title: Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine.
abstract: In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Clark
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Inhye
authors.initials: I
authors.lastname: Park
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Florio
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Cichon
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rustin
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Jugov
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Ruhina
authors.initials: R
authors.lastname: Maeshima
authors.affiliation: Cancer Section, Developmental Biology & Cancer Programme, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Electronic address: A.stoker@ucl.ac.uk.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stoker
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D014638:Vanadates / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D011753:Pyrones; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D019328:Buthionine Sulfoximine
keywords: Bis(maltolato)oxovanadium(IV); Glutathione; Neuroblastoma; Tyrosine phosphatase; Vanadate