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A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation

Jiang, J and Belikova, NA and Hoye, AT and Zhao, Q and Epperly, MW and Greenberger, JS and Wipf, P and Kagan, VE (2008) A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation. International Journal of Radiation Oncology Biology Physics, 70 (3). 816 - 825. ISSN 0360-3016

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Abstract

Purpose: To evaluate the in vitro radioprotective effect of the mitochondria-targeted hemigramicidin S-conjugated 4-amino-2,2,6,6-tetramethyl-piperidine-N-oxyl (hemi-GS-TEMPO) 5-125 in γ-irradiated mouse embryonic cells and adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells BEAS-2B and explore the mechanisms involved in its radioprotective effect. Methods and Materials: Cells were incubated with 5-125 before (10 minutes) or after (1 hour) γ-irradiation. Superoxide generation was determined by using dihydroethidium assay, and lipid oxidation was quantitated by using a fluorescence high-performance liquid chromatography-based Amplex Red assay. Apoptosis was characterized by evaluating the accumulation of cytochrome c in the cytosol and externalization of phosphatidylserine on the cell surface. Cell survival was measured by means of a clonogenic assay. Results: Treatment (before and after irradiation) of cells with 5-125 at low concentrations (5, 10, and 20 μm) effectively suppressed γ-irradiation-induced superoxide generation, cardiolipin oxidation, and delayed irradiation-induced apoptosis, evaluated by using cytochrome c release and phosphatidylserine externalization. Importantly, treatment with 5-125 increased the clonogenic survival rate of γ-irradiated cells. In addition, 5-125 enhanced and prolonged γ-irradiation-induced G2/M phase arrest. Conclusions: Radioprotection/mitigation by hemi-GS-TEMPO likely is caused by its ability to act as an electron scavenger and prevent superoxide generation, attenuate cardiolipin oxidation in mitochondria, and hence prevent the release of proapoptotic factors from mitochondria. Other mechanisms, including cell-cycle arrest at the G2/M phase, may contribute to the protection. © 2008 Elsevier Inc. All rights reserved.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Jiang, Jjjf73@pitt.eduJJF73
Belikova, NA
Hoye, AT
Zhao, Q
Epperly, MW
Greenberger, JSjoelg@pitt.eduJOELG
Wipf, Ppwipf@pitt.eduPWIPF
Kagan, VEkagan@pitt.eduKAGAN
Date: 1 March 2008
Date Type: Publication
Journal or Publication Title: International Journal of Radiation Oncology Biology Physics
Volume: 70
Number: 3
Page Range: 816 - 825
DOI or Unique Handle: 10.1016/j.ijrobp.2007.10.047
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0360-3016
MeSH Headings: Animals; Apoptosis--drug effects; Cardiolipins--metabolism; Cell Division--drug effects; Cell Division--physiology; Cell Survival--drug effects; Cell Survival--physiology; Cells, Cultured; Cyclic N-Oxides--metabolism; Cyclic N-Oxides--pharmacology; Cytochromes c--secretion; Embryonic Stem Cells--drug effects; Embryonic Stem Cells--metabolism; Embryonic Stem Cells--radiation effects; Ethidium--metabolism; G2 Phase--drug effects; G2 Phase--physiology; Gamma Rays; Humans; Mice; Mitochondria--drug effects; Mitochondria--metabolism; Phosphatidylserines--secretion; Polyethylene Glycols--pharmacology; Radiation Injuries--prevention & control; Reactive Oxygen Species--metabolism; Superoxide Dismutase--pharmacology; Superoxides--metabolism; Time Factors
Other ID: NLM NIHMS42294, NLM PMC2527544
PubMed Central ID: PMC2527544
PubMed ID: 18262096
Date Deposited: 22 Jul 2013 18:18
Last Modified: 23 Nov 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/19343

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