Caspase Inhibitors As Molecular Probes Of Cell Death

Recognition of the importance of programmed cell death in basic biological processes as well as its relevance to clinical problems has led to a surge of research interest in this area in recent years. The appealing idea behind much of this research is that an endogenous death pathway is present in most cells which can be triggered to kill cells by physiological signals or when they encounter some types of stressful conditions. In spite of the rapid progress made in some respects, fundamental issues in this field remain unresolved, and the major challenge is still to molecularly characterize this death pathway and understand the controls which lead to its activation. Recent research in a number of laboratories has identified a family of enzymes which at very least now provides a testable candidate for a central player in such physiological death pathways. Specific inhibitors of these enzymes are newly available tools which can be used to test for their participation in particular physiological and experimental cell death systems (Henkart, 1996). In this paper we will present examples illustrating their use from our own studies on lymphoid cells. For reasons which will become clear, we believe that a functional death criterion based on inhibiting enzyme function provides a more significant characterization of cell death than the commonly used apoptotic death phenotypes.