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Article

New Approaches and Therapeutics Targeting Apoptosis in Disease

Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany

Abstract

I. Introduction

II. The Apoptotic Machinery

III. Death Receptors on the Trail to Tumor-Selective Cell Death

IV. Drug Design of Caspase Inhibitors

V. Caspase Activators

VI. Inhibitor of Apoptosis Protein-Based Therapeutics: Releasing the Apoptotic Brakes

VII. Bcl-2 Family Proteins As Targets of Drug Design

VIII. Targeting Mitochondria Directly

IX. Tumor Suppressor p53

X. Viral Death Proteins Apoptin and E4orf4

XI. Interfering with Protein Degradation: Targeting the Proteasome

XII. Prospects of Apoptosis-Targeted Therapies

Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. Presumably, even more important is a causative or contributing role of apoptosis to various human diseases. These include situations with unwanted cell accumulation (cancer) and failure to eradicate aberrant cells (autoimmune diseases) or disorders with an inappropriate loss of cells (heart failure, stroke, AIDS, neurodegenerative diseases, and liver injury). The past decade has witnessed a tremendous progress in the knowledge of the molecular mechanisms that regulate apoptosis and the mediators that either prevent or trigger cell death. Consequently, apoptosis regulators have emerged as key targets for the design of therapeutic strategies aimed at modulating cellular life-and-death decisions. Numerous novel approaches are currently being followed employing gene therapy and antisense strategies, recombinant biologics, or classical organic and combinatorial chemistry to target specific apoptotic regulators. Convincing proof-of-principle evidence obtained in several animal models confirms the validity of strategies targeting apoptosis and revealed an enormous potential for therapeutic intervention in a variety of illnesses. Although numerous apoptotic drugs are currently being developed, several therapeutics have progressed to clinical testing or are already approved and marketed. Here we review the recent progress of apoptosis-based therapies and survey some highlights in a very promising field of drug development.

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