title: Gamma-glutamyltransferase-dependent resistance to arsenic trioxide in melanoma cells and cellular sensitization by ascorbic acid.
abstract: The cell ability of tumor cells to tolerate stress conditions is a typical feature of solid tumors. In particular, the resistance to oxidative stress of melanoma cells likely contributes to their intrinsic drug resistance. In an attempt to develop novel strategies for overcoming the mechanisms of cellular protection against oxidative stress, in this study we have explored the efficacy of the combination of two prooxidant agents in two human melanoma cell clones. The selected clones are characterized by a marked difference in expression of gamma-glutamyltransferase, which is known to produce a persistent low level of oxidative stress resulting in the stimulation of protective systems. The gamma-glutamyltransferase-overexpressing clone exhibited a low susceptibility to arsenic trioxide-induced apoptosis, associated with low reactive oxygen species induction and increased catalase activity. The combination of arsenic trioxide with subtoxic concentrations of ascorbic acid resulted in a sensitization to apoptotic cell death. The expression of protective mechanisms, in particular catalase activity, accounted for the behavior of the resistant clone. The sensitization achieved by the combination was associated with a cellular response involving the ASK1/p38 axis, which is implicated in the regulation of catalase expression and the activation of apoptotic signals. In conclusion, the results of our study provide evidence that a rational combination of prooxidant agents may be effective in overcoming cellular tolerance to oxidative stress.
authors.affiliation: Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giommarelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Supino
authors.forename: Enrica
authors.initials: E
authors.lastname: Favini
authors.forename: Aldo
authors.initials: A
authors.lastname: Paolicchi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Pompella
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D019610:Cytoprotection; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010087:Oxides / Q000627:therapeutic use*; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D002374:Catalase; D005723:gamma-Glutamyltransferase; D048848:MAP Kinase Kinase Kinase 5; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide