A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.
A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.
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DOI：
10.1016/j.ijrobp.2009.09.024
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发表时间：
2010-02-01
影响因子：
7
通讯作者：
Yazlovitskaya, Eugenia M.
中科院分区：
文献类型：
--
作者：
Thotala, Dinesh K.;Geng, Ling;Dickey, Amy K.;Hallahan, Dennis E.;Yazlovitskaya, Eugenia M.
开发新的治疗方法对于有效防止辐射引起的损伤至关重要。在这里，我们研究了开发GSK-3β的小分子抑制剂SB 216763或SB 415286作为减轻肠损伤的辐射防护剂的潜力。使用C57/BL 6小鼠进行存活研究以评价GSK-3β抑制剂的辐射防护作用。采用TUNEL法和免疫组化法检测Bax和Bcl-2的表达。使用IEC-6细胞进行克隆形成存活研究、凋亡测定（用膜联蛋白V或DAPI染色）和β-连环蛋白、Bcl-2、Bax和半胱天冬酶-3的免疫印迹分析。SB 415286预处理显著提高了8和12戈伊照射小鼠的存活率。与单独辐射相比，用SB 216763或SB 415286预处理的小鼠在4和/或8戈伊辐射后4小时和/或12小时，肠腺中的TUNEL和Bax阳性细胞显着减少，而Bcl-2阳性细胞增加。与仅用放射处理的细胞相比，用GSK-3β抑制剂预处理经放射处理的IEC-6细胞显著增加了克隆形成存活。这种增加是由于辐射诱导的细胞凋亡的衰减，如通过膜联蛋白V和DAPI测定以及Bcl-2、Bax和caspase-3的免疫印迹分析所证明的。GSK-3β小分子抑制剂在细胞培养和体内保护小鼠肠道免受辐射诱导的损伤，并提高小鼠的存活率。这种保护作用的分子机制涉及由Bcl-2、Bax和caspase-3调节的减弱的辐射诱导的细胞凋亡。因此，GSK-3β抑制剂可减少肠道照射的有害后果，从而改善放射治疗期间的生活质量。
Development of new treatments is critical to effective protection against radiation-induced injury. Here we investigate the potential of developing small molecule inhibitors of GSK-3β, SB216763 or SB415286, as radioprotective agents to attenuate intestinal injury. Survival study was done using C57/BL6 mice to evaluate radioprotective effect of GSK-3β inhibitors. TUNEL assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in small intestines of the treated mice. Clonogenic survival study, apoptosis assays (staining with Annexin V or DAPI), and immunoblot analysis of β-catenin, Bcl-2, Bax, and caspase-3 were done using IEC-6 cells. Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed significant reduction in TUNEL- and Bax-positive 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 to radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3β inhibitors significantly increased clonogenic survival compared to cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as demonstrated by Annexin V and DAPI assays, and immunoblot analysis of Bcl-2, Bax, and caspase-3. GSK-3β small molecule inhibitors protect mouse intestines 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-3β inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.
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影响因子：
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作者：
CHENG, H;LEBLOND, CP
通讯作者：
LEBLOND, CP
DOI：
10.1152/ajpgi.00391.2006
发表时间：
2007-02-01
影响因子：
4.5
作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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