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.
Highlights
Protection from exposure to ionizing radiation (IR) has become an important issue due to ever increasing threats associated with proliferation of nuclear materials, terrorism and occupational risks associated with medical and space exploration [1,2]
Compound Screening and in vitro Activity To identify compounds that protect cells from the damaging effects of IR, we developed a cell-based screening assay in which normal diploid human fetal lung fibroblasts (HFL-1 cells) were treated for 24 hrs with various concentrations of compounds derived from a focused compound library developed in our laboratory to modulate the activity of mammalian kinases
Acute Radiation Syndrome (ARS) results from DNA damage caused by radiation in rapidly dividing cells of the bone marrow (BM), gastrointestinal tract (GI), skin, and neurological tissue [3,10,11,12]
Summary
Protection from exposure to ionizing radiation (IR) has become an important issue due to ever increasing threats associated with proliferation of nuclear materials, terrorism and occupational risks associated with medical and space exploration [1,2]. Due to the limited availability of radioprotective agents, we performed a screen of our small molecule chemical library [5] for compounds that protect cells from the damaging effects of IR using a high throughput cell based assay. From this screen, we have identified several compounds that effectively show radioprotective activity [6] and one of them, ON01210 (4-carboxystyrl-4chlorbenzysulfone), was found to have the most desirable characteristics for drug development. The same compound has been tested in mice to show a significant increase in survival rate when the compound is injected before exposure to gamma radiation [7]
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