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
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| Status: |
Published |
| Creators/Authors: |
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| 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: |
13 Jun 2021 01:55 |
| URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/19343 |
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