Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons

dc.contributor.authorBehrouzi, Adib
dc.contributor.authorXia, Hanyu
dc.contributor.authorThompson, Eric L.
dc.contributor.authorKelley, Mark R.
dc.contributor.authorFehrenbacher, Jill C.
dc.contributor.departmentPharmacology and Toxicology, School of Medicineen_US
dc.date.accessioned2023-05-02T09:41:12Z
dc.date.available2023-05-02T09:41:12Z
dc.date.issued2022-02-08
dc.description.abstractCisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationBehrouzi A, Xia H, Thompson EL, Kelley MR, Fehrenbacher JC. Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons. Int J Mol Sci. 2022;23(3):1909. Published 2022 Feb 8. doi:10.3390/ijms23031909en_US
dc.identifier.urihttps://hdl.handle.net/1805/32745
dc.language.isoen_USen_US
dc.publisherMDPIen_US
dc.relation.isversionof10.3390/ijms23031909en_US
dc.relation.journalInternational Journal of Molecular Sciencesen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectCisplatinen_US
dc.subjectDNA damageen_US
dc.subjectOxidative stressen_US
dc.subjectChemotherapy-induced peripheral neuropathyen_US
dc.subjectSensory neuronen_US
dc.subjectNeuropeptideen_US
dc.subjectNeurite outgrowthen_US
dc.subjectBase excision repairen_US
dc.titleOxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neuronsen_US
dc.typeArticleen_US
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