Pharmacological Modulation of Caspase Activation

Deregulation of apoptosis resulting either in inappropriate loss or accumulation of cells is a major cause of many severe pathological conditions such as cancer, autoimmune diseases, microbial infections and degenerative disorders. Consequently, great interest has emerged in devising therapeutic strategies for intervening with cell death, either in a pro- or antiapoptotic direction. Among the different apoptosis-based drug targets, caspases, a family of intracellular cysteine proteases are most promising candidates, because they form the central core of the apoptotic machinery that coordinate cell death from various signals. Inappropriate cell death can be efficiently blocked by caspase inhibitors, whereas caspase activation or the inhibition of endogenous caspase inhibitors might be useful for the eradication of unwanted cells. Currently, numerous novel approaches are being followed employing gene therapy, antisense strategies, recombinant biologics or organic chemistry in order to target caspases or their endogenous inhibitors. Exciting proof-of-principle evidence obtained in several animal models confirms the validity of strategies targeting caspases and their enormous therapeutic potential. Although mostly in preclinical state, several therapeutics have recently progressed to clinical testing or were even approved by drug administration. This review summarizes the recent advances in the field of caspase targeting and discusses its wide-ranging opportunities for different human diseases.