Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models
Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models
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DOI：
10.1016/j.canlet.2010.11.008
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发表时间：
2011-03-28
期刊：
影响因子：
9.7
通讯作者：
Schoenthal, Axel H.
中科院分区：
文献类型：
--
作者：
Chen, Thomas C.;Wang, Weijun;Schoenthal, Axel H.
烷化剂替莫唑胺，结合手术和放射治疗，是目前治疗胶质母细胞瘤患者的标准药物。然而，尽管有这种广泛的治疗努力，纳入替莫唑胺只能将生存期延长短短几个月。导致化疗耐药的因素之一是内质网(ER)伴侣蛋白GRP78(葡萄糖调节蛋白78；BiP)的表达增加，GRP78是ER应激反应系统中促进生存的关键成分。由于绿茶成分EGCG(表没食子儿茶素没食子酸酯)已被证明抑制GRP78的功能，我们研究了这种多酚类药物是否能够在胶质母细胞瘤的临床前模型中增加替莫唑胺的治疗效果。将人U87(野生型p53)或U251(突变型)人胶质母细胞瘤细胞移植到小鼠脑内，分别用替莫唑胺和EGCG单独或联合治疗。我们发现，单用EGCG并不能提供生存益处，但显著改善了替莫唑胺的现有治疗效果，即与单用替莫唑胺治疗相比，联合治疗的寿命延长幅度要大得多。肿瘤组织的免疫组织化学分析显示，替莫唑胺治疗的动物GRP78的表达水平增加，当替莫唑胺与EGCG联合使用时，这种表达水平降低。针对GRP78或其主要促凋亡拮抗剂CHOP(CCAAT/增强子结合蛋白同源蛋白/GADD153)的siRNA的平行体外实验进一步确立了ER应激反应系统的关键作用，其中si-GRP78使细胞对替莫唑胺治疗敏感，si-CHOP提供了对药物诱导的毒性的保护。因此，内质网应激调节成分影响胶质母细胞瘤细胞对替莫唑胺治疗的化疗反应，而EGCG的包含能够增加这种DNA损伤剂的治疗效果。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
The alkylating agent temozolomide, in combination with surgery and radiation, is the current standard of care for patients with glioblastoma. However, despite this extensive therapeutic effort, the inclusion of temozolomide extends survival only by a few short months. Among the factors contributing to chemoresistance is elevated expression of the endoplasmic reticulum (ER) chaperone GRP78 (glucose-regulated protein 78; BiP), a key pro-survival component of the ER stress response system. Because the green tea component EGCG (epigallocatechin 3-gallate) had been shown to inhibit GRP78 function, we investigated whether this polyphenolic agent would be able to increase the therapeutic efficacy of temozolomide in preclinical models of glioblastoma. Mice with intracranially implanted human U87 (p53 wild type) or U251 (p53 mutant) glioblastoma cells were treated with temozolomide and EGCG, alone and in combination. We found that EGCG alone did not provide survival benefit, but significantly improved the existing therapeutic effect of temozolomide, i.e., life extension was substantially greater under combination therapy as compared to temozolomide therapy alone. Immunohistochemical analysis of tumor tissue revealed increased expression levels of GRP78 in temozolomide-treated animals, which was diminished when temozolomide was combined with EGCG. Parallel in vitro experiments with siRNA targeting GRP78 or its major pro-apoptotic antagonist CHOP (CCAAT/enhancer binding protein homologous protein/GADD153) further established a critical role of the ER stress response system, where si-GRP78 sensitized cells to treatment with temozolomide, and si-CHOP provided protection from drug-induced toxicity. Thus, ER stress-regulatory components affect the chemotherapeutic response of glioblastoma cells to treatment with temozolomide, and inclusion of EGCG is able to increase the therapeutic efficacy of this DNA-damaging agent. (C) 2010 Elsevier Ireland Ltd. All rights reserved.