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Hypothesis: apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular
1Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Abstract:
1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl-2 can frequently prevent apoptotic changes and/or delay cell death. 2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl-2 can control. Our hypothesis is that apoptosis is used as an anti-viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself. 3. Experiments on the effect of sodium azide upon growth factor-dependent cells support this idea. Bcl-2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells. 4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub-lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.
Insights
Cells may trigger apoptosis, a programmed cell death, as an anti-viral defense against metabolic disturbances. This programmed cell death pathway, regulated by bcl-2, could be targeted for treating diseases like cancer and stroke.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Over 100 agents can induce apoptosis, a regulated cell death.
- The anti-apoptotic gene bcl-2 frequently inhibits these cell death pathways.
- The precise triggers and purpose of apoptosis remain incompletely understood.
Purpose of the Study:
- To investigate the hypothesis that apoptosis serves as an anti-viral defense mechanism.
- To explore the role of metabolic disturbance detection in initiating apoptosis.
- To examine the potential therapeutic applications of modulating apoptosis.
Main Methods:
- Investigated the effect of sodium azide on growth factor-dependent cells.
- Utilized electron microscopy to observe apoptotic changes.
- Assessed the inhibitory effects of bcl-2 on azide-induced cell death.
Main Results:
- Sodium azide induced cell death, with bcl-2 delaying but not preventing it.
- Bcl-2 inhibited observable apoptotic changes induced by azide.
- Findings support the hypothesis that cells initiate apoptosis in response to metabolic disturbances.
Conclusions:
- Apoptosis may function as an anti-viral strategy, with cells interpreting metabolic stress as infection.
- Modulating apoptosis holds therapeutic potential for ischemic diseases (e.g., stroke) and neoplastic diseases (e.g., cancer).
- Blocking apoptosis could limit tissue damage in stroke, while enhancing it may improve anti-cancer therapies.