The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF).
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.
Duverger
V
V
EiRx Therapeutics Ltd, 2800 Cork Airport Business Park, Kinsale Road, Cork, Ireland.
Murphy
A-M
AM
Sheehan
D
D
England
K
K
Cotter
T G
TG
Hayes
I
I
Murphy
F J
FJ
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
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