Why is apoptosis important to clinicians?

Apoptosis—programmed cell death—was discovered in 1972,¹ and now that it approaches its 30th birthday its clinical importance is becoming clear. The excitement of apoptosis for doctors lies in the clinical implications of perturbed-restored control of cell number and function through a balance between cell death and cell survival.

Apoptosis may become disrupted in two major ways, and, as predicted over 20 years ago,² each seems to be associated with different types of disease. Inappropriate activation of the apoptotic process leads to disorders associated with pathological loss of cells—such as the immune defect in AIDS and possibly neurodegenerative diseases. In contrast, inadequate apoptosis, leading to inappropriate cell survival, leads to diseases associated with excessive accumulations of cells—such as cancer, chronic inflammatory conditions, and autoimmune diseases.

The defect in immunity associated with AIDS is the result of a profound reduction in the population size of CD4 + T helper cells caused by excessive apoptosis; this occurs even at comparatively low levels of HIV infectivity, so that many non-infected T cells must also be lost. The exact mechanisms are uncertain but may include transfer of regulatory viral gene products (such as HIV-1 Tat) from HIV infected cells to bystander T cells, rendering them susceptible to T cell receptor-induced, CD95-mediated apoptosis.³ Neurodegenerative disorders have also attracted attention,⁴ but the relative contribution of apoptosis to neurone cell loss in Alzheimer's disease is uncertain because not all degenerating neurons show clear features of apoptosis (which are extraordinarily difficult to quantify in situ, especially in chronic disease processes).

Nevertheless, an increasing body of indirect evidence suggests that neuronal cell apoptosis may be triggered by amyloid β and other neurotoxic abnormal protein structures or aggregates in Alzheimer's and other adult neurodegenerative diseases (including Huntington's chorea, Parkinson's disease, and amyotrophic lateral sclerosis).⁴ A central role for amyloid β protein is supported by the effects of genetic mutations that cause Alzheimer's disease, all of which predispose to amyloid deposition. It is also supported by the observation that amyloid β can exert neurotoxic effects in vitro and in vivo, and by mechanisms which may involve the generation of intracellular oxidative stress and increases in calcium ions, both of which can trigger apoptosis in susceptible cell types.⁴ These effects may be induced by amyloid β cross linking receptors for advanced glycosylation end products (RAGE), amyloid precursor protein (APP), or a receptor called P75, all of which can trigger neuronal apoptosis. In situ, however, the situation is much more complex, and other resident cells may play important roles. For example, microglial activation, which occurs in response to local amyloid plaque formation, is known to stimulate secretion of the tumour necrosis factor α and other factors that can induce apoptosis in vitro.

Many therapeutic approaches to counter inappropriate apoptosis have been mooted. Since proteolytic enzymes called caspases are critical to the control of apoptosis (they reorganise the dying cell from within and make it ready for safe clearance by phagocytes), several pharmaceutical companies are developing potent and specific caspase inhibitors. None is yet suitable for use in humans. Nevertheless, non-specific caspase inhibitors have shown great promise in in vitro and murine models of inappropriate neuronal apoptosis.⁵

Cancer, on the other hand, occurs when mutations affect the control mechanisms of apoptosis and cell survival. Indeed, the bcl-2 gene was identified as blocking apoptosis because of its abnormal overexpression in follicular lymphoma. Furthermore, mutations in p53 (a protein believed to be the “guardian of the genome”) prevent the deletion, by apoptosis, of cells with damaged DNA, so that tumours develop. Inflammatory disorders such as rheumatoid arthritis may also reflect prolonged survival of leucocytes that are normally programmed to die by apoptosis.

In both cases the therapeutic objective is to remove unwanted cells. The treatment of certain lymphomas by antisense oligonucleotides (which block gene transcription) to bcl-2 is a realistic prospect. Furthermore, death-inducing cytokines of the tumour necrosis factor family, such as TRAIL, are showing promise in colon cancer. Recent evidence has shown that normal and cancerous cells show major differential susceptibility to apoptosis stimulated by TRAIL.⁶ Moreover, death receptor-mediated apoptosis may be particularly valuable in cancer treatment since it is likely to be independent of p53 status (which is corrupted in 50% of all primary cancer tumours) and it is also largely independent of Bcl-2.⁷ Nevertheless, caution is necessary, since excessive generalised activation of cell death pathways can trigger a fatal form of haemorrhagic liver necrosis.

Thus apoptosis is no longer an arcane pathological phenomenon. Instead, the molecular basis of programmed death and cell survival is one of the most vibrant areas of laboratory research. Clinical trials are imminent, so we predict that this promising youngster will show many achievements by its 50th birthday.

See Clinical review pp 1525-31 Education and debate pp 1536-40