，评估了STX-0119对我们已建立的TMZ耐药U87细胞株的疗效。STX-0119对U87和TMZ-R U87细胞的生长抑制作用中等(IC50分别为34和45mU)。特别是，STX-0119对U87肿瘤的生长没有明显的抑制作用，但与对照组相比，它对TMZ-R U87裸鼠移植瘤的生长抑制了50%以上，并延长了中位生存期。定量聚合酶链式反应显示，STX-0119处理后，YKL-40、MAGEC1、MGMT、几个EMT基因、间充质基因和STAT3靶基因表达上调，但大部分基因表达下调。此外，STX-0119显著抑制TMZ-R U87细胞的侵袭活性。STX-0119可显著降低TMZ-R U87细胞及其培养上清液中YKL-40的水平。这些结果表明，STX-0119是克服复发的GBM肿瘤对TMZ耐药的有效药物，可能是下一步导致生存延长的化合物，YKL-40可能是STAT3靶向的一个可能的替代标志物。
Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC50, 34 and 45 mu M, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Quantitative PCR revealed that YKL-40, MAGEC1, MGMT, several EMT genes, mesenchymal genes and STAT3 target genes were upregulated, but most of those genes were downregulated by STX-0119 treatment. Furthermore, the invasive activity of TMZ-R U87 cells was significantly inhibited by STX-0119. YKL-40 levels in TMZ-R U87 cells and their supernatants were significantly decreased by STX-0119 administration. These results suggest that STX-0119 is an efficient therapeutic to overcome TMZ resistance in recurrent GBM tumors, and could be the next promising compound leading to survival prolongation, and YKL-40 may be a possible surrogate marker for STAT3 targeting.