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

// Yu Dong 1, 5 , Takuya Furuta 1, 2 , Hemragul Sabit 1 , Tomohiro Kitabayashi 1 , Shabierjiang Jiapaer 1 , Masahiko Kobayashi 3 , Yasushi Ino 4 , Tomoki Todo 4 , Lei Teng 5 , Atsushi Hirao 3 , Shi-Guang Zhao 5 and Mitsutoshi Nakada 1 1 Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan 2 Department of Pathology, Kurume University School of Medicine, Kurume, Japan 3 Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan 4 Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan 5 Department 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.