Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma

Ashizawa,Tadashi; Miyata,Haruo; Iizuka,Akira; Komiyama,Masaru; Oshita,Chie; Kume,Akiko; Nogami,Masahiro; Yagoto,Mika; Ito,Ichiro; Oishi,Takuma; Watanabe,Reiko; Mitsuya,Koichi; Matsuno,Kenji; Furuya,Toshio; Okawara,Tadashi; Otsuka,Masami; Ogo,Naohisa; Asai,Akira; Nakasu,Yoko; Yamaguchi,Ken; Akiyama,Yasuto

doi:10.3892/ijo.2013.1916

Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma

Authors:
- Tadashi Ashizawa
- Haruo Miyata
- Akira Iizuka
- Masaru Komiyama
- Chie Oshita
- Akiko Kume
- Masahiro Nogami
- Mika Yagoto
- Ichiro Ito
- Takuma Oishi
- Reiko Watanabe
- Koichi Mitsuya
- Kenji Matsuno
- Toshio Furuya
- Tadashi Okawara
- Masami Otsuka
- Naohisa Ogo
- Akira Asai
- Yoko Nakasu
- Ken Yamaguchi
- Yasuto Akiyama
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Affiliations: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan, Division of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan, Division of Neurosurgery, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan, PharmaDesign, Inc., Chuo-ku, Tokyo 104-0032, Japan, Kumamoto Health Science University, Kumamoto 861-5598, Japan, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan, Shizuoka Institute of Environment and Hygiene, Aoi-ku, Shizuoka 420-8637, Japan
Published online on: April 23, 2013 https://doi.org/10.3892/ijo.2013.1916
Pages: 219-227

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Abstract

Signal transducer and activator of transcription (STAT) 3, a member of a family of DNA-binding molecules, is a potential target in the treatment of cancer. The highly phosphorylated STAT3 in cancer cells contributes to numerous physiological and oncogenic signaling pathways. Furthermore, a significant association between STAT3 signaling and glioblastoma multiforme stem-like cell (GBM-SC) development and maintenance has been demonstrated in recent studies. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the present study, we focused on cancer stem-like cells derived from recurrent GBM patients and investigated the efficacy of STX-0119. Three GBM stem cell lines showed many stem cell markers such as CD133, EGFR, Nanog, Olig2, nestin and Yamanaka factors (c-myc, KLF4, Oct3/4 and SOX2) compared with parental cell lines. These cell lines also formed tumors in vivo and had similar histological to surgically resected tumors. STAT3 phosphorylation was activated more in the GBM-SC lines than serum-derived GB cell lines. The growth inhibitory effect of STX-0119 on GBM-SCs was moderate (IC50 15-44 µM) and stronger compared to that of WP1066 in two cell lines. On the other hand, the effect of temozolomide was weak in all the cell lines (IC50 53-226 µM). Notably, STX-0119 demonstrated strong inhibition of the expression of STAT3 target genes (c-myc, survivin, cyclin D1, HIF-1α and VEGF) and stem cell-associated genes (CD44, Nanog, nestin and CD133) as well as the induction of apoptosis in one stem-like cell line. Interestingly, VEGFR2 mRNA was also remarkably inhibited by STX-0119. In a model using transplantable stem-like cell lines in vivo GB-SCC010 and 026, STX-0119 inhibited the growth of GBM-SCs at 80 mg/kg. STX-0119, an inhibitor of STAT3, may serve as a novel therapeutic compound against GBM-SCs even in temozolomide-resistant GBM patients and has the potential for GBM-SC-specific therapeutics in combination with temozolomide plus radiation therapy.

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