Haloperidol Induced Cell Cycle Arrest and Apoptosis in Glioblastoma Cells

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.

Antiproliferative activity of CD44 siRNA-PEI-PEG nanoparticles in glioblastoma: involvement of AKT signaling

“…In addition, Papadopoulos et al . showed that alteration in the expression of CD24 and CD44 genes using haloperidol in GBM U87MG, U251, and T98 cell lines induces M/G2 cell cycle arrest and increases the population of cells in the G0/G1 phase ( 25 ).…”

Mechanisms of Cell Cycle Arrest and Apoptosis in Glioblastoma

“…Recently, antipsychotic drugs have emerged as potential anticancer agents, whereas 12 candidate substances have been identified [117,118]. Treatment with haloperidol, in particular, has been reported to promote G2/M cell cycle arrest in the U87 GBM cell line [119].…”

Repurposing Antipsychotics for Cancer Treatment

“…However, haloperidol is a non-selective inhibitor for D2 receptors and also has antimuscarinic, anti-adrenergic (a1), and antihistaminic (H1) effects [ 10 , 11 ]. Except for its use as an antipsychotic drug, haloperidol has also been found, mainly at an experimental level, to have anti-neoplastic, anti-fungal, anti-viral, and immunomodulatory properties [ 12 , 13 , 14 , 15 ].…”

“…Regarding its antineoplastic properties, haloperidol has been found to induce autophagy, apoptosis, and cell cycle arrest [ 15 , 16 ]. In an in vitro study, Papadopoulos et al observed that glioblastoma (GBM) U87, U251, and T-98 cell lines are sensitive to haloperidol.…”

“…Additionally, they found that haloperidol induces G 2 /M cell inhibition, increases the percentage of cells found in sub G 0 /G 1 phase, and promotes caspase-8 activation, the latter suggesting the induction of apoptosis. Except for haloperidol’s effect in the cell cycle progression, they observed that haloperidol decreases the expression of CD24, CD44 adhesion molecules, inhibits wound-generated cell migration, and enhances GBM cell death when combined with the alkylating agent temozolomide (TMZ) and radiotherapy [ 15 ]. The synergistic effect of haloperidol in the treatment of GBM with TMZ was also supported in another study [ 17 ].…”