title: ON01210.Na (Ex-RAD®) mitigates radiation damage through activation of the AKT pathway.
abstract: Development of radio-protective agents that are non-toxic is critical in light of ever increasing threats associated with proliferation of nuclear materials, terrorism and occupational risks associated with medical and space exploration. In this communication, we describe the discovery, characterization and mechanism of action of ON01210.Na, which effectively protects mouse and human bone marrow cells from radiation-induced damage both in vitro and in vivo. Our results show that treatment of normal fibroblasts with ON01210.Na before and after exposure to ionizing radiation provides dose dependent protection against radiation-induced damage. Treatment of mice with ON01210.Na prior to radiation exposure was found to result in a more rapid recovery of their hematopoietic system. The mechanistic studies described here show that ON01210.Na manifests its protective effects through the up-regulation of PI3-Kinase/AKT pathways in cells exposed to radiation. These results suggest that ON 01210.Na is a safe and effective radioprotectant and could be a novel agent for use in radiobiological disasters.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Marie
authors.initials: M
authors.lastname: Bonagura
authors.forename: Manoj
authors.initials: M
authors.lastname: Manair
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C520364:(E)-4-carboxystyryl-4-chlorobenzylsulfone, sodium salt; D011837:Radiation-Protective Agents; D054852:Small Molecule Libraries; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt