Document Detail

Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway.
MedLine Citation:
PMID:  22530672     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: Resveratrol has been regarded as a promising candidate for cancer prevention and treatment. The present study was to investigate the impact of resveratrol on the antitumor effects of temozolomide (TMZ), a standard treatment regiment of glioblastoma (GBM), in vitro and in vivo.
METHODS AND RESULTS: We found that the combination of resveratrol and TMZ significantly resulted in G(2)/M cell cycle arrest by flow cytometry, triggered a robust increase in expression of astrocyte differentiation marker glial fibrillary acid protein (GFAP), downregulated the expression of matrix metalloproteinase-9 (MMP-9) by immunohistochemistry and western blot analysis as well as inhibited cell migration by scratch wound assay. Further study revealed that TMZ in combination with resveratrol remarkably increased reactive oxygen species (ROS) production, which serves as an upstream signal for AMP-activated protein kinase (AMPK) activation. Subsequently, activated AMPK inhibited mTOR signaling and downregulated antiapoptosis protein Bcl-2, which was contributed to the additive antiproliferation effects of combination treatment. In an orthotopic xenograft model of GBM, TMZ plus resveratrol treatment significantly reduced the volume of tumor, which was confirmed by decreased expression of Ki-67, a marker of proliferation index.
CONCLUSIONS: Our findings demonstrate for the first time that resveratrol can enhance TMZ-mediated antitumor effects in GBM in vitro and in vivo, via ROS-dependent AMPK-TSC-mTOR signaling pathway.
Yuan Yuan; Xue Xue; Ruo-Bing Guo; Xiu-Lan Sun; Gang Hu
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-25
Journal Detail:
Title:  CNS neuroscience & therapeutics     Volume:  18     ISSN:  1755-5949     ISO Abbreviation:  CNS Neurosci Ther     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2013-05-20     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101473265     Medline TA:  CNS Neurosci Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  536-46     Citation Subset:  IM    
Copyright Information:
© 2012 Blackwell Publishing Ltd.
Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China.
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MeSH Terms
AMP-Activated Protein Kinases / antagonists & inhibitors,  metabolism*
Antineoplastic Agents, Alkylating / administration & dosage
Calcium-Binding Proteins / antagonists & inhibitors,  metabolism
Cell Line, Tumor
Dacarbazine / administration & dosage,  analogs & derivatives*
Drug Synergism
Drug Therapy, Combination
Glioblastoma / drug therapy*,  metabolism
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Reactive Oxygen Species / metabolism*
Signal Transduction / drug effects,  physiology*
Stilbenes / administration & dosage*
TOR Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Calcium-Binding Proteins; 0/Reactive Oxygen Species; 0/Stilbenes; 0/TSC protein, human; 4342-03-4/Dacarbazine; 85622-93-1/temozolomide; EC protein, human; EC Serine-Threonine Kinases; EC Protein Kinases; Q369O8926L/resveratrol

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