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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3053-3063
Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the
Absence of CD95 Receptor/Ligand Interaction
Sebastian Wesselborg,
Ingo H. Engels,
Evi Rossmann,
Marek Los, and
Klaus Schulze-Osthoff
From the Department of Internal Medicine I,
Eberhard-Karls-University, Tübingen, Germany.
Proteases of the caspase family are the critical executioners of
apoptosis. Their activation has been mainly studied upon triggering of
death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1,
which recruit caspase-8/FLICE as the most proximal effector to the
receptor complex. Because apoptosis induced by anticancer drugs has
been proposed to involve CD95/CD95 ligand interaction, we investigated
the mechanism of caspase activation by daunorubicin, doxorubicin,
etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs
induced apoptosis and the cleavage of procaspase-8 to its active p18
subunit. However, cells resistant to CD95 were equally susceptible to
anticancer drugs and activated caspase-8 with a similar kinetic and
dose response as CD95-sensitive cells. The broad caspase inhibitor
benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis
and caspase-8 activation in response to CD95 and drug treatment,
whereas a neutralizing CD95 decoy as well as a dominant-negative FADD
construct selectively abrogated CD95, but not drug-induced effects. A
potent activation of caspase-8 was also induced by cycloheximide,
indicating that it was independent of protein synthesis. Our data,
therefore, show that (1) anticancer drug-induced apoptosis does not
require de novo synthesis of death ligands or CD95 interaction, and (2)
that caspase-8 can be activated in the absence of a death receptor signaling.
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