Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 52, Issue 2, Pages 377-391Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.10.487
Keywords
Autophagy; Apoptosis; Glioma; Temozolomide; Resveratrol; ROS; ERK; Free radicals
Funding
- National Science Council [NSC99-2320-B-038-008-MY3]
- Shin Kong Wu Ho-Su Memorial Hospital, Taiwan [SKH-TMU-96-11]
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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.
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