Key Points
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Physiological cell death, or apoptosis, has an important role in several normal processes, ranging from fetal development to ageing, and defects in the physiological pathways for apoptosis have a role in many diseases. Too little or too much cell death contributes to about half of the main medical illnesses for which adequate therapy or prevention is lacking. Consequently, great interest has emerged in devising therapeutic strategies for modulating the key molecules that make life-or-death decisions in cells.
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Apoptosis is caused by proteases known as 'caspases' — cysteine aspartyl-specific proteases. Among all the apoptosis-based drug targets, strategies that target caspases are at the forefront for blocking apoptosis in numerous diseases. Proof-of-concept data have been obtained in animal models, using peptidyl inhibitors of caspases that have shown substantial protection in rodent models of stroke.
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Several caspase activation pathways are known, including: the formation of a death-induced signalling complex (DISC) that contains members of the tumour-necrosis factor (TNF) family of cytokine receptors; the release of cytochrome c from mitochondria; and the injection of apoptosis-inducing proteases, such as granzyme B, into immune cells through perforin channels.
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Regulatory molecules of caspases, such as apoptosis-activating factor 1 (APAF1), have nucleotide-binding domains. APAF1 also contains a caspase-associated recruitment domain (CARD), which binds specifically to a complementary CARD within the prodomain of procaspase-9. To the extent that selective inhibitors of caspase-9 might be difficult to generate, drugs that attack the nucleotide-binding domain of APAF1 might represent a viable alternative.
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Inhibitor-of-apoptosis proteins (IAPs) keep caspases in check. Some IAPs are overexpressed in cancers, and are associated with resistance to apoptosis. Among these are survivin and melanoma IAP (MLIAP), which are expressed at low levels in normal adult tissues, but are found at high levels in certain types of tumour. Interest has arisen in strategies for interfering with IAP function, so that caspases can be freed to induce apoptosis of cancer cells. Antisense experiments have also helped to validate certain IAPs as potential drug targets for cancer.
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BCL2-family proteins regulate the release of cytochrome c and other proteins from mitochondria, with pro-apoptotic BCL2-family proteins promoting, and anti-apoptotic family members suppressing, protein release by affecting the permeability of mitochondrial membranes. Several approaches have been proposed for exploiting BCL2-family proteins for therapeutic gain. Strategies for generating small-molecule inhibitors of members of the BCL2 family, based on functional and structural studies of their dimerization, have been investigated. Compounds have been reported that bind to anti-apoptotic BCL2 or BCL-XL and promote apoptosis of cancer cells.
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Opportunities exist to indirectly affect apoptosis by modulating inputs into cell-death pathways through protein kinases, protein phosphatases, transcription factors and cell-surface receptors for cytokines, neurotrophins, cardiotrophins and growth factors. Although many signal-transducing proteins ultimately link to apoptosis pathways at some level, there are a few candidate drug discovery targets that directly modulate the expression or function of core death-machinery genes and proteins.
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Advances in understanding the molecular mechanisms of apoptosis proteins have revealed strategies for potential therapeutic intervention in a wide range of ailments in which cell survival and death are unbalanced. Some of these strategies have progressed to clinical testing in humans, and will undoubtedly teach us much about the prospects for modulating apoptosis as a therapeutic approach.
Abstract
Many of today's medical illnesses can be attributed directly or indirectly to problems with apoptosis — a programmed cell-suicide mechanism. Disorders in which defective regulation of apoptosis contributes to disease pathogenesis or progression can involve either cell accumulation, in which cell eradication or cell turnover is impaired, or cell loss, in which the cell-suicide programme is inappropriately triggered. Identification of the genes and gene products that are responsible for apoptosis, together with emerging information about the mechanisms of action and structures of apoptotic regulatory and effector proteins, has laid a foundation for the discovery of drugs, some of which are now undergoing evaluation in human clinical trials.
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Acknowledgements
I thank R. Cornell and A. Sawyer for manuscript preparation, and G. Salvesen and S. Frisch for helpful discussions.
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Glossary
- APOPTOSIS
-
A constellation of morphological changes that is observed by microscopy in cells that are undergoing programmed cell death.
- CASPASES
-
A family of intracellular cysteine proteases that are responsible for apoptosis.
- ZYMOGEN
-
The inactive pro-form of an enzyme. Typically, zymogens are activated by proteolysis.
- CHROMATIN
-
Nuclear DNA complexed with proteins, including histones, as well as with RNA.
- INDUCED PROXIMITY
-
A mechanism of caspase activation whereby the unprocessed pro-forms of caspases (zymogens) are brought into close proximity through interactions with other proteins. Because the zymogen forms of caspases have low levels of protease activity, bringing them into close proximity allows them to cleave each other, inducing their transition to the fully active state.
- NF-κB
-
A heterodimeric transcription factor of the REL family. NF-κB is known to bind to the promoters, and induce the transcription, of several anti-apoptotic proteins.
- INHIBITOR-OF-APOPTOSIS PROTEIN
-
(IAP). IAPs contain at least one copy of a Baculovirus IAP repeat (BIR) domain and suppress apoptosis when overexpressed. Several IAPs directly bind and inhibit caspases.
- BCL2
-
The founding member of a family of apoptosis-regulating proteins. Many BCL2-family members regulate mitochondria-dependent steps in cell-death pathways, with some suppressing, and others promoting, the release of apoptogenic proteins from these organelles.
- DEATH-INDUCING SIGNALLING COMPLEX
-
(DISC). The DISC refers to a complex of proteins that is assembled around the cytosolic domains of certain tumour-necrosis factor (TNF)-family death receptors that contain the death-domain structure. Invariant proteins of the DISC include the adaptor protein FADD and caspase-8. Other proteins can be found in some circumstances, depending on the TNF-family receptor and the cell type.
- APOPTOSOME
-
A multiprotein complex that consists of several (probably seven) molecules of APAF1 bound to cytochrome c and caspase-9. The apoptosome represents a holoenzyme complex, which maintains caspase-9 in an active conformation.
- LOCOREGIONAL
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Refers to an anatomic location or a region of the body. Typically used in the context of gene therapy, for which the delivery of viral vectors is limited to a tissue or body location.
- IATROGENIC INSULT
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Side effects or undesirable consequences that result from physician intervention.
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Reed, J. Apoptosis-based therapies. Nat Rev Drug Discov 1, 111–121 (2002). https://doi.org/10.1038/nrd726
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DOI: https://doi.org/10.1038/nrd726
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