title: 4'-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death.
abstract: OBJECTIVE
  To examine the antitumor effect of 4'-chloro-3,5-dihydroxystilbene, a resveratrol derivative, on lung adenocarcinoma A549 cells.
  
  
  METHODS
  The cytotoxic IC(50) was determined by direct cell counting. Flow cytometry, monodansylcadaverine (MDC) staining, transfection, Western blot and a proteasome activity assay were used to study the cellular mechanism of 4'-chloro-3,5-dihydroxystilbene. A xenograft nude mouse model was used to analyze the antitumor effect in vivo.
  
  
  RESULTS
  4'-Chloro-3,5-dihydroxystilbene induced a rapid and persistent increase in the intracellular reactive oxygen species in the cells, but the cell death could not be inhibited by two antioxidant agents. The derivative caused sub-G(1) formation, a decrease in the mitochondria membrane potential and poly (ADP-ribose) polymerase degradation, and the caspase inhibitor Z-VAD-FMK could partially prevent cell death. It also induced a significant increase in intracellular acidic vacuoles, LC3-II formation and intracellular GFP-LC3 aggregation. An autophagic inhibitor partially reversed cell death. Additionally, 4'-chloro-3,5-dihydroxystilbene induced the accumulation of ubiquitinated conjugates and inhibited proteasome activity in cells. In an in vivo study, 4'-chloro-3,5-dihydroxystilbene retarded tumor growth in nude mice.
  
  
  CONCLUSIONS
  These data suggest that the resveratrol derivative 4'-chloro-3,5-dihydroxystilbene could be developed as an anti-tumor compound.
authors.affiliation: Graduate Institute of Biomedical and Biopharmaceutical Sciences, National Chiayi University, Chiayi, Taiwan, China.
authors.forename: Jin-yi
authors.initials: JY
authors.lastname: Wu
authors.forename: Kun-wei
authors.initials: KW
authors.lastname: Tsai
authors.forename: Jia-jen
authors.initials: JJ
authors.lastname: Shee
authors.forename: Yi-zhen
authors.initials: YZ
authors.lastname: Li
authors.forename: Ching-hsein
authors.initials: CH
authors.lastname: Chen
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Chuang
authors.forename: Yi-wen
authors.initials: YW
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C547694:4'-chloro-3,5-dihydroxystilbene; D000972:Antineoplastic Agents, Phytogenic; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D013267:Stilbenes; D049452:Green Fluorescent Proteins; D011065:Poly(ADP-ribose) Polymerases