Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug
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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
Mitsutoshi Nakada, email: firstname.lastname@example.org
Keywords: glioma stem cell; glioblastoma; drug screening; drug repositioning
Received: May 02, 2017 Accepted: November 15, 2017 Published: December 04, 2017
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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