Ashizawa Tadashi, Akiyama Yasuto, Miyata Haruo, Iizuka Akira, Komiyama Masaru, Kume Akiko, Omiya Maho, Sugino Takashi, Asai Akira, Hayashi Nakamasa, Mitsuya Koichi, Nakasu Yoko, Yamaguchi Ken
Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka 411-8777, Japan.
Division of Pathology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan.
Int J Oncol. 2014 Jul;45(1):411-8. doi: 10.3892/ijo.2014.2439. Epub 2014 May 12.
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 µM, 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.
多形性胶质母细胞瘤（GBM）是最恶性和侵袭性最强的肿瘤之一，预后极差，中位生存时间不足2年。一旦复发，几乎没有治疗方法能够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极难治疗，因此迫切需要一种克服耐药性的新方法。此前，我们报道了一种新型的STAT3二聚化小分子抑制剂STX-0119可作为癌症治疗药物。在本研究中，我们使用基于定量PCR的基因表达分析、体外试验和动物实验，评估了STX-0119对我们建立的TMZ耐药U87细胞系的疗效。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45 μM）。特别是，STX-0119对U87肿瘤生长未显示出显著抑制作用；然而，它使裸鼠体内TMZ-R U87肿瘤的生长抑制超过50%，并与对照组相比延长了中位生存时间。定量PCR显示，YKL-40、MAGEC1、MGMT、多个上皮-间质转化（EMT）基因、间充质基因和STAT3靶基因均上调，但这些基因中的大多数在STX-0119处理后下调。此外，STX-0119显著抑制了TMZ-R U87细胞的侵袭活性。给予STX-0119后，TMZ-R U87细胞及其上清液中的YKL-40水平显著降低。这些结果表明，STX-0119是克服复发性GBM肿瘤中TMZ耐药性的有效治疗药物，可能是下一个有望延长生存期的化合物，并且YKL-40可能是靶向STAT3的潜在替代标志物。
