Abstract
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.
Highlights
Unrepaired DNA double strand breaks (DSBs) are signals for apoptosis [1] and drugs to induce DSBs or protect non-tumorous tissue from DSBs have been developed to treat cancers
All groups increased freezing over the four tones (p < 0.001) and four inter-stimulus intervals (ISI; p < 0.001, Figure 2B), indicating similar fear learning
To the best of our knowledge, this is the first study to examine the effects of systemic injections of DSB-altering agents commonly used during cancer treatment on learning, memory, and immediate early genes (IEGs) expression in both sexes
Summary
Unrepaired DNA double strand breaks (DSBs) are signals for apoptosis [1] and drugs to induce DSBs or protect non-tumorous tissue from DSBs have been developed to treat cancers. Amifostine (WR-2721) is metabolized into the active agent WR-1065, and protects cells from DSBs by scavenging free radicals, inducing cellular anoxia, and condensing DNA [2–4]. Recent evidence suggests that DSBs may induce immediate-early gene (IEG) expression [6, 7]. The precisely timed expression of IEGs is essential for learning and memory [8]. The fos family of genes, including fos proto-oncogene (cFos) and FosB, are IEGs important in www.oncotarget.com fear learning and memory [9]. CFos is transiently expressed, with low basal levels that rapidly increase upon stimulation, and return to baseline levels within hours [10]. FosB has low basal levels, though the truncated form (ΔFosB) accumulates over time and persists for weeks following a stimulus [11]. Hippocampal cFos and ΔFosB are essential for contextual learning and hippocampal synaptic plasticity [12, 13]. The mechanism underlying the rapid expression of IEGs is unclear
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