title: Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma.
abstract: Glutathione (GSH) depletion is widely used to sensitize cells to anticancer treatment inducing the progression of programmed cell death and overcoming chemoresistance. It has been reported that neuroblastoma cells with MYCN amplification are unable to start TRAIL-dependent death and MYCN, in concert with cytotoxic drugs, efficiently induces the mitochondrial pathway of apoptosis through oxidative mechanisms. In this study, we show that GSH loss induced by L-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis, leads to overproduction of reactive oxygen species (ROS) and triggers apoptosis of MYCN-amplified neuroblastoma cells. BSO susceptibility of SK-N-BE-2C, a representative example of MYCN-amplified cells, has been attributed to stimulation of total SOD activity in the absence of changes in the level and the activity of catalase. Therefore, the unbalanced intracellular redox milieu has been demonstrated to be critical for the progression of neuroblastoma cell death that was efficiently prevented by antioxidants and rottlerin. These results describe a novel pathway of apoptosis dependent on ROS formation and PKC-delta activation and independent of p53, bcl-2, and bax levels; the selective redox modulation of PKC-delta might be suggested as a potential strategy for sensitizing MYCN-amplified cells to therapeutic approaches.
authors.affiliation: Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Marengo
authors.forename: Chiara
authors.initials: C
authors.lastname: De Ciucis
authors.forename: Daniela
authors.initials: D
authors.lastname: Verzola
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.forename: Stefania
authors.initials: S
authors.lastname: Patriarca
authors.forename: Emanuela
authors.initials: E
authors.lastname: Balbis
authors.forename: Nicola
authors.initials: N
authors.lastname: Traverso
authors.forename: Damiano
authors.initials: D
authors.lastname: Cottalasso
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pronzato
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Marinari
authors.forename: Cinzia
authors.initials: C
authors.lastname: Domenicotti
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D009861:Onium Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001205:Ascorbic Acid; D001578:Benzopyrans; D001713:Biphenyl Compounds; D019328:Buthionine Sulfoximine; D002154:Calpain; D020169:Caspases; D002374:Catalase; D005978:Glutathione; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D009861:Onium Compounds; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C459801:MYCN protein, human; C000606290:SOD1 protein, human; C031291:diphenyliodonium; C085746:rottlerin