Abstract
There is currently no FDA approved therapeutic agent for ARS mitigation post radiation exposure. Here we report that the small molecule YH250, which specifically antagonizes p300/catenin interaction, stimulates hematopoiesis in lethally or sublethally irradiated mice. A single administration of YH250 24 hours post irradiation can significantly stimulate HSC proliferation, improve survival and accelerate peripheral blood count recovery. Our studies suggest that promotion of the expansion of the remaining HSC population via stimulation of symmetric non-differentiative proliferation is at least part of the mechanism of action.
Highlights
Mass casualties due to accidental radiation exposure represent a serious threat to society
We first decided to investigate whether YH250 administration could enhance hematopoietic recovery after sublethal irradiation via expansion of the hematopoietic stem/progenitor population (HSPC)
YH250 treatment increased the percentage of bone marrow cells in S phase, suggesting an increase in cycling activated cells (S1B Fig)
Summary
Mass casualties due to accidental radiation exposure represent a serious threat to society. Radioprotective agents are partially successful given prior to radiation exposure post exposure they have limited utility. This motivated us to search for agents that could alleviate radiation damage post-exposure. It is preferable to achieve significant radiation mitigation up to 24 h after exposure. Acute radiation syndrome (ARS) after total body exposure to radiation describes an array of symptoms. Primarily of a hematopoietic nature occur at doses of less than 8Gy [1]. Universal lethality occurs at doses of more than 10Gy due to damage to the gastrointestinal (GI) tract [2]. Current medical countermeasures have limited efficacy and no FDA approved treatment to alleviate ARS or to effectively treat/protect first responders from ARS currently exists
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