The health of multicellular organisms depends not only on the body's ability to produce new cells but also on controlled cell death. Apoptosis, or programmed cell death, is the opposite of mitosis. It is an active process for destruction of unwanted and superfluous cells. Changes in cell survival contribute to the pathogenesis of such varied disorders as cancer, many viral infections, neuropathies and immunopathies. The growing understanding of apoptosis forms the basis for development of new therapeutic strategies controlling cell death. This article describes mechanisms involved in the programmed cellular suicide.

In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.

Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997;48:267-81.

Regulation of the homeostatic balance between cell proliferation and cell death is essential for development and maintenance of multicellular organisms. Physiologic, or programmed, cell death is dependent on a genetically encoded and evolutionarily conserved pathway that induces a form of cellular suicide known as apoptosis. In the past decade, it has become clear that the regulatory mechanisms controlling programmed cell death are as fundamental, and as complex, as those regulating cell proliferation. Perturbation of the signaling cascades regulating apoptosis, whether by extracellular triggers, acquired or germline genetic mutations, or viral mimicry of signaling molecules, can result in a wide variety of human diseases. Analysis of these regulatory pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases including AIDS, autoimmune diseases, and neurodegenerative/neurodevelopmental diseases. Our understanding of the regulation of programmed cell death in health and disease is far from complete, and the challenge of converting that understanding into new therapeutic modalities has only begun to be approached.

Apoptosis and the cell cycle.Prog Cell Cycle Res. 1996;2:147-63.

Apoptosis is a genetically controlled response by which eukaryotic cells undergo programmed cell death. This phenomenon plays a major role in developmental pathways (1), provides a homeostatic balance of cell populations, and is deregulated in many diseases including cancer. Control of cell number is determined by an intricate balance of cell death and cell proliferation. Accumulation of cells through suppression of death can contribute to cancer and to persistent viral infections, while excessive death can result in impaired development and in degenerative diseases. Identification of genes that control cell death, and understanding of the impact of apoptosis in both development and disease has advanced our knowledge of apoptosis in the past few years. There appears to be a linkage between apoptosis and cell cycle control mechanisms. Elucidating the mechanisms that link cell cycle control with apoptosis will be of key importance in understanding tumour progression and designing new models of effective tumour therapy.

Apoptosis in tumorigenesis and cancer therapy.Front Biosci. 1997 Jul 15;2:d353-79.

Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents during both normal development as well as in adult pathological states. Much progress has recently been made in understanding the molecular pathways which regulate this process as well as new intersections between these. A direct interaction between components of the 'executioner'--the ICE-family of cysteine proteases--and the Bcl-2 family of proteins, which modulate a cell's propensity to undergo apoptosis, has recently been demonstrated. New pathways to cell survival, like the PI3-K/Akt signal transduction pathway, are also providing new clues as to the regulation of cell death by growth factors and extracellular matrix for example. The links which exist between apoptosis and cancer research are several. Genetic alterations in components of the apoptosis pathway occur during tumorigenesis and confer resistance to a variety of physiological (oncogene-induced cell death, loss of adhesion, growth under hypoxia) as well as therapeutic (chemotherapy and radiation) death triggers. Similarly, antineoplastic therapies are thought to induce tumor cell apoptosis, and consequently, common mutations in apoptosis-regulatory genes carry a poor prognosis for the patient. A more detailed understanding of the biochemistry of apoptosis and the ways in which it is disabled in tumors will likely reveal new transformation selective death triggers which stimulate cell death in ways independent of components like p53 and increase the therapeutic window of these drugs in the clinics.