Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10899447 | Cancer Letters | 2015 | 5 Pages |
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 (O2â
- ) 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 O2â
- is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-α release. Addition of O2â
- 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 10âµM KO2 resulted in dramatically increased levels of TNF-α produced. These findings, together with our prior results, provide strong evidence that O2â
- and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-α release.
- ) 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 O2â
- is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-α release. Addition of O2â
- 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 10âµM KO2 resulted in dramatically increased levels of TNF-α produced. These findings, together with our prior results, provide strong evidence that O2â
- and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-α release.
Keywords
HNEDNPHBCANBTApoA-I4-Hydroxy-2-trans-nonenalDOXLPSBCIPnuclear factor κ-light-chain enhancer of activated B cellsKO2NF-κBO2−•2,4-dinitrophenylhydrazineBSADMSONO•ROSHydrogen peroxidebovine serum albuminALPApolipoprotein A-Ibicinchoninic acidNitro blue tetrazolium chloridetumor necrosis factor-alphaDoxorubicinDimethyl sulfoxideHydroxyl radicalSODBlood–brain barrierBBBSuperoxideSuperoxide dismutaseCancer chemotherapyTNF-αlipopolysaccharideMacrophagewild-typeNitric oxideH2O2protein carbonylReactive oxygen species•OH
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Authors
Jeriel T.R. Keeney, Sumitra Miriyala, Teresa Noel, Jeffrey A. Moscow, Daret K. St. Clair, D. Allan Butterfield,