He Ling, Bhat Kruttika, Ioannidis Angeliki, Pajonk Frank
bioRxiv. 2023 Jan 20:2023.01.18.524632. doi: 10.1101/2023.01.18.524632.
Dopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.
Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescence and .
We report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells both and . Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis.
We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials.
Combination therapy of dopamine receptor antagonists with radiation have entered clinical trials against glioblastoma but the normal tissue toxicity of this combination has not been fully explored yet. Here we present evidence that some dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells either by protecting neural stem/progenitor cells from radiation or inducing an expansion of the stem cell pool, suggesting that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be further explored in clinical trials.
多巴胺受体拮抗剂是最初针对精神疾病开发的精神药物。我们最近将多巴胺受体拮抗剂鉴定为潜在的抗癌药物，其中一些已进入针对胶质母细胞瘤的临床试验。已知放疗会通过消除神经干/祖细胞以及随后神经发生的丧失，导致接受颅脑照射的患者出现认知障碍。
使用通过巢蛋白启动子驱动的增强型绿色荧光蛋白表达来报告神经干/祖细胞存在的转基因小鼠，在成球试验、流式细胞术和免疫荧光中评估多巴胺受体拮抗剂单独或与辐射联合对小鼠神经干/祖细胞的影响。
我们报告说，几种多巴胺受体拮抗剂对神经干/祖细胞均表现出性别依赖性效应。单独使用或与辐射联合使用的羟嗪、三氟拉嗪、氨磺必利、奈莫必利或喹硫平可显著增加雌性神经球中神经干/祖细胞的数量，但对雄性小鼠则无此作用。多巴胺受体拮抗剂要么保护神经干/祖细胞免受辐射，要么扩大干细胞池，因此表明这种针对胶质母细胞瘤的联合治疗不会通过增加神经干/祖细胞的消除以及随后神经发生的丧失来增加辐射诱导的认知衰退。
我们得出结论多巴胺受体拮抗剂与辐射联合治疗可能存在一个治疗窗口，使其成为一种针对胶质母细胞瘤的新型联合治疗方法。这种联合治疗的正常组织毒性可能因年龄和性别而异，在设计临床试验时应予以考虑。
多巴胺受体拮抗剂与辐射的联合治疗已进入针对胶质母细胞瘤的临床试验，但这种联合治疗的正常组织毒性尚未得到充分探索。在这里，我们提供证据表明，一些多巴胺受体拮抗剂通过保护神经干/祖细胞免受辐射或诱导干细胞池扩张而对神经干/祖细胞表现出性别依赖性效应，这表明这种针对胶质母细胞瘤的联合治疗不会通过增加神经干/祖细胞的消除以及随后神经发生的丧失来增加辐射诱导的认知衰退。这种联合治疗的正常组织毒性可能因年龄和性别而异，应在临床试验中进一步探索。
