Two Strategies for the Development of Mitochondrion-Targeted Small Molecule Radiation Damage Mitigators

Journal Article · Fri Jul 01 00:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2011.01.059· OSTI ID:21587561

Rwigema, Jean-Claude M ^[1]; Beck, Barbara ^[2]; Wei, Wang ^[3]; Doemling, Alexander ^[3]; Epperly, Michael W ^[1]; Shields, Donna; Goff, Julie P; Franicola, Darcy; Dixon, Tracy ^[1]; Frantz, Marie-Celine ^[4]; Wipf, Peter ^[4]; Tyurina, Yulia ^[5]; Kagan, Valerian E ^[6]; Wang, Hong ^[7]

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1. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
2. Morphochem AG, Muenchen (Germany)
3. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
4. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
5. Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
6. Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)
7. Dept. of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (United States)

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{sup +/+} and p53{sup -/-} 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{sup +/+} (p = 0.0396 and p = 0.0071, respectively) and p53{sup -/-} cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53{sup -/-} 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.

• OSTI ID: 21587561
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 80, Issue 3; Other Information: DOI: 10.1016/j.ijrobp.2011.01.059; PII: S0360-3016(11)00233-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
BONE MARROW
DRUGS
MICE
MITOCHONDRIA
NITRIC OXIDE
PEPTIDES
RADIATION INJURIES
WHOLE-BODY IRRADIATION
ANIMAL TISSUES
ANIMALS
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
BODY
CELL CONSTITUENTS
CHALCOGENIDES
DISEASES
EXTERNAL IRRADIATION
HEMATOPOIETIC SYSTEM
INJURIES
IRRADIATION
MAMMALS
NITROGEN COMPOUNDS
NITROGEN OXIDES
ORGANIC COMPOUNDS
ORGANS
OXIDES
OXYGEN COMPOUNDS
PROTEINS
RADIATION EFFECTS
RODENTS
VERTEBRATES