title: Transient alteration of cellular redox buffering before irradiation triggers apoptosis in head and neck carcinoma stem and non-stem cells.
abstract: BACKGROUND
  Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. The major focus of this work was to design a transient glutathione depleting strategy during the course of irradiation of HNSCC in order to overcome their radioresistance associated with redox adaptation.
  
  
  RESULTS
  Treatment of SQ20B cells with dimethylfumarate (DMF), a GSH-depleting agent, and L-Buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis 4 h before a 10 Gy irradiation led to the lowering of the endogenous GSH content to less than 10% of that in control cells and to the triggering of radiation-induced apoptotic cell death. The sequence of biochemical events after GSH depletion and irradiation included ASK-1 followed by JNK activation which resulted in the triggering of the intrinsic apoptotic pathway through Bax translocation to mitochondria.
  
  
  CONCLUSIONS
  This transient GSH depletion also triggered radiation-induced cell death in SQ20B stem cells, a key event to overcome locoregional recurrence of HNSCC. Finally, our in vivo data highlight the relevance for further clinical trials of endogenous redox modulation to enhance the cytotoxic effects of radiotherapy.
authors.affiliation: Université de Lyon, Université Lyon-I, Lyon, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Boivin
authors.forename: Maité
authors.initials: M
authors.lastname: Hanot
authors.forename: Céline
authors.initials: C
authors.lastname: Malesys
authors.forename: Mira
authors.initials: M
authors.lastname: Maalouf
authors.forename: Robert
authors.initials: R
authors.lastname: Rousson
authors.forename: Claire
authors.initials: C
authors.lastname: Rodriguez-Lafrasse
authors.forename: Dominique
authors.initials: D
authors.lastname: Ardail
mesh_terms: D000222:Adaptation, Physiological; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002021:Buffers; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000473:pathology / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D010084:Oxidation-Reduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D002021:Buffers; D005650:Fumarates; D051028:bcl-2-Associated X Protein; D019328:Buthionine Sulfoximine; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D000069462:Dimethyl Fumarate; D005978:Glutathione