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. 2024 Dec:201:110562.
doi: 10.1016/j.radonc.2024.110562. Epub 2024 Sep 27.

Effects of dopamine receptor antagonists and radiation on mouse neural stem/progenitor cells

Ling He  1 , Kruttika Bhat  2 , Angeliki Ioannidis  2 , Frank Pajonk  3
Affiliations

Effects of dopamine receptor antagonists and radiation on mouse neural stem/progenitor cells

Ling He et al. Radiother Oncol. 2024 Dec.

Abstract

Background: Dopamine receptor antagonists have recently been identified as potential anti-cancer agents in combination with radiation, and a first drug of this class is in clinical trials against pediatric glioma. Radiotherapy causes cognitive impairment primarily by eliminating neural stem/progenitor cells and subsequent loss of neurogenesis, along with inducing inflammation, vascular damage, and synaptic alterations. Here, we tested the combined effects of dopamine receptor antagonists and radiation on neural stem/progenitor cells.

Methods: Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of EGFP, the effects of dopamine receptor antagonists alone or in combination with radiation on neural stem/progenitor cells were assessed in sphere-formation assays, extreme limiting dilution assays, flow cytometry and real-time PCR in vitro and in vivo in both sexes.

Results: We report that hydroxyzine and trifluoperazine exhibited sex-dependent effects on murine newborn neural stem/progenitor cells in vitro. In contrast, amisulpride, nemonapride, and quetiapine, when combined with radiation, significantly increased the number of neural stem/progenitor cells in both sexes. In vivo, trifluoperazine showed sex-dependent effects on adult neural stem/progenitor cells, while amisulpride demonstrated significant effects in both sexes. Further, amisulpride increased sphere forming capacity and stem cell frequency in both sexes when compared to controls.

Conclusion: We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exists, making it a novel combination therapy against glioblastoma. Normal tissue toxicity following this treatment scheme likely differs depending on age and sex and should be taken into consideration when designing clinical trials.

Keywords: Combination therapy; Dopamine receptor antagonists; Gender difference; Neural stem/progenitor cells; Radiation.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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