Ultra-High Dose Rate FLASH Irradiation Induced Radio-Resistance of Normal Fibroblast Cells Can Be Enhanced by Hypoxia and Mitochondrial Dysfunction Resulting From Loss of Cytochrome C.
Ultra-High Dose Rate FLASH Irradiation Induced Radio-Resistance of Normal Fibroblast Cells Can Be Enhanced by Hypoxia and Mitochondrial Dysfunction Resulting From Loss of Cytochrome C.
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细胞色素 C 丢失导致的缺氧和线粒体功能障碍可增强超高剂量率 FLASH 照射诱导的正常成纤维细胞的放射抗性
DOI：
10.3389/fcell.2021.672929
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发表时间：
2021
影响因子：
5.5
通讯作者：
Yang G
中科院分区：
文献类型：
--
作者：
Han J;Mei Z;Lu C;Qian J;Liang Y;Sun X;Pan Z;Kong D;Xu S;Liu Z;Gao Y;Qi G;Shou Y;Chen S;Cao Z;Zhao Y;Lin C;Zhao Y;Geng Y;Chen J;Yan X;Ma W;Yang G
超高剂量率闪光辐射（Ultra-highdosityrateflashirradiation，FLASH-IR）与常规剂量率照射相比，能在保持肿瘤杀伤效果的同时，对正常组织有更好的保护作用，因而受到广泛关注。FLASH-IR诱导的对正常组织的保护作用表现为受照射的正常细胞的辐射抗性，并且被认为与氧耗尽有关。然而，详细的细胞死亡概况和途径仍不清楚。在低氧和常氧条件下，用超快激光产生的粒子，以10-40戈伊的剂量，对目前正常的小鼠胚胎成纤维细胞进行了10 ~ 109戈伊/s的FLASH照射。结果表明，FLASH-IR可诱导正常成纤维细胞发生早期凋亡、晚期凋亡和坏死，且在缺氧和常氧条件下，细胞凋亡水平均随时间延长而增加。另外，缺氧组早期凋亡、晚期凋亡和坏死的比例明显低于常氧组，表明缺氧可增强FLASH-IR下正常成纤维细胞的辐射抗性。为了进一步研究细胞凋亡相关的概况和潜在的途径，还照射了由细胞色素c（cyt c-/-）损失引起的线粒体功能障碍细胞。结果表明，与照射后的正常细胞（cyt c+/+）相比，照射后cyt c-/-细胞在缺氧和常氧条件下晚期凋亡和坏死的比例均显著降低，而早期凋亡的比例无明显变化，提示线粒体功能障碍增加了照射后细胞的辐射抗性。综上所述，就我们有限的知识而言，这是第一份关于缺氧和常氧条件下FLASH-IR下正常和cyt c-/-细胞死亡特征和途径的报告，这可能有助于我们提高对FLASH-IR诱导的正常细胞保护作用的理解，从而可能有助于优化未来的临床FLASH治疗。
Ultra-high dose rate FLASH irradiation (FLASH-IR) has got extensive attention since it may provide better protection on normal tissues while maintain tumor killing effect compared with conventional dose rate irradiation. The FLASH-IR induced protection effect on normal tissues is exhibited as radio-resistance of the irradiated normal cells, and is suggested to be related to oxygen depletion. However, the detailed cell death profile and pathways are still unclear. Presently normal mouse embryonic fibroblast cells were FLASH irradiated (∼109 Gy/s) at the dose of ∼10–40 Gy in hypoxic and normoxic condition, with ultra-fast laser-generated particles. The early apoptosis, late apoptosis and necrosis of cells were detected and analyzed at 6, 12, and 24 h post FLASH-IR. The results showed that FLASH-IR induced significant early apoptosis, late apoptosis and necrosis in normal fibroblast cells, and the apoptosis level increased with time, in either hypoxic or normoxic conditions. In addition, the proportion of early apoptosis, late apoptosis and necrosis were significantly lower in hypoxia than that of normoxia, indicating that radio-resistance of normal fibroblast cells under FLASH-IR can be enhanced by hypoxia. To further investigate the apoptosis related profile and potential pathways, mitochondria dysfunction cells resulting from loss of cytochrome c (cyt c–/–) were also irradiated. The results showed that compared with irradiated normal cells (cyt c+/+), the late apoptosis and necrosis but not early apoptosis proportions of irradiated cyt c–/– cells were significant decreased in both hypoxia and normoxia, indicating mitochondrial dysfunction increased radio-resistance of FLASH irradiated cells. Taken together, to our limited knowledge, this is the first report shedding light on the death profile and pathway of normal and cyt c–/– cells under FLASH-IR in hypoxic and normoxic circumstances, which might help us improve the understanding of the FLASH-IR induced protection effect in normal cells, and thus might potentially help to optimize the future clinical FLASH treatment.
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影响因子：
1.6
作者：
Doria, D.;Kakolee, K. F.;Borghesi, M.
通讯作者：
Borghesi, M.
影响因子：
5.7
作者：
Montay-Gruel, Pierre;Bouchet, Audrey;Vozenin, Marie-Catherine
通讯作者：
Vozenin, Marie-Catherine
影响因子：
1.3
作者：
Manti, L.;Perozziello, F. M.;Tramontana, A.
通讯作者：
Tramontana, A.
KillerRed 靶向线粒体 (mtKR) 诱导的 ROS 通过 Cyt c/Caspase-3 途径增强辐射引起的细胞凋亡
影响因子：
--
作者：
Li, Xin;Fang, Fang;Wang, Zhicheng
通讯作者：
Wang, Zhicheng
DOI：
10.1016/j.bbamcr.2010.09.013
发表时间：
2011-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Kinnally KW;Peixoto PM;Ryu SY;Dejean LM
通讯作者：
Dejean LM