Nitric Oxide Radicals Choreograph a Radioadaptive Response

Abstract

The reduced biological effects of radiation exposure seen in cells after conditioning exposures to a low dose or at a low-dose rate (i.e., the acquisition of resistance against high-dose radiation) is called the "radioadaptive response" and many studies concerning this phenomenon have been reported since the 1980s. Radioadaptive responses have been observed using various end points, such as chromosomal aberrations, mutations, and clonogenic survival. However, the mechanisms of the radioadaptive response are not fully known. Here, we show that radiation-induced nitric oxide (NO) radicals contribute to the induction of radioresistance as determined by cell survival after a subsequent high-dose exposure. An accumulation of inducible NO synthase was produced, and the concentration of nitrite in the culture medium increased when cells were exposed to gamma-rays at a low-dose rate or to X-rays for a low dose followed by an acute high-dose X-irradiation. In addition, the induction of radioresistance was not observed in the presence of an inhibitor of inducible NO synthase or a scavenger of NO radicals. Moreover, radioresistance was observed when cultures were treated with a NO radical-generating agent. These findings suggest that NO radicals are an initiator of the radioadaptive response.