Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy
Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy
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DOI：
10.1016/j.freeradbiomed.2011.10.487
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发表时间：
2012-01-15
影响因子：
7.4
通讯作者：
Shih, Chwen-Ming
中科院分区：
文献类型：
--
作者：
Lin, Chien-Ju;Lee, Chin-Cheng;Shih, Chwen-Ming
烷基化剂替莫唑胺（TMZ）是临床上用于治疗恶性胶质瘤的主要化疗药物。本研究探讨了TMZ诱导细胞死亡的机制以及白藜芦醇增加TMZ疗效的可能性。TMZ通过活性氧（reactive oxygen species， ROS）爆发和细胞外信号调节激酶（extracellular signal-regulated kinase， ERK）激活诱导凋亡细胞死亡和细胞保护性自噬，而ERK被白藜芦醇抑制，导致自噬减少，细胞凋亡增加，表明ROS/ERK通路在TMZ处理后细胞的命运中起着至关重要的作用。等密度分析表明，TMZ与白藜芦醇联合使用具有协同作用。此外，一项小鼠体内异种移植研究也表明，白藜芦醇和TMZ联合使用可通过抑制ROS/ erk介导的自噬并随后诱导细胞凋亡来减少肿瘤体积。综上所述，我们的数据表明，TMZ诱导的ROS/ erk介导的自噬可以保护胶质瘤细胞免于凋亡，白藜芦醇与TMZ联合使用可以提高脑肿瘤化疗的疗效。(C) 2011爱思唯尔公司版权所有。
The alkylating agent temozolomide (TMZ) is the major chemotherapeutic drug used clinically in the treatment of malignant gliomas. This study investigated the mechanism behind TMZ-induced cell death and the possibility that resveratrol might increase TMZ efficacy. TMZ induced both apoptotic cell death and cytoprotective autophagy through a reactive oxygen species (ROS) burst and extracellular signal-regulated kinase (ERK) activation, which was suppressed by resveratrol, resulting in a decrease in autophagy and an increase in apoptosis, suggesting that the ROS/ERK pathway plays a crucial role in the fate of cells after TMZ treatment. Isobolographic analysis indicated that the combination of TMZ and resveratrol has a synergistic effect. Moreover, an in vivo mouse xenograft study also showed that coadministration of resveratrol and TMZ reduced tumor volumes by suppressing ROS/ERK-mediated autophagy and subsequently inducing apoptosis. Taken together, our data indicate that TMZ-induced ROS/ERK-mediated autophagy protected glioma cells from apoptosis, and the combination of resveratrol with TMZ could improve the efficacy of chemotherapy for brain tumors. (C) 2011 Elsevier Inc. All rights reserved.