Haloperidol Induced Cell Cycle Arrest and Apoptosis in Glioblastoma Cells.

Fotios Papadopoulos,Athanasios P Kyritsis,Evrysthenis Vartholomatos,Thomas Tsalios,Georgios S Markopoulos,Chrissa Sioka,Vasiliki Galani,George A Alexiou,Rafaela Isihou,Pericles Tsekeris

doi:10.3390/biomedicines8120595

Fotios Papadopoulos, Athanasios P Kyritsis + Show 8 more

Open Access

https://doi.org/10.3390/biomedicines8120595

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Journal: Biomedicines	Publication Date: Dec 11, 2020
Citations: 22	License type: CC BY 4.0

Affiliation: University of Ioannina

Abstract

Although several antipsychotic drugs have been shown to possess anticancer activities, haloperidol, a “first-generation” antipsychotic drug, has not been extensively evaluated for potential antineoplastic properties. The aim of this study was to investigate the antitumoral effects of haloperidol in glioblastoma (GBM) U87, U251 and T98 cell lines, and the effects of combined treatment with temozolomide (TMZ) and/or radiotherapy, using 4 Gy of irradiation. The viability and proliferation of the cells were evaluated with trypan blue exclusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis, using the annexin-propidium iodide (PI), and cell cycle, cluster of differentiation (CD) expression and caspase-8 activation were measured using flow cytometry. Treatment with haloperidol significantly reduced cell viability in U87, U251 and T98 GBM cell lines. Haloperidol induced apoptosis in a dose-dependent manner, inhibited cell migration and produced an alteration in the expression of CD24/CD44. The additional effect of haloperidol, combined with temozolomide and radiation therapy, increased tumor cell death. Haloperidol was observed to induce apoptosis and to increase caspase-8 activation. In conclusion, haloperidol may represent an innovative strategy for the treatment of GBM and further studies are warranted in glioma xenograft models and other malignancies.

Highlights

Glioblastoma (GBM) is the most aggressive glial brain tumor in adults, with a median life expectancy of 15 months, despite gross total excision, radiotherapy and temozolomide (TMZ)-based chemotherapy [1]
The present study demonstrated that haloperidol was an effective treatment for malignant glioma
Haloperidol induced the suppression of GBM cell growth, inhibited migration and

Summary

Introduction

Glioblastoma (GBM) is the most aggressive glial brain tumor in adults, with a median life expectancy of 15 months, despite gross total excision, radiotherapy and temozolomide (TMZ)-based chemotherapy [1]. Biomedicines 2020, 8, 595 in a patient with GBM, resulted in survival of 6.5 years [4]. Pimozide, another antipsychotic drug, was found to impair GBM cell growth and stem cell survival [5], and several other antipsychotic drugs, including thioridazine, remoxipride and MRJF4, a novel haloperidol metabolite II prodrug, have been tested in glioma cell-based experiments [6,7,8,9,10]. Haloperidol is a dopamine D2 receptor antagonist that was developed in the 1950s and belongs to the typical or ‘’first generation” antipsychotics [11]

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