Investigation of radiosensitivity enhanced by inflammatory responses after irradiation based on a cell-killing model considering non-targeted effects

Takahashi, Rei*; Saga, Ryo*; Matsuya, Yusuke  ; Hasegawa, Kazuki*; Fukui, Roman*; Hosokawa, Yoichiro*

Inflammatory responses after irradiation induce antioxidant activity, leading to radioresistance in cancer cells. In our previous study, it was found that a hyaluronan synthesis inhibitor (4-MU) can suppress inflammatory responses, however the underlying mechanisms are still unknown. In this study, we aimed to clarify the radiosensitization mechanism induced by 4-MU in the application of cell-killing models. In terms of in vitro experiments, cultured human fibrosarcoma cells were exposed to X-rays in presence of 100 M 4-MU and scavenger of intercellular signalling (1% DMSO, 40 M c-PTIO), and we measured the relation between dose and cell viability by means of colony assay. The experimental results were also interpreted by using integrated cell-killing model which has been developed so as to consider non-targeted effects. From the experiments, it was found that a combination of 4-MU treatment and irradiation significantly reduced the cell survival. This reduced viability was suppressed in the presence of DMSO or c-TPIO. Meanwhile, the model analysis showed such an increase of cell-killing is predominantly attributed by non-targeted effects. These results suggest that the radiosensetization promoted by 4-MU treatment is predominantly attributed to the accumulation in non-targeted effects.