title: Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2.
abstract: Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan.
authors.affiliation: Department of Neurology, University of Tübingen, School of Medicine, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Reber
authors.forename: U
authors.initials: U
authors.lastname: Wüllner
authors.forename: M
authors.initials: M
authors.lastname: Trepel
authors.forename: J
authors.initials: J
authors.lastname: Baumgart
authors.forename: J
authors.initials: J
authors.lastname: Seyfried
authors.forename: T
authors.initials: T
authors.lastname: Klockgether
authors.forename: J
authors.initials: J
authors.lastname: Dichgans
authors.forename: M
authors.initials: M
authors.lastname: Weller
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002066:Busulfan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine / Q000627:therapeutic use*; D004357:Drug Synergism; D018014:Gene Transfer Techniques; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D000091402:Prohibitins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; C000717331:PHB2 protein, human; D000091402:Prohibitins; D019253:Proto-Oncogene Proteins c-bcl-2; D019328:Buthionine Sulfoximine; C018404:treosulfan; D002066:Busulfan; D005978:Glutathione