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.

Salicylic acid-induced resistance to viruses and other pathogens: a parting of the ways?

Resistance genes allow plants to recognize specific pathogens. Recognition results in the activation of a variety of defence responses, including localized programmed cell death (the hypersensitive response), synthesis of pathogenesis-related proteins and induction of systemic acquired resistance. These responses are co-ordinated by a branching signal transduction pathway. In tobacco, one branch activates virus resistance, and might require the mitochondrial alternative oxidase to operate. Here we discuss the evidence for this virus-specific branch of the transduction pathway and assess what must be done to further understand virus resistance and the role of the alternative oxidase in its induction.