title: Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators.
abstract: OBJECTIVE
  To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA.
authors.forename: Jean-Claude M
authors.initials: JC
authors.lastname: Rwigema
authors.forename: Barbara
authors.initials: B
authors.lastname: Beck
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Alexander
authors.initials: A
authors.lastname: Doemling
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Donna
authors.initials: D
authors.lastname: Shields
authors.forename: Julie P
authors.initials: JP
authors.lastname: Goff
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon
authors.forename: Marie-Céline
authors.initials: MC
authors.lastname: Frantz
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Yulia
authors.initials: Y
authors.lastname: Tyurina
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects*; D004249:DNA Damage; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000528:radiation effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000494:pharmacology; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000401:mortality; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D014916:Whole-Body Irradiation
chemical_list: C559766:BEB55 compound; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; C544775:JP4-039; C559767:MCF201-89; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents; D013843:Thiazines; D016159:Tumor Suppressor Protein p53; D019001:Nitric Oxide Synthase