Peer-Reviewed Journal Details
Mandatory Fields
Duverger, V,Murphy, AM,Sheehan, D,England, K,Cotter, TG,Hayes, I,Murphy, FJ;
2004
February
British Journal of Cancer
The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)
Validated
()
Optional Fields
mithramycin A GM-CSF TNF anti-Fas apoptosis bcl-2 NF-KAPPA-B CHRONIC GRANULOCYTIC-LEUKEMIA DEATH DOMAIN PROTEIN GM-CSF CD95 APO-1/FAS BLAST PHASE BCL-2 INHIBITION EXPRESSION ACTIVATION
90
2025
2031
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. (C) 2004 Cancer Research UK.
DOI 10.1038/sj.bjc.6601824
Grant Details