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

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.

Case of metastatic glioblastoma with primitive neuronal component to the lung

“…We tested for the following immunohistochemical markers: glial fibrillary acidic protein (GFAP) (Dako, Tokyo, Japan; 1:4000 dilution), Napsin A (Nichirei Biosciences, Tokyo, Japan; ready to use), neuronal cell adhesion molecule (NCAM) (Genetex, Irvine, CA, USA; 1:3000 dilution), surfactant protein‐A (SP‐A) (Novocastra Leica Biosystems, Wetzlar, Germany; 1:200 dilution), synaptophysin (Abcam, Cambridge, MA, USA; 1:100 dilution) and thyroid transcription factor‐1 (TTF‐1) (Dako, Tokyo, Japan; 1:100 dilution). The immunohistochemical signal was revealed using an Envision+ (Dako, Tokyo, Japan) system, as previously reported . Positive and negative controls were used for each marker.…”

“…The immunohistochemical signal was revealed using an Envision+ (Dako, Tokyo, Japan) system, as previously reported. 5 Positive and negative controls were used for each marker.…”

Ion Channels as Therapeutic Targets in High Grade Gliomas

“…Another neuroleptic agent, fluspirilene causes decreased cell viability, p-STAT expression and dose-dependent neurosphere formation in GSCs and GBM cell lines [ 109 ]. The efficacy of repurposing calcium channel blockers has also been demonstrated in other cancers; pimozide and penfluridol are effective in decreasing the viability in retinoblastoma and breast cancer cells [ 135 ] and disrupts cell cycle activity in pancreatic cancer cell lines [ 136 ].…”

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

“…To prevent culture‐induced drift, patient‐derived GSCs were generated from the surgical samples of primary GBM (Figure ). Cells were cultured in serum‐free DMEM/F12 supplemented with B21, 1% GlutaMAX™‐I, 20 ng/mL of epidermal growth factor, and 20 ng/mL of b‐FGF, as previously described 19 …”