Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
Research Institute for Biomedical Sciences, Tokyo University of Science.
Biol Pharm Bull. 2020 Mar 1;43(3):516-525. doi: 10.1248/bpb.b19-00976. Epub 2019 Dec 21.
It is therapeutically important to elucidate the factors involved in the radiation resistance of tumors. We previously showed that ATP is released from mouse melanoma B16 cells in response to γ-irradiation, but the role of adenosine, a metabolite of ATP, is still unclear. Here, we show that the adenosine A2B receptor is involved in DNA damage repair and radioresistance in mouse melanoma B16 cells. The DNA damage response after γ-irradiation was attenuated by pretreatment with A2B receptor antagonists, such as PSB603, while it was enhanced by pretreatment with A2B receptor agonists, such as BAY60-6583. γ-Irradiation decreased the cell survival rate, and pretreatment with PSB603 further reduced the survival rate. On the other hand, pretreatment with BAY60-6583 increased the cell survival rate after irradiation. The DNA damage response and the cell survival rate after γ-irradiation were both decreased in A2B-knockdown cells. In vivo experiments in mice confirmed that tumor growth was suppressed and delayed in the irradiated group pretreated with PSB603, compared with the irradiation-alone group. Our results indicate that adenosine A2B receptor contributes to radioresistance, and could be a new target for the development of agents to increase the efficacy of radiotherapy.
阐明与肿瘤辐射抗性相关的因素具有治疗学意义。我们之前的研究表明，γ 射线照射会导致小鼠黑色素瘤 B16 细胞释放 ATP，但 ATP 的代谢产物腺苷的作用仍不清楚。本研究表明，腺苷 A2B 受体参与了小鼠黑色素瘤 B16 细胞的 DNA 损伤修复和辐射抗性。γ 射线照射后的 DNA 损伤反应可被 A2B 受体拮抗剂 PSB603 预处理所减弱，而被 A2B 受体激动剂 BAY60-6583 预处理所增强。γ 射线照射降低了细胞存活率，而 PSB603 的预处理进一步降低了存活率。另一方面，BAY60-6583 的预处理增加了照射后的细胞存活率。A2B 基因敲低细胞的 DNA 损伤反应和γ 射线照射后的细胞存活率均降低。在小鼠的体内实验中，与单纯照射组相比，PSB603 预处理的照射组的肿瘤生长受到抑制并延迟。我们的研究结果表明，腺苷 A2B 受体有助于辐射抗性，可能成为提高放射治疗效果的新靶点。
