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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Abstract

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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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Rwigema, JCM Beck, B Wang, W Doemling, A Epperly, MW Shields, D Goff, JP Franicola, D Dixon, T Frantz, MC Wipf, P pwipf@pitt.edu PWIPF Tyurina, Y yyt1@pitt.edu YYT1 Kagan, VE kagan@pitt.edu KAGAN Wang, H how8@pitt.edu HOW8 0000-0003-0477-2908 Greenberger, JS joelg@pitt.edu JOELG
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:	13 Jun 2021 00:55
URI:	http://d-scholarship-dev.library.pitt.edu/id/eprint/18756

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