title: Administration of ON 01210.Na after exposure to ionizing radiation protects bone marrow cells by attenuating DNA damage response.
abstract: BACKGROUND
  Ionizing radiation-induced hematopoietic injury could occur either due to accidental exposure or due to diagnostic and therapeutic interventions. Currently there is no approved drug to mitigate radiation toxicity in hematopoietic cells. This study investigates the potential of ON 01210.Na, a chlorobenzylsulfone derivative, in ameliorating radiation-induced hematopoietic toxicity when administered after exposure to radiation. We also investigate the molecular mechanisms underlying this activity.
  
  
  METHODS
  Male C3H/HeN mice (n = 5 mice per group; 6-8 weeks old) were exposed to a sub-lethal dose (5 Gy) of γ radiation using a ¹³⁷Cs source at a dose rate of 0.77 Gy/min. Two doses of ON 01210.Na (500 mg/kg body weight) were administered subcutaneously at 24 h and 36 h after radiation exposure. Mitigation of hematopoietic toxicity by ON 01210.Na was investigated by peripheral white blood cell (WBC) and platelet counts at 3, 7, 21, and 28 d after radiation exposure. Granulocyte macrophage colony forming unit (GM-CFU) assay was done using isolated bone marrow cells, and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) was performed on bone marrow sections at 7 d post-exposure. The DNA damage response pathway involving ataxia telangiectasia mutated (ATM) and p53 was investigated by Western blot in bone marrow cells at 7 d post-exposure.
  
  
  RESULTS
  Compared to the vehicle, ON 01210.Na treated mice showed accelerated recovery of peripheral WBC and platelet counts. Post-irradiation treatment of mice with ON 01210.Na also resulted in higher GM-CFU counts. The mitigation effects were accompanied by attenuation of ATM-p53-dependent DNA damage response in the bone marrow cells of ON 01210.Na treated mice. Both phospho-ATM and phospho-p53 were significantly lower in the bone marrow cells of ON 01210.Na treated than in vehicle treated mice. Furthermore, the Bcl2:Bax ratio was higher in the drug treated mice than the vehicle treated groups.
  
  
  CONCLUSIONS
  ON 01210.Na treatment significantly mitigated the hematopoietic toxicity induced by a sub-lethal radiation dose. Mechanistically, attenuation of ATM-p53 mediated DNA damage response by ON 01210.Na is contributing to the mitigation of radiation-induced hematopoietic toxicity.
authors.affiliation: Department of Biochemistry and Molecular & Cell Biology, Georgetown University Medical Center, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057-1468, USA.
authors.forename: Shubhankar
authors.initials: S
authors.lastname: Suman
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Kamal
authors.initials: K
authors.lastname: Datta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects* / Q000528:radiation effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D005720:Gamma Rays / Q000009:adverse effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011832:Radiation Injuries / Q000517:prevention & control*; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: C520364:(E)-4-carboxystyryl-4-chlorobenzylsulfone, sodium salt; D013449:Sulfonamides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor