title: The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF).
abstract: In this report we show that mithramycin considerably increases the direct cytotoxic effect of tumour necrosis factor (TNF) on tumour cells in vitro. Sensitisation to TNF-induced apoptosis was prevented by the broad caspase inhibitor zVAD-fmk, whereas overexpression of Bcl-2 had no effect. Mithramycin also potentiated cell death induced by Fas agonistic antibodies. In contrast, mithramycin reduced the percentage of cells undergoing apoptosis due to factor withdrawal. TNF-induced activation of NF-kappaB (NF-kappaB)-dependent gene expression was not modulated by mithramycin treatment. Concomitantly with the increased sensitivity, the protein level of the short-spliced cFLIP variant was downregulated. These results indicate that mithramycin enhances TNF-induced cell death in an NF-kappaB-independent manner, and suggest that the Fas-associated death domain protein plays a crucial role in the TNF-sensitising effect of mithramycin.
authors.affiliation: EiRx Therapeutics Ltd, 2800 Cork Airport Business Park, Kinsale Road, Cork, Ireland.
authors.forename: V
authors.initials: V
authors.lastname: Duverger
authors.forename: A-M
authors.initials: AM
authors.lastname: Murphy
authors.forename: D
authors.initials: D
authors.lastname: Sheehan
authors.forename: K
authors.initials: K
authors.lastname: England
authors.forename: T G
authors.initials: TG
authors.lastname: Cotter
authors.forename: I
authors.initials: I
authors.lastname: Hayes
authors.forename: F J
authors.initials: FJ
authors.lastname: Murphy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D053200:Fas-Associated Death Domain Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C066851:mithramycin A; D008926:Plicamycin