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Fukui, Roman*; Saga, Ryo*; Matsuya, Yusuke; Tomita, Kazuo*; Kuwahara, Yoshikazu*; Ouchi, Kentaro*; Sato, Tomoaki*; Okumura, Kazuhiko*; Date, Hiroyuki*; Fukumoto, Manabu*; et al.
Scientific Reports (Internet), 12(1), p.1056_1 - 1056_12, 2022/01
Times Cited Count：10 Percentile：91.34(Multidisciplinary Sciences)Alive cancer cells after fractionated irradiations with 2 Gy X-rays per day for more than 30 days show clinically relevant radioresistant. Such radioresistance is experimentally interpreted to attributed to the increment of stem-like cell content. However, only an experimental approach cannot clarify the cell responses (DNA damage and cell death induction) of cancer stem cells, so the radioresistant mechanisms remain uncertain. In addition to the conventional cell experiments using radio-resistant cell lines established after fractionated irradiations, in this study we developed a mathematical model (so called integrated microdosimetric-kinetic (IMK) model) explicitly considering cancer stem-like cell content and DNA damage responses and investigated radioresistant mechanisms acquired after fractionated irradiations. The IMK model analysis suggested that the changes of stem-like cell fraction and DNA repair efficiency play important roles of radioresisitance acquired after irradiations. Considering these into the IMK model, we successfully reproduced the experimental survival of various cell lines and various irradiation conditions. This work would contribute to not only the precise understanding of the radioresistant mechanisms induced after irradiation but also predicting curative effects with high precision.
Takahashi, Rei*; Saga, Ryo*; Matsuya, Yusuke; Hasegawa, Kazuki*; Fukui, Roman*; Hosokawa, Yoichiro*
no journal, ,
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.
