Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.
Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.
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DOI：
10.18632/oncotarget.28180
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Raber J
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文献类型：
--
作者：
Boutros SW;Krenik D;Holden S;Unni VK;Raber J
DNA双链断裂（DSB）在癌症的背景下已经被高度研究，因为DSB可以导致细胞凋亡或肿瘤发生。在癌症治疗期间，几种药物被广泛用于靶向DSB。氨磷汀（WR-2721）和依托泊苷是两种常用的药物：氨磷汀减少DSB，而依托泊苷增加DSB。最近，一个新的作用DSB在立即早期基因表达，学习和记忆已被提出。在没有混杂因素的情况下，尚未评估氨磷汀和依托泊苷对学习和记忆的影响。此外，这些药物的性别依赖性影响尚未报道。我们给3-4个月大的雄性和雌性C57 Bl/6 J小鼠在恐惧条件训练之前或之后施用氨磷汀或依托泊苷，并评估学习、记忆和立即早期基因。我们观察到性别依赖性基线和药物诱导的差异，女性表达的cFos和FosB水平高于男性。这些都受到阿米福汀和依托泊苷。训练后注射氨磷汀影响长期的背景恐惧记忆;依托泊苷影响背景和线索恐惧记忆。这些数据支持DSB有助于学习和记忆的假设，并且这些可能在常见治疗方案中的认知副作用中发挥作用。在考虑治疗计划时，性别依赖效应也突出了一个重要因素。
DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3–4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.