本研究的目的是测试电离辐射（IR）治疗是否与3,3'-二硒代丙酸（DSePA）（一种氧化还原活性的有机二硒代物）联用，通过抑制肺癌细胞的生长和迁移，实现更好的肿瘤控制。结果表明，IR（2Gy）后的DSePA（5μM）处理导致细胞死亡显著高于DSePA和IR单独处理的细胞死亡。重要的是，综合治疗还显示出降低癌症干细胞比例和A549细胞的克隆生存率。机理研究表明，综合治疗虽然在早期时间点（放射后2-6小时）表现出还原环境（以ROS的降低和GSH / GSSG的增加为标志），但减缓了DNA修复，抑制了上皮-间充质转化（EMT）/细胞迁移并诱导了显著水平的凋亡。DSePA介导的ATM / DNAPKs / p53（DNA损伤响应信号）和Akt / G-CSF（EMT）通路的抑制似乎是其广泛调节辐射活性的主要机制。最后，IR（4次2Gy）合并DSePA（每日口服0.1-0.25mg / kg体重）治疗在小鼠模型中显示出比DSePA和IR单独治疗更显著的A549异种移植瘤抑制。总之，IR后的DSePA处理通过抑制DNA修复和细胞迁移增强了对A549细胞的细胞杀伤作用。©2023国际生物化学和分子生物学联合会。

Aim of the present study was to test whether ionizing radiation (IR) treatment along with 3,3'-diselenodipropionic acid (DSePA), a redox active organodiselenide achieved better tumor control by suppressing the growth and migration of lung cancer cells. The results indicated that post-IR (2 Gy) treatment of DSePA (5 μM) led to a significantly higher cell death as compared to that of DSePA and IR treatments separately. Importantly, combinatorial treatment also showed reduction in the proportion of cancer stem cells and the clonogenic survival of A549 cells. The mechanistic studies indicated that combinatorial treatment although exhibited reductive environment (marked by decrease in ROS and increase of GSH/GSSG) at early time points (2-6 h postradiation), slowed DNA repair, inhibited epithelial-mesenchymal transition (EMT)/cell migration and induced significant level of apoptosis. DSePA mediated suppression of ATM/DNAPKs/p53 (DNA damage response signaling) and Akt/G-CSF (EMT) pathways appeared to be the major mechanism responsible for its radio-modulating activity. Finally, the combined treatment of IR (2 Gy × 4) and DSePA (0.1-0.25 mg/kg body weight daily through oral gavage) showed a significantly higher tumor suppression of the A549 xenograft as compared to that of DSePA and IR treatments separately in the mouse model. In conclusion, post-IR treatment of DSePA augmented cell kill by inhibiting DNA repair and cell migration in A549 cells.© 2023 International Union of Biochemistry and Molecular Biology.