Oncotarget

Research Papers:

Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug

Yu Dong, Takuya Furuta, Hemragul Sabit, Tomohiro Kitabayashi, Shabierjiang Jiapaer, Masahiko Kobayashi, Yasushi Ino, Tomoki Todo, Lei Teng, Atsushi Hirao, Shi-Guang Zhao and Mitsutoshi Nakada _

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Oncotarget. 2017; 8:111728-111741. https://doi.org/10.18632/oncotarget.22904

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Abstract

Yu Dong1,5, Takuya Furuta1,2, Hemragul Sabit1, Tomohiro Kitabayashi1, Shabierjiang Jiapaer1, Masahiko Kobayashi3, Yasushi Ino4, Tomoki Todo4, Lei Teng5, Atsushi Hirao3, Shi-Guang Zhao5 and Mitsutoshi Nakada1

1Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

2Department of Pathology, Kurume University School of Medicine, Kurume, Japan

3Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

4Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan

5Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China

Correspondence to:

Mitsutoshi Nakada, email: mnakada@med.kanazawa-u.ac.jp

Keywords: glioma stem cell; glioblastoma; drug screening; drug repositioning

Received: May 02, 2017    Accepted: November 15, 2017    Published: December 04, 2017

ABSTRACT

Glioma stem cell (GSC)-targeted therapy is expected to be one of the most innovative approaches to treat patients with glioblastoma (GBM). A number of the drugs that restrain the signaling pathway essential for GSC maintenance have been under clinical trials. Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs, and investigated its therapeutic effects against GBM with the purpose of drug repositioning. To develop novel therapeutics targeting GSCs, we initially screened drug libraries for small-molecule compounds showing a greater efficacy, compared to that of controls, in inhibiting the proliferation and survival of different GSC lines using cell proliferation assay. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Finally, we found three drugs showing remarkable antiproliferative effects on GSCs at low concentrations and investigated their therapeutic effects on GSCs, glioma cell lines, and in a GBM mouse model. Of the three compounds, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.


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