title: Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin.
abstract: We have investigated the effects of the protein kinase inhibitor wortmannin (WM) on the cytotoxic mechanisms of etoposide and ionising radiation (IR) in the Chinese hamster ovary K1 (CHO-K1) cell line, and its radiation-sensitive derivative, xrs-6, which is defective in DNA-dependent protein kinase (DNA-PK) function. WM potentiated the cytotoxicity of etoposide and IR in CHO-K1 cells approximately 1.6 and 3-fold, respectively, and this potentiation was abolished in xrs-6 cells, which were themselves more sensitive to etoposide and IR alone. WM partially inhibited the repair of etoposide-induced DNA double-strand breaks. Etoposide treatment caused a biphasic inhibition of DNA synthesis in both cell lines, and this was abrogated by co-incubation with WM. These data suggest that WM inhibits in intact cells both DNA-PK and either or both the ataxia telangiectasia (AT) and AT-related gene products ATM and ATR.
authors.affiliation: Department of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Boulton
authors.forename: S
authors.initials: S
authors.lastname: Kyle
authors.forename: B W
authors.initials: BW
authors.lastname: Durkacz
mesh_terms: D000730:Androstadienes / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D016466:CHO Cells / Q000187:drug effects*; D018797:Cell Cycle Proteins; D006224:Cricetinae; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D005047:Etoposide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D000077191:Wortmannin