BACKGROUND: Histone modifications and DNA methylation are two major factors in 
epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are 
known to exert radiosensitizing effects, there have only been a few studies thus 
far concerning the role of DNA methyltransferase (DNMT) inhibitors as 
radiosensitizers. The principal objective of this study was to evaluate the 
effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, 
and to elucidate the mechanisms relevant to that process.
METHODS: A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to 
radiation with or without six DNMT inhibitors (5-azacytidine, 
5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and 
psammaplin A) for 18 hours prior to radiation, after which cell survival was 
evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow 
cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via 
Western blotting. Expression of γH2AX, a marker of radiation-induced DNA 
double-strand break, was examined by immunocytochemistry.
RESULTS: Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine 
radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A 
increased the sub-G1 fraction of A549 cells, as compared to cells exposed to 
radiation alone. Prolongation of γH2AX expression was observed in the cells 
treated with DNMT inhibitors prior to radiation as compared with those treated 
by radiation alone.
CONCLUSIONS: Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce 
radiosensitivity in both A549 and U373MG cell lines, and suggest that this 
effect might be associated with the inhibition of DNA repair.