title: Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Xue
authors.initials: X
authors.lastname: Xue
authors.forename: Ruo-Bing
authors.initials: RB
authors.lastname: Guo
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013267:Stilbenes / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002135:Calcium-Binding Proteins; D017382:Reactive Oxygen Species; D013267:Stilbenes; C486009:TESC protein, human; D003606:Dacarbazine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol; D000077204:Temozolomide