• 2019-07
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  • 2020-07
  • 2020-08
  • 2021-03
  • Variations in DNA repair genes seem to be


    Variations in DNA repair genes seem to be related to cancer risk; in particular, some studies reported the association between genes in the Omadacycline structure excision repair (BER) pathway, such as 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease (APE1/APEX1), and risk of developing tumors [73]. Since patients with high levels of DNA damage before treatment seem to be more prone to develop cognitive impairment, polymorphisms of genes associated with low efficiency BER mechanisms have been proposed to be associated with CICI [74]. OGG1 is a bifunctional glycosylase involved in the BER process. One of the most frequent mutagenic DNA alterations that occur during oxidative DNA damage is the formation of 8-oxoguanine (8-oxoG). OGG1, thanks to its dual lyase and glycosylase activity, removes 8-oxoG base cutting the DNA backbone [75]. OGG1 activity is present in neurons and glial cells in several CNS regions, and its levels and activity are found to be increased after neuronal injuries linked to the presence of oxidative stress, such as ischemia and reperfusion, confirming its role in repairing neuronal oxidative damage [76]. Moreover, the decreased levels of OGG1 are related to the aging process and AD [77,78]. APEX1 gene encodes for DNA- (apurinic or apyrimidinic site) lyase. Apurinic/apyrimidinic (AP) sites are consequences of spontaneous lysis of the phosphodiester linkage, DNA damage or the excision of abnormal bases by DNA endonuclease. In the presence of oxidative stress, APEX1 is also involved in the activation of transcription factors through a redox mechanism [79]. Furthermore, increased APEX1 staining has been reported in hippocampus, surrounding temporal cortex and cerebral cortex in AD brains [80]. These studies suggest that APEX1 increases in AD in response to oxidative stress to repair oxidative DNA damage and to regulate the expression of transcriptional factors induced by oxidative stress [81]. These findings suggest that OGG1 and APEX1 are important to protect DNA from oxidative damage, and that a genetic deficit in those genes potentially could be linked to an increased risk to developing cognitive impairment before and after chemotherapy due to neuronal loss.
    Telomere shortening accelerates aging and cognitive deficits after chemotherapy Telomeres are regions of repetitive nuclear base sequences at the end of chromosomes; these sequences shorten by 20–200 base pairs during each normal DNA replication of mitotic cells. When telomeres reach a critical length, the cell undergoes senescence and apoptosis [82]. The physiological shortening of telomeres is associated with aging processes, but several factors can affect the telomere shortening processes such as genetic variation, oxidative stress, chemotherapy or neurodegenerative disorders such as AD [83,84]. Telomere length also is crucial for cancer cells. Indeed, in 80% of human cancers, the immortal phenotype of cancer cells is due to an increase in telomerase activity; telomerase is an enzyme capable to rebuild telomeres which are not active in most normal somatic cells. For this reason, emerging studies aim to develop new anti-cancer approaches focusing on the telomere shortening process and telomerase activity in cancer cells [85]. Chemotherapy directed at telomerase can lead to telomere shortening in off-target cells, in addition to its effects on cancer cells, accelerating the aging process [86]. In CNS, neuronal cells are largely post-mitotic but glial cells are subjected to the telomere shortening process [87]. The notion of the acceleration of the aging process linked to telomere shortening after chemotherapy is another proposed mechanism for CICI onset.
    Oxidative stress and pro-inflammatory cytokines play important roles in mechanisms of CICI Oxidative stress and correlated mitochondrial damage often occur in cancer patients or survivors after treatment of chemotherapeutic agents and are considered as one of main candidate mechanisms of CICI [2,88]. Although some cancer patients reportedly may have high level of oxidative stress and cognitive impairment before chemotherapy, many chemotherapeutic agents are ROS-generating and are associated with DNA and protein damage in both the periphery and brain [2,3]. Immune responses follow the increase in oxidative stress, increasing pro-inflammatory cytokines locally and activate immune cells in brain. Superoxide (O2−) can increase the level of oxidative stress markers in mice plasma and activate macrophages with a large production of TNF-α after incubating plasma or macrophage culture with potassium superoxide [89]. As noted above, ROS also is an initiator of BBB disruption, triggering BBB oxidative damage, tight junction modification and matrix metalloproteinase activation [54]. Dexrazoxane, an iron chelator that can interfere with and decrease free radical formation by its putative antioxidant ability, is reportedly cardioprotective when it is administrated with Dox [90,91]. This study supports the notion that free oxidative damage is integral to CICI [2]. Protein oxidation, lipid peroxidation and dysfunctional BBB make drugs and cytokines easier to enter the brain, the organ which is more vulnerable to oxidative stress due to its high oxygen consumption rate and large presence of unsaturated fatty acid with associated labile allylic hydrogen atoms. Impaired mitochondria in brain secondary to chemotherapy-induced oxidative and nitrosative damage result in elevation of oxidative stress and eventual neuronal death, along with decreased antioxidant level and glucose dysmetabolism by inactivation of complex I [92,93]. Although not relevant to CICI directly since Dox does not cross the BBB, mitochondrial damage was found in Dox-treated neurons [94] and is associated with cognitive impairment in aging, traumatic brain injury, or neurodegenerative disorders such as PD or AD [[95], [96], [97]]. Accumulation of lipofuscin was also found in brain of Dox-treated mice brain along with altered autophagosomes [94].