title: Superoxide induces protein oxidation in plasma and TNF-α elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy.
abstract: Chemotherapy-induced cognitive impairment (CICI) is a quality of life-altering consequence of chemotherapy experienced by a large percentage of cancer survivors. Approximately half of FDA-approved anti-cancer drugs are known to produce ROS. Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, generates superoxide (O2(-)•) via redox cycling. Our group previously demonstrated that Dox, which does not cross the BBB, induced oxidative damage to plasma proteins leading to TNF-α elevation in the periphery and, subsequently, in brain following cancer chemotherapy. We hypothesize that such processes play a central role in CICI. The current study tested the notion that O2(-)• is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-α release. Addition of O2(-)• as the potassium salt (KO2) to plasma resulted in significantly increased oxidative damage to proteins, indexed by protein carbonyl (PC) and protein-bound HNE levels. We then adapted this protocol for use in cell culture. Incubation of J774A.1 macrophage culture using this KO2-18crown6 protocol with 1 and 10 µM KO2 resulted in dramatically increased levels of TNF-α produced. These findings, together with our prior results, provide strong evidence that O2(-)• and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-α release.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Jeriel T R
authors.initials: JT
authors.lastname: Keeney
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.affiliation: Department of Pediatrics, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Moscow
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536-0305, USA; Department of Radiation Medicine, University of Kentucky, Lexington, KY 40506-9983, USA.
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000447:Aldehydes / Q000097:blood; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001798:Blood Proteins / Q000378:metabolism*; D002460:Cell Line; D003072:Cognition Disorders / Q000097:blood / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000209:etiology*; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects*; D013481:Superoxides / Q000633:toxicity*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000447:Aldehydes; D000903:Antibiotics, Antineoplastic; D001798:Blood Proteins; D014409:Tumor Necrosis Factor-alpha; C462359:tert-4-hydroxy-2-nonenal; D013481:Superoxides; C039316:potassium superoxide; D004317:Doxorubicin
keywords: Cancer chemotherapy; Chemotherapy induced cognitive impairment; Macrophage; Superoxide free radical and doxorubicin induced oxidative stress; Tumor necrosis factor-alpha