Abstract
Recent research shows that chemotherapy agents can be more toxic to healthy brain cells than to the target cancer cells. They cause a range of side effects, including memory loss and cognitive dysfunction that can persist long after the completion of treatment. This condition is known as chemo brain. The molecular and cellular mechanisms of chemo brain remain obscure. Here, we analyzed the effects of two cytotoxic chemotherapy drugs—cyclophosphamide (CPP) and mitomycin C (MMC) - on transcriptomic and epigenetic changes in the murine prefrontal cortex (PFC) and hippocampal regions. We for the first time showed that CPP and MMC treatments led to profound sex- and brain region-specific alterations in gene expression profiles. Gene expression changes were most prominent in the PFC tissues of female mice 3 weeks after MMC treatment, and the gene expression response was much greater for MCC than CPP exposure. MMC exposure resulted in oxidative DNA damage, evidenced by accumulation of 8-oxo-2′-deoxyguanosine (8-oxodG) and a decrease in the level of 8-oxodG repair protein OGG1 in the PFC of female animals 3 weeks after treatment. MMC treatment decreased global DNA methylation and increased DNA hydroxymethylation in the PFC tissues of female mice. The majority of the changes induced by chemotherapy in the PFC tissues of female mice resembled those that occur during the brain's aging processes. Therefore, our study suggests a link between chemotherapy-induced chemo brain and brain aging, and provides an important roadmap for future analysis.
Highlights
The recent report by the American Cancer Society showed that 14.1 million new cancer cases were diagnosed worldwide in 2012, and 8 million of those occurred in developed countries
We demonstrated that CPP and mitomycin C (MMC) treatment led to substantial noticeable sex- and brain region-specific alterations in gene expression profiles, oxidative DNA damage, and changes in global levels of cytosine DNA methylation and hydroxymethylation
The key findings of our study are: (i) chemotherapy altered the gene expression profiles in the murine prefrontal cortex (PFC) and hippocampus tissues; (ii) gene expression changes were most prominent in the PFC tissues of female animals 3 weeks after MMC treatment; (iii) the magnitude of gene expression response was much greater for MCC than CPP treatment; (iv) MMC treatment resulted in accumulation of 8-oxodG, decreased global DNA methylation, and increased DNA hydroxymethylation in the PFC tissues of female animals; and (v) the majority of the changes induced by MMC in the PFC tissues of female mice resembled those that occur during the aging processes
Summary
The recent report by the American Cancer Society showed that 14.1 million new cancer cases were diagnosed worldwide in 2012, and 8 million of those occurred in developed countries. It is projected that by 2030 newly diagnosed cancer cases will reach 21.7 million worldwide (http://www.cancer.org/research/ acsresearchupdates/more/10-must-know-2015-globalcancer-facts). The development of new chemotherapeutic agents and regimens for cancer therapy has led to increasing rates of survival in cancer patients and, it is important to ensure that cancer survivors suffer minimal side effects and have good quality of life. Recent research showed that chemotherapy agents were more toxic to healthy brain cells than to the cancer cells. Wefel and Schagen (2012), reported that with regard to breast cancer alone, more than 60 studies found various degrees of association between chemotherapy and cognitive impairments [5]
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