This series of reviews on pharmacological manipulation of 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.
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.
Douglas R. Green, Guido Kroemer
The Akt and Pim kinases are cytoplasmic serine/threonine kinases that control programmed cell death by phosphorylating substrates that regulate both apoptosis and cellular metabolism. The PI3K-dependent activation of the Akt kinases and the JAK/STAT–dependent induction of the Pim kinases are examples of partially overlapping survival kinase pathways. Pharmacological manipulation of such kinases could have a major impact on the treatment of a wide variety of human diseases including cancer, inflammatory disorders, and ischemic diseases.
Ravi Amaravadi, Craig B. Thompson
IκB kinase/NF-κB (IKK/NF-κB) signaling pathways play critical roles in a variety of physiological and pathological processes. One function of NF-κB is promotion of cell survival through induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells. NF-κB can also prevent programmed necrosis by inducing genes encoding antioxidant proteins. Regardless of mechanism, many cancer cells, of either epithelial or hematopoietic origin, use NF-κB to achieve resistance to anticancer drugs, radiation, and death cytokines. Hence, inhibition of IKK-driven NF-κB activation offers a strategy for treatment of different malignancies and can convert inflammation-induced tumor growth to inflammation-induced tumor regression.
Jun-Li Luo, Hideaki Kamata, Michael Karin
Induction of heat shock proteins (Hsps) following cellular damage can prevent apoptosis induced by both the intrinsic and the extrinsic pathways. The intrinsic pathway is characterized by mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome assembly, and caspase activation. Hsps promote cell survival by preventing MOMP or apoptosome formation as well as via regulation of Akt and JNK activities. Engagement of the TNF death receptors induces the extrinsic pathway that is characterized by Fas-associated death domain–dependent (FADD-dependent) caspase-8 activation or induction of NF-κB to promote cellular survival. Hsps can directly suppress proapoptotic signaling events or stabilizing elements of the NF-κB pathway to promote cellular survival.
Helen M. Beere
Cell death by apoptosis or necrosis is often important in the etiology and treatment of disease. Since mitochondria play important roles in cell death pathways, these organelles are potentially prime targets for therapeutic intervention. Here we discuss the mechanisms through which mitochondria participate in the cell death process and also survey some of the pharmacological approaches that target mitochondria in various ways.
Lisa Bouchier-Hayes, Lydia Lartigue, Donald D. Newmeyer
The commitment to programmed cell death involves complex interactions among pro- and antiapoptotic members of the Bcl-2 family of proteins. The physiological result of a decision by these proteins to undergo cell death is permeabilization of the mitochondrial outer membrane. Pharmacologic manipulation of proteins in this family appears both feasible and efficacious, whether the goal is decreased cell death, as in ischemia of the myocardium or brain, or increased cell death, as in cancer.
Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
Chunyan Xu, Beatrice Bailly-Maitre, John C. Reed
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.
Inna N. Lavrik, Alexander Golks, Peter H. Krammer
Recent studies have shown that members of the inhibitor of apoptosis (IAP) protein family are highly expressed in several classes of cancer. The primary implication of these findings is that the elevated expression of IAPs is not coincidental but actually participates in oncogenesis by helping to allow the malignant cell to avoid apoptotic cell death. This concept, together with the discovery of several IAP-regulatory proteins that use a conserved mode of action, has stimulated a major effort by many research groups to devise IAP-targeting strategies as a means of developing novel antineoplastic drugs. In this Review, we consider the evidence both for and against the IAPs being valid therapeutic targets, and we describe the types of strategies being used to neutralize their functions.
Casey W. Wright, Colin S. Duckett
The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.
Beth Levine, Junying Yuan