title: Synthetic β-nitrostyrene derivative CYT-Rx20 as inhibitor of oral cancer cell proliferation and tumor growth through glutathione suppression and reactive oxygen species induction.
abstract: The β-nitrostyrene family possesses anticancer properties. In this study, β-nitrostyrene derivative CYT-Rx20 (3'-hydroxy-4'-methoxy-β-methyl-β-nitrostyrene) was synthesized and investigated its anticancer activity in oral cancer.
  
  
  
  Anticancer activity of CYT-Rx20 and the underlying mechanisms were analyzed using cell viability assay, reactive oxygen species (ROS) generation assay, fluorescence-activated cell sorter analysis, annexin V staining, comet assay, glutathione (GSH)/glutathione disulfide (GSSG) ratio, immunoblotting, soft agar assay, nude mice xenograft study, and immunohistochemistry.
  
  
  
  CYT-Rx20-induced cell apoptosis via ROS generation and mitochondrial membrane potential reduction, associated with release of mitochondrial cytochrome C to cytosol and activation of downstream caspases and poly ADP-ribose polymerase (PARP). Furthermore, CYT-Rx20 induced mitochondrial ROS accumulation and mitochondrial dysfunction, followed by GSH downregulation. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In nude mice, CYT-Rx20 inhibited oral tumor growth accompanied by increased expression of γH2AX, GSH reductase, and cleaved-caspase-3.
  
  
  
  CYT-Rx20 has the potential to be further developed into an antioral cancer drug clinically. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1055-1064, 2017.
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Yun
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Division of Oral Pathology and Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Oral and Maxillofacial Imaging Center, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yuk-Kwan
authors.initials: YK
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Stephen Chu-Sung
authors.initials: SC
authors.lastname: Hu
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.affiliation: Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Obstetrics and Gynecology and Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shyng-Shiou F
authors.initials: SF
authors.lastname: Yuan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001707:Biopsy, Needle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013343:Styrenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C512238:3-hydroxy-4-methoxy-beta-methyl-beta-nitrostyrene; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013343:Styrenes; D005978:Glutathione
keywords: apoptosis; glutathione (GSH); oral cancer; reactive oxygen species (ROS); β-Nitrostyrene