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Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators

Rwigema, JCM and Beck, B and Wang, W and Doemling, A and Epperly, MW and Shields, D and Goff, JP and Franicola, D and Dixon, T and Frantz, MC and Wipf, P and Tyurina, Y and Kagan, VE and Wang, H and Greenberger, JS (2011) Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators. International Journal of Radiation Oncology Biology Physics, 80 (3). 860 - 868. ISSN 0360-3016

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Purpose: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules. Methods and Materials: We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/mdm4 protein complex inhibitor BEB55 to mitigate radiation effects by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3 and the human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell lines. The p53-dependent mechanism of action was tested with p53+/+ and p53-/- murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected i.p. with JP4-039, MCF201-89, or BEB55 individually or in combination, after receiving 9.5 Gy total body irradiation (TBI). Results: Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all three compounds increased the survival of 32D cl 3 (p = 0.0021, p = 0.0011, p = 0.0038, and p = 0.0073, respectively) and IB3 cells (p = 0.0193, p = 0.0452, p = 0.0017, and p = 0.0019, respectively) significantly relative to that of control irradiated cells. KM101 cells were protected by individual drugs (p = 0.0007, p = 0.0235, p = 0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53+/+ (p = 0.0396 and p = 0.0071, respectively) and p53 -/- cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53-/- cells. Drugs administered individually or as a mixtures of all three after TBI significantly increased mouse survival (p = 0.0234, 0.0009, 0.0052, and 0.0167, respectively). Conclusion: Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice. © 2011 Elsevier Inc.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Rwigema, JCM
Beck, B
Wang, W
Doemling, A
Epperly, MW
Shields, D
Goff, JP
Franicola, D
Dixon, T
Frantz, MC
Wipf, Ppwipf@pitt.eduPWIPF
Tyurina, Yyyt1@pitt.eduYYT1
Kagan, VEkagan@pitt.eduKAGAN
Wang, Hhow8@pitt.eduHOW80000-0003-0477-2908
Greenberger, JSjoelg@pitt.eduJOELG
Date: 1 July 2011
Date Type: Publication
Journal or Publication Title: International Journal of Radiation Oncology Biology Physics
Volume: 80
Number: 3
Page Range: 860 - 868
DOI or Unique Handle: 10.1016/j.ijrobp.2011.01.059
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0360-3016
MeSH Headings: Animals; Cell Line--drug effects; Cell Line--radiation effects; Cell Survival--drug effects; DNA Damage; Enzyme Inhibitors; Female; Humans; Imidazoles--pharmacology; Indoles--pharmacology; Mice; Mice, Inbred C57BL; Mitochondria--drug effects; Mitochondria--radiation effects; Nitric Oxide Synthase--antagonists & inhibitors; Nitrogen Oxides--pharmacology; Radiation Dosage; Radiation Injuries, Experimental--drug therapy; Radiation Injuries, Experimental--mortality; Radiation-Protective Agents--pharmacology; Thiazines--pharmacology; Tumor Suppressor Protein p53--antagonists & inhibitors; Whole-Body Irradiation
Other ID: NLM NIHMS270260, NLM PMC3104115
PubMed Central ID: PMC3104115
PubMed ID: 21493014
Date Deposited: 28 May 2013 15:17
Last Modified: 22 Jun 2021 13:56


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