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 journalArticlepeer-review

128 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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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