title: Phenethyl isothiocyanate enhances TRAIL-induced apoptosis in oral cancer cells and xenografts.
abstract: OBJECTIVE
  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts.
  
  
  METHODS
  Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant human oral cancer cells, SAS and Ca9-22.
  
  
  RESULTS
  PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone.
  
  
  CONCLUSIONS
  We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo.
  
  
  CONCLUSIONS
  PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers.
authors.affiliation: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Yeh
authors.affiliation: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Dentistry, National Taiwan University Hospital, Hsinchu Branch, 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu, Taiwan.
authors.forename: Hui-Hsin
authors.initials: HH
authors.lastname: Ko
authors.affiliation: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Hsieh
authors.affiliation: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Dentistry, National Taiwan University Hospital, Hsinchu Branch, 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu, Taiwan.
authors.forename: King-Jean
authors.initials: KJ
authors.lastname: Wu
authors.affiliation: School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Mark Yen-Ping
authors.initials: MY
authors.lastname: Kuo
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Hsinchu Branch, 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu, Taiwan. q95422002@ntu.edu.tw.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Deng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D020287:In Situ Nick-End Labeling; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D009062:Mouth Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D000873:Anthracenes; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C432165:pyrazolanthrone; C058305:phenethyl isothiocyanate; D000111:Acetylcysteine
keywords: Apoptosis; Death receptors; Oral cancer; PEITC; TRAIL
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