Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line

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

doi:10.3892/ijo.2014.2439

Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line

Authors:
- Tadashi Ashizawa
- Yasuto Akiyama
- Haruo Miyata
- Akira Iizuka
- Masaru Komiyama
- Akiko Kume
- Maho Omiya
- Takashi Sugino
- Akira Asai
- Nakamasa Hayashi
- Koichi Mitsuya
- Yoko Nakasu
- Ken Yamaguchi
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Affiliations: 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, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan, Division of Neurosurgery, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka 411-8777, Japan
Published online on: May 12, 2014 https://doi.org/10.3892/ijo.2014.2439
Pages: 411-418

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Abstract

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.

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