一类新型的分子靶向放射性防护剂：GSK-3β 抑制剂。
A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.
机构信息
Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA.
出版信息
Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):557-65. doi: 10.1016/j.ijrobp.2009.09.024.
PURPOSE
Development of new treatments is critical to effective protection against radiation-induced injury. We investigate the potential of developing small-molecule inhibitors of glycogen synthase kinase 3beta (GSK-3beta)-SB216763 or SB415286-as radioprotective agents to attenuate intestinal injury.
METHODS AND MATERIALS
A survival study was done by use of C57BL/6J mice to evaluate the radioprotective effect of GSK-3beta inhibitors. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in the small intestines of the treated mice. A clonogenic survival study, apoptosis assays (staining with annexin V or 4',6-diamidino-2-phenylindole), and immunoblot analysis of beta-catenin, Bcl-2, Bax, and caspase 3 were done by use of Rat intestinal epithelial cell line IEC-6 cells.
RESULTS
Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed a significant reduction in TUNEL- and Bax-positive cells and an increase in Bcl-2-positive cells in intestinal crypts at 4 and/or 12 h after radiation with 4 and/or 8 Gy compared with radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3beta inhibitors significantly increased clonogenic survival compared with cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as shown by annexin V and 4',6-diamidino-2-phenylindole assays, as well as immunoblot analysis of Bcl-2, Bax, and caspase 3.
CONCLUSIONS
Glycogen synthase kinase 3beta small-molecule inhibitors protect mouse intestine from radiation-induced damage in cell culture and in vivo and improve survival of mice. Molecular mechanisms of this protection involve attenuated radiation-induced apoptosis regulated by Bcl-2, Bax, and caspase 3. Therefore GSK-3beta inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.
目的
开发新的治疗方法对于有效预防辐射诱导损伤至关重要。我们研究了使用糖原合酶激酶 3β（GSK-3β）小分子抑制剂 SB216763 或 SB415286 作为放射保护剂来减轻肠道损伤的潜力。
方法和材料
通过使用 C57BL/6J 小鼠进行生存研究，评估 GSK-3β 抑制剂的放射保护作用。末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）测定和 Bax 和 Bcl-2 的免疫组织化学染色用于评估治疗小鼠小肠中的细胞凋亡。克隆存活研究、凋亡测定（用 Annexin V 或 4',6-二脒基-2-苯基吲哚染色）以及免疫印迹分析β-连环蛋白、Bcl-2、Bax 和 caspase 3，使用 Rat 肠上皮细胞系 IEC-6 细胞进行。
结果
用 SB415286 预处理可显著提高接受 8 和 12 Gy 照射的小鼠的存活率。与单独照射相比，用 SB216763 或 SB415286 预处理的小鼠在 4 和/或 12 小时后，在接受 4 和/或 8 Gy 辐射后，小肠隐窝中的 TUNEL 和 Bax 阳性细胞减少，Bcl-2 阳性细胞增加。与单独接受辐射的细胞相比，用 GSK-3β 抑制剂预处理照射的 IEC-6 细胞可显著增加克隆存活。这种增加是由于辐射诱导的凋亡减少所致，如 Annexin V 和 4',6-二脒基-2-苯基吲哚测定以及 Bcl-2、Bax 和 caspase 3 的免疫印迹分析所示。
结论
糖原合酶激酶 3β 小分子抑制剂可保护小鼠肠道免受细胞培养和体内辐射损伤，并提高小鼠的存活率。这种保护的分子机制涉及通过 Bcl-2、Bax 和 caspase 3 调节的辐射诱导凋亡减少。因此，GSK-3β 抑制剂减少了肠道照射的有害后果，从而提高了放射治疗期间的生活质量。
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