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GS-nitroxide (JP4-039)-mediated radioprotection of human fanconi anemia cell lines

Bernard, ME and Kim, H and Berhane, H and Epperly, MW and Franicola, D and Zhang, X and Houghton, F and Shields, D and Wang, H and Bakkenist, CJ and Frantz, MC and Forbeck, EM and Goff, JP and Wipf, P and Greenberger, JS (2011) GS-nitroxide (JP4-039)-mediated radioprotection of human fanconi anemia cell lines. Radiation Research, 176 (5). 603 - 612. ISSN 0033-7587

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Fanconi anemia (FA) is an inherited disorder characterizedby defective DNA repair and cellular sensitivity to DNAcrosslinking agents. Clinically, FA is associated with highrisk for marrow failure, leukemia and head and necksquamous cell carcinoma (HNSCC). Radiosensitivity in FApatients compromises the use of total-body irradiation forhematopoietic stem cell transplantation and radiationtherapy for HNSCC. A radioprotector for the surroundingtissue would therefore be very valuable during radiotherapyfor HNSCC. Clonogenic radiation survival curves weredetermined for pre- or postirradiation treatment with theparent nitroxide Tempol or JP4-039 in cells of four FApatient-derived cell lines and two transgene-correctedsubclonal lines. FancG-/- (PD326) and FancD2-/- (PD20F)patient lines were more sensitive to the DNA crosslinkingagent mitomycin C (MMC) than their transgene-restoredsubclonal cell lines (both P , 0.0001). FancD2-/- cells weremore radiosensitive than the transgene restored subclonalcell line (n2.0 6 0.7 and 4.7 6 2.2, respectively, P 0.03).In contrast, FancG-/- cells were radioresistant relative to thetransgene-restored subclonal cell line (n 9.4 6 1.5 and 2.26 05, respectively, P0.001). DNA strand breaks measuredby the comet assay correlated with radiosensitivity. Celllines from a Fanc-C and Fanc-A patients showed radiosensitivitysimilar to that of Fanc-D2-/- cells. A fluorophoretaggedJP4-039 (BODIPY-FL) analog targeted the mitochondriaof the cell lines. Preirradiation or postirradiationtreatment with JP4-039 at a lower concentration thanTempol significantly increased the radioresistance andstabilized the antioxidant stores of all cell lines. Tempolincreased the toxicity of MMC in FancD2-/- cells. These dataprovide support for the potential clinical use of JP4-039 fornormal tissue radioprotection during chemoradiotherapy inFA patients. © 2011 by Radiation Research Society.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bernard, ME
Kim, H
Berhane, H
Epperly, MW
Franicola, D
Zhang, Xxichen@pitt.eduXICHEN
Houghton, F
Shields, D
Wang, Hhow8@pitt.eduHOW80000-0003-0477-2908
Bakkenist, CJcjb38@pitt.eduCJB38
Frantz, MC
Forbeck, EM
Goff, JP
Wipf, Ppwipf@pitt.eduPWIPF
Greenberger, JSjoelg@pitt.eduJOELG
Date: 1 November 2011
Date Type: Publication
Journal or Publication Title: Radiation Research
Volume: 176
Number: 5
Page Range: 603 - 612
DOI or Unique Handle: 10.1667/rr2624.1
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0033-7587
MeSH Headings: Biological Transport; Cell Line; Clone Cells; DNA Breaks, Double-Stranded--drug effects; DNA Breaks, Double-Stranded--radiation effects; Fanconi Anemia--pathology; Fanconi Anemia Complementation Group D2 Protein--deficiency; Fanconi Anemia Complementation Group G Protein--deficiency; Glutathione--metabolism; Humans; Mitochondria--drug effects; Mitochondria--metabolism; Mitochondria--radiation effects; Mitomycin--pharmacology; Nitrogen Oxides--metabolism; Nitrogen Oxides--pharmacology; Radiation-Protective Agents--metabolism; Radiation-Protective Agents--pharmacology; Transgenes--genetics
Other ID: NLM NIHMS334619, NLM PMC3209664
PubMed Central ID: PMC3209664
PubMed ID: 21939290
Date Deposited: 28 May 2013 14:52
Last Modified: 26 Jan 2021 19:58


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