title: Depletion of glutathione by buthionine sulfoxine is cytotoxic for human neuroblastoma cell lines via apoptosis.
abstract: Buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) synthesis and has been used to sensitize tumor cells to alkylating agents, but has minimal single-agent cytotoxicity for most cell types. We determined the cytotoxicity of BSO for 18 (12 MYCN amplified; 6 MYCN nonamplified) human neuroblastoma cell lines using DIMSCAN, a digital image microscopy cytotoxicity assay. D-L(R:S) BSO was highly cytotoxic (>3 logs of cell kill) for most neuroblastoma cell lines, with 17/18 cell lines having IC90 values (range 2. 1->1000 microM) below equivalent steady state plasma levels of L(R:S) BSO reported in adult human trials. Cell lines with genomic amplification of MYCN were more sensitive to BSO than MYCN nonamplified cell lines (P = 0.04). D-L(R:S) BSO (500 microM for 72 h) induced apoptosis as detected by DNA laddering, nuclear morphology, and TUNEL staining of DNA fragments using flow cytometry. Maximal cell killing occurred within 48 h and was antagonized byic value in neuroblastoma.
authors.affiliation: Division of Hematology-Oncology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California, 90027, USA. cpreynol@hsc.usc.edu
authors.forename: C P
authors.initials: CP
authors.lastname: Anderson
authors.forename: J M
authors.initials: JM
authors.lastname: Tsai
authors.forename: W E
authors.initials: WE
authors.lastname: Meek
authors.forename: R M
authors.initials: RM
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.forename: H J
authors.initials: HJ
authors.lastname: Forman
authors.forename: C P
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005784:Gene Amplification; D016259:Genes, myc / Q000235:genetics; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D014810:Vitamin E; D019328:Buthionine Sulfoximine; D005978:Glutathione; D001205:Ascorbic Acid