title: Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer.
abstract: The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC).
  
  
  
  At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells. Dual silencing of the genes for GCLM and TrxR1 induced GSH depletion, Trx activity inhibition, and ROS accumulation, synergistically killing HNC cells. Inhibition of the GSH and Trx systems resulted in activation of the Nrf2-antioxidant response element (ARE) pathway, which may result in suboptimal GSH and Trx inhibition where HNC is resistant. Genetic inhibition of Nrf2 and/or HO-1 or trigonelline enhanced growth suppression, ROS accumulation, and cell death from GSH and Trx inhibition. The in vivo effects of GSH, Trx, and Nrf2 system inhibition were confirmed in a mouse HNC xenograft model by achieving growth inhibition >60% compared with those of control. Innovations: This study is the first to show that triple inhibition of GSH, Trx, and Nrf2 pathways could be an effective method to overcome the resistance of HNC.
  
  
  
  Inhibition of the Nrf2-ARE pathway in addition to dual inhibition of the GSH and Trx antioxidant systems can effectively eliminate resistant HNC. Antioxid. Redox Signal. 27, 106-114.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea.
authors.forename: Daiha
authors.initials: D
authors.lastname: Shin
mesh_terms: D000818:Animals; D001310:Auranofin / Q000008:administration & dosage* / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013879:Thioredoxins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C491203:TXN protein, human; D001310:Auranofin; D019328:Buthionine Sulfoximine; D013879:Thioredoxins; D005978:Glutathione
keywords: Nrf2; glutathione; head and neck cancer; reactive oxygen species; thioredoxin