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


ABSTRACT: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules.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).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).Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.

SUBMITTER: Rwigema JC 

PROVIDER: S-EPMC3104115 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Rwigema Jean-Claude M JC   Beck Barbara B   Wang Wei W   Doemling Alexander A   Epperly Michael W MW   Shields Donna D   Goff Julie P JP   Franicola Darcy D   Dixon Tracy T   Frantz Marie-Céline MC   Wipf Peter P   Tyurina Yulia Y   Kagan Valerian E VE   Wang Hong H   Greenberger Joel S JS  

International journal of radiation oncology, biology, physics 20110413 3


<h4>Purpose</h4>To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules.<h4>Methods and materials</h4>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  ...[more]

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