Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity.
Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity.
复制标题
DOI：
10.1016/j.freeradbiomed.2016.07.009
复制
发表时间：
2016-10
影响因子：
7.4
通讯作者：
Grdina DJ
中科院分区：
文献类型：
--
作者：
Miller RC;Murley JS;Rademaker AW;Woloschak GE;Li JJ;Weichselbaum RR;Grdina DJ
将细胞暴露于低至5 mGy的电离辐射剂量可诱导由随后暴露于较高剂量的细胞表达的辐射敏感性的变化。这被称为适应性效应。我们描述了一种独特的生存素相关的适应性反应，其中增加的辐射抗性或敏化细胞可以通过暴露于5毫戈瑞或活性氧（ROS）产生药物大黄素（1，3，8-三羟基-6-甲基蒽醌），一种天然存在的蒽醌诱导。本研究的目的是确定活性氧产生过程中的作用，影响细胞内定位的凋亡抑制蛋白生存素及其随后的影响辐射反应的存在或不存在的抗氧化剂N-乙酰-L-半胱氨酸（NAC）。使用两种充分表征的鼠肉瘤进行实验：SA-NH p53野生型（WT）和FSa p53突变体（Mut），其在培养物中生长或作为C3 H小鼠右后腿中的实体瘤生长。使用5 mGy或50 μM大黄素的剂量，使用多剂量范例诱导这些肿瘤细胞对较高辐射暴露的反应的变化。在存在或不存在10 mM NAC处理的情况下，确定SA-NH和FSa细胞对辐射敏感性的影响作为存活素易位到细胞质或细胞核的函数。进行体外存活测定（2戈伊/次，每日两次）和肿瘤生长延迟（TGD）（5戈伊/次，每日五次）研究。生存素的细胞内定位通过酶联免疫吸附试验（ELISA）测定，并与生存反应和治疗条件相关。2戈伊单独照射对Survivin的胞内转位无影响。当提前15分钟进行5 mGy或大黄素暴露时，与p53 Mut FSa细胞的细胞核相比，存活素在p53 WT SA-NH的细胞质中升高。与此相反，用p53小干扰RNA（siRNA）转染的SA-NH细胞，如果在每次2戈伊照射之前暴露于5 mGy戈伊，则对p53 Mut FSa细胞的反应类似，变得更辐射敏感。与它们各自对5次每日一次5戈伊分次的反应相反，SA-NH肿瘤通过在每次每日5戈伊剂量之前15分钟给予5 m戈伊暴露而受到保护，如通过更快速的生长（TGD减少1.9天，P=0.032）所证明的，而FSa肿瘤被致敏，以慢得多的速率生长（TGD增加4.5天，P < 0.001）。暴露于10 mM NAC的SA-NH和FSa肿瘤细胞抑制5 mGy和大黄素诱导生存素细胞内易位和相应的改变适应性生存反应的能力。存活素相关的适应性反应可以在多次给药方案之后诱导，其中非常低的辐射剂量之后不久是与目前广泛用于癌症治疗的标准图像引导的放射疗法方案一致的较高剂量。虽然通过暴露于ROS产生的应力诱导，但辐射反应变化的最终表达取决于肿瘤相关蛋白存活素及其细胞内易位的双功能性。
Exposure of cells to a dose of ionizing radiation as low as 5 mGy can induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses at later times. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to 5 mGy or to the reactive oxygen species (ROS) generating drug Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a naturally occurring anthraquinone. The purpose of this study was to determine the role of ROS generating processes in affecting both the intracellular localization of the inhibitor of apoptosis protein survivin and its subsequent effect on radiation response in the presence or absence of the anti-oxidant N-acetyl-L-cysteine (NAC). Experiments were performed using two well characterized murine sarcomas: SA-NH p53 wild-type (WT) and FSa p53 mutant (Mut), grown either in culture or as solid tumors in the right hind legs of C3H mice. Doses of 5 mGy or 50 μM Emodin were used to induce changes in the response of these tumor cells to higher radiation exposures using a multi-dosing paradigm. Effects on radiation sensitivity were determined for SA-NH and FSa cells as a function of survivin translocation either to the cytoplasm or nucleus in the presence or absence of 10 mM NAC treatment. In vitro survival assays (2 Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5 Gy per fraction, five once daily fractions) studies were performed. Intracellular localization of survivin was determined by enzyme-linked immunosorbent assay (ELISA) and correlated to survival response and treatment conditions. 2 Gy alone had no effect on intracellular translocation of survivin. When preceded 15 min earlier by 5 mGy or Emodin exposures, survivin became elevated in the cytoplasm of p53 WT SA-NH as compared to the nuclei of p53 Mut FSa cells. SA-NH cells transfected with p53 small interfering RNA (siRNA), in contrast, responded similarly to p53 Mut FSa cells by becoming more radiation sensitive if exposed to 5 mGy prior to each 2 Gy irradiation. In contrast to their respective responses to five once daily 5 Gy fractions, SA-NH tumors were protected by 5 mGy exposures administered 15 min prior to each daily 5 Gy dose as evidenced by a more rapid growth (1.9 day decrease in TGD, P=0.032), while FSa tumors were sensitized, growing at a much slower rate (4.5 day increase in TGD, P < 0.001). Exposure of SA-NH and FSa tumor cells to 10 mM NAC inhibited the ability of 5 mGy and Emodin to induce intracellular translocation of survivin and the corresponding altered adaptive survival response. The survivin-associated adaptive response can be induced following a multi-dosing scheme in which very low radiation doses are followed shortly thereafter by higher doses consistent with a standard image guided radiotherapy protocol that is currently widely used in the treatment of cancer. While induced by exposure to ROS generating stresses, the ultimate expression of changes in radiation response is dependent upon the bi-functionality of the tumor associated protein survivin and its intracellular translocation.
登录
查看更多内容
影响因子：
11.2
作者：
Grdina DJ;Murley JS;Miller RC;Mauceri HJ;Sutton HG;Li JJ;Woloschak GE;Weichselbaum RR
通讯作者：
Weichselbaum RR
影响因子：
4.8
作者：
Connell, Claire M.;Colnaghi, Rita;Wheatley, Sally P.
通讯作者：
Wheatley, Sally P.
影响因子：
3.4
作者：
Halpern, HJ;Yu, C;Teicher, BA
通讯作者：
Teicher, BA
氨磷汀可在正常组织和可移植肿瘤中诱导抗氧化酶活性，从而影响放射反应。
DOI：
10.1016/j.ijrobp.2008.10.061
发表时间：
2009-03-01
影响因子：
7
作者：
Grdina, David J.;Murley, Jeffrey S.;Kataoka, Yasushi;Baker, Kenneth L.;Kunnavakkam, Rangesh;Coleman, Mitchell C.;Spitz, Douglas R.
通讯作者：
Spitz, Douglas R.
DOI：
10.1155/2012/208650
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Kodiha M;Stochaj U
通讯作者：
Stochaj U