Predictive DNA damage signaling for low‑dose ionizing radiation

Abstract

Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low-dose radiation-sensitive markers. The HuT 78 and IM-9 cell lines were irradiated in a concentration-dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration-dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sub-lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub-lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML-277, pifithrin-α, and nutlin-3a were evaluated for their ability to modulate radiation-induced cell death. The use of BML-277 led to a decrease in radiation-induced p-CHK2 and γH2AX levels and mitigated radiation-induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation-sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.