Pharmacological manipulation of cell death: clinical applications in sight?

Abstract

This series of Reviews on cell death explores the creation of new therapies for correcting excessive or deficient cell death in human disease. Signal transduction pathways controlling cell death and the molecular core machinery responsible for cellular self-destruction have been elucidated with unprecedented celerity during the last decade, leading to the design of novel strategies for blocking pathological cell loss or for killing unwanted cells. Thus, an increasing number of compounds targeting a diverse range of apoptosis-related molecules are being explored at the preclinical and clinical levels. Beyond the agents that are already FDA approved, a range of molecules targeting apoptosis-regulatory transcription factors, regulators of mitochondrial membrane permeabilization, and inhibitors or activators of cell death-related proteases are under close scrutiny for drug development.

Figure 1

Checkpoints for apoptosis in the mitochondrial pathway. Most mammalian cell death proceeds via the mitochondrial pathway, as illustrated. Stimuli for the induction of apoptosis predominantly act by engaging proapoptotic members of the Bcl-2 family, which work to cause MOMP, and this is countered by the antiapoptotic Bcl-2 family members. Other cell death stimuli can cause MOMP by the induction of a mitochondrial permeability transition. In either case, release of proteins from the intermembrane space triggers the activation of caspases via the formation of an Apaf-1 apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates the executioner caspases. The activation of caspase-3, -7, and -9 is antagonized by XIAP, which in turn can be inhibited by Smac, Omi, and other proteins released upon MOMP. Not shown here are other pathways of caspase activation and apoptosis, including the death receptor pathway, and those resulting in activation of caspase-1 and -2 (see text). ANT, adenosine nuclear transporter; VDAC, voltage-dependent anion channel; IMS, intermembrane space; ΔΨ_m, mitochondrial transmembrane potential.