Caspases: pharmacological manipulation of cell death

Abstract

Caspases, a family of cysteine proteases, play a central role in apoptosis. During the last decade, major progress has been made to further understand caspase structure and function, providing a unique basis for drug design. This Review gives an overview of caspases and their classification, structure, and substrate specificity. We also describe the current knowledge of how interference with caspase signaling can be used to pharmacologically manipulate cell death.

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…So far, the possibility that modulation of apoptotic factors could be accomplished in vivo and could produce significant effects has mostly been studied in animal models of acute ischaemic injury (stroke and myocardial infarction). Peptide inhibitors of caspases can reduce ischaemic injury 107,108 , and one small-molecule, non-peptide inhibitor, IDN6556 (Pfizer), had entered phase II clinical trials. However, for cancer, the goal is to increase, rather than inhibit, apoptosis.…”

“…However, for cancer, the goal is to increase, rather than inhibit, apoptosis. Various strategies are being pursued, including small molecules that lead to the activation of caspase 3, and small molecules that are inhibitors of prosurvival pathways such as Akt 107 .…”

“…IAPs are overexpressed in some cancers, and the cells of such cancers are relatively resistant to apoptosis. However, virus-mediated gene transfer of IAPs to the brain has been shown to reduce ischaemic injury in stroke models 107 . Thus, strategies for cancer therapeutics targeting apoptotic pathways are often diametrically opposed to strategies for cardiovascular therapeutics 109 .…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…The extrinsic pathway receives signals through the binding of extracellular protein ligands to proapoptotic death receptors (DRs), located on the cell surface (Ashkenazi and Dixit, 1998). Both pathways lead to hierarchical activation of specialized cysteine-aspartate proteases called caspases (Lavrik et al, 2005b;Li and Yuan, 2008). Apoptotic signals first activate initiator caspases, including caspase-2, -8, -9 and -10, by inducing their oligomerization at multiprotein platforms (Chen et al, 2002;Boatright et al, 2003;Bouchier-Hayes et al, 2009).…”

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

“…Apoptosis or type I 'programmed cell death' (PCD), upon activation, proceeds via 'extrinsic' (death receptor activation) and 'intrinsic' (mitochondrial) pathways, both converging at the level of caspase-3. 1 Anoikis is induced in cells after their detachment from the extracellular matrix (ECM) switching on apoptotic signaling pathways. 2 Necrosis, also known as unorganized way of dying or bioenergetic catastrophe, has been recently shown to be 'programmed' under certain conditions.…”