The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicinand Taxol
IntroductionApoptosis, a morphologically and biochemically defined form of cell death, 1 plays a role in a wide variety of biologic systems, including tissue homeostasis and regulation of the immune system. 2,3 The process is a highly orchestrated cellular pathway leading to activation of the downstream death machinery. The central mediator and executioner of the death machinery is a proteolytic system involving a family of cysteinyl proteases, called caspases (for review, see Thornberry and Lazebnik 4 ). Triggering of the apoptotic cascade by different death stimuli, such as ionizing radiation 5 and chemotherapeutic drugs, 6 culminates in caspasedependent cleavage of a set of regulatory proteins, degradation of cellular DNA, and complete disassembly of the cell. Thus far, 14 caspase family members have been identified, and some of them, such as caspase-8, mediate apoptotic signals after the activation of death receptors. 7,8 Others, such as caspase-9, are part of the apoptosome and play a role in signal transduction after mitochondrial damage. 9 Recently, an endoplasmic-reticulum-specific pathway of apoptosis has been described that is mediated by caspase-12. 10 Previous data suggest that cytotoxic drugs induce cell death through CD95/Fas-CD95 ligand interaction, 11 and the relevance of this particular death pathway has been shown, for instance, in doxorubicin-induced apoptosis of leukemic T cells. 12 However, other groups were unable to confirm these findings and showed CD95/Fas-independent induction of apoptosis by chemotherapeutic drugs-for example, doxorubicin and etoposide-in Tlymphoma cells. 13,14 The finding that CD95/Fas-signaling and DNA damage induce different apoptosis-signaling pathways has also been shown in a murine and a human B-lymphoma cell line. 15 Furthermore, experimental evidence has been provided that neither FADD 16 nor caspase-8 17 is required for drug-induced apoptosis.In B cells, the induction of apoptosis plays important roles in humoral immunity. In this context, it has been shown that the antigen receptor BCR and the CD95/Fas receptor transduce pro-apoptotic signals in mature B cells (for review, see Tsubata 18 ). We previously showed that activation-induced apoptosis of normal and malignant B lymphocytes upon antigen-receptor ligation is independent of CD95/Fas and CD95/Fas ligand. 19 This has been confirmed by another study demonstrating that B-cell receptormediated apoptosis, in contrast to activation-induced T-cell apoptosis, is not mediated through known death receptor systems, nor does it involve the initial activation of caspase-8. 20 We nevertheless For personal use only. on May 12, 2018. by guest www.bloodjournal.org From observed that drug treatment leads to processing and activation of procaspase-8. We therefore focused our interest on the specific mechanisms leading to apoptotic death after the treatment of immature and mature B-lymphoma cells wi...