Abstract
Cisplatin 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.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a very common ailment of cancer patients and survivors [1] and is defined by the presence of one or more of the following symptoms starting in the hands and feet: dysesthesia, numbness, sharp stabbing or burning pain, hypersensitivity to cold, and loss of reflexes
We previously demonstrated that APE1/Ref-1 knockdown exacerbates the neuronal effects of cisplatin and that overexpression of APE1/Ref-1 rescues the neurons [7,21,22], suggesting that oxidative DNA damage mediates, at least in part, the deleterious effects of cisplatin on neuronal function
Cellular exposure to cisplatin causes the formation of platin-DNA crosslinks and the generation of reactive oxygen species (ROS) [22,30–32], producing oxidative DNA damage that is primarily repaired by the base excision repair (BER) pathway [33]
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a very common ailment of cancer patients and survivors [1] and is defined by the presence of one or more of the following symptoms starting in the hands and feet: dysesthesia, numbness, sharp stabbing or burning pain, hypersensitivity to cold, and loss of reflexes. Work in cancer cells has demonstrated that the presence of oxidative DNA lesions alone can alter gene transcription [24–27]; additional work has shown that the binding of enzymes critical for BER can elicit changes in transcription that could have variable effects on gene transcription [28,29]. Inhibition of OGG1 glycosylase activity by the small molecule, TH5487, prevents inflammatory gene expression changes induced by cellular exposure to TNFα [28] In these studies, we expand on our previous findings to identify the relative roles of the major glycosylase required for 8oxo-dG lesion removal, OGG1, and APE1/Ref-1 on mitigating the damage to sensory neurons induced by cisplatin. Inhibition of the BER enzymes appears to exacerbate the effects of cisplatin to facilitate the desensitization of neuropeptide release from sensory neurons These data support a role for oxidative DNA damage, and 8oxo-dG formation, as a mediator of cisplatin-induced neurotoxicity
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