Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy

Chien Ju Lin, Chin Cheng Lee, Yung Luen Shih, Tsung Yao Lin, Sheng Hao Wang, Yuh Feng Lin, Chwen Ming Shih

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)377-391
Number of pages15
JournalFree Radical Biology and Medicine
Volume52
Issue number2
DOIs
Publication statusPublished - Jan 15 2012

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Keywords

  • Apoptosis
  • Autophagy
  • ERK
  • Free radicals
  • Glioma
  • Resveratrol
  • ROS
  • Temozolomide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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