title: Resveratrol and arsenic trioxide act synergistically to kill tumor cells in vitro and in vivo.
abstract: OBJECTIVE
  Arsenic trioxide (As2O3), which used as an effective agent in the treatment of leukaemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden heart death have been implicated in the cardiotoxicity of As2O3. The present study was designed to explore whether the combination of As2O3 and resveratrol could generate a more powerful anti-cancer effect both in vitro and in vivo.
  
  
  METHODS
  MTT assay was performed to assess the proliferation of Hela, MCF-7 and NB4 cells. Isobolographic analysis was used to evaluate combination index values from cell viability data. The apoptosis and the cellular reactive oxygen species (ROS) level were assessed by fluorescent microscopy and flow cytometry separately in vitro. The effect of As2O3, alone and in combination with resveratrol on Hela tumor growth in an orthotopic nude mouse model was also investigated. The tumor volume and the immunohistochemical analysis of CD31, CD34 and VEGF were determined.
  
  
  RESULTS
  Resveratrol dramatically enhanced the anti-cancer effect induced by As2O3 in vitro. In addition, isobolographic analysis further demonstrated that As2O3 and resveratrol generated a synergistic action. More apoptosis and ROS generation were observed in the combination treatment group. Similar synergistic effects were found in nude mice in vivo. The combination of As2O3 and resveratrol dramatically suppressed both tumor growth and angiogenesis in nude mice.
  
  
  CONCLUSIONS
  Combining As2O3 with resveratrol would be a novel strategy to treat cancer in clinical practice.
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
authors.forename: You-Ran
authors.initials: YR
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Li
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Dou
authors.affiliation: Department of Neurology, The Ninth People's Hospital of Chongqing, Chongqing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol; D000077237:Arsenic Trioxide