title: Role of platinum DNA damage-induced transcriptional inhibition in chemotherapy-induced neuronal atrophy and peripheral neurotoxicity.
abstract: Platinum-based anticancer drugs cause peripheral neurotoxicity by damaging sensory neurons within the dorsal root ganglia (DRG), but the mechanisms are incompletely understood. The roles of platinum DNA binding, transcription inhibition and altered cell size were investigated in primary cultures of rat DRG cells. Click chemistry quantitative fluorescence imaging of RNA-incorporated 5-ethynyluridine showed high, but wide ranging, global levels of transcription in individual neurons that correlated with their cell body size. Treatment with platinum drugs reduced neuronal transcription and cell body size to an extent that corresponded to the amount of preceding platinum DNA binding, but without any loss of neuronal cells. The effects of platinum drugs on neuronal transcription and cell body size were inhibited by blocking platinum DNA binding with sodium thiosulfate, and mimicked by treatment with a model transcriptional inhibitor, actinomycin D. In vivo oxaliplatin treatment depleted the total RNA content of DRG tissue concurrently with altering DRG neuronal size. These findings point to a mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. DRG neurons may be particularly vulnerable to this mechanism of toxicity because of their requirements for high basal levels of global transcriptional activity. Findings point to a new stepwise mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. Dorsal root ganglion neurons may be particularly vulnerable to this neurotoxicity because of their high global transcriptional outputs, demonstrated in this study by click chemistry quantitative fluorescence imaging.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Johnson J
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ip
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Stephen M F
authors.initials: SM
authors.lastname: Jamieson
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McKeage
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004358:Drug Therapy; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010984:Platinum / Q000494:pharmacology*; D051381:Rats
chemical_list: D027682:Cation Transport Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D004247:DNA
keywords: DNA damage; DRG neurons; anticancer drug toxicity; global transcription; neuronal atrophy; neurotoxicity