Execution of apoptosis: Converging or diverging pathways?

There is increasing evidence that apoptosis and necrosis represent only two of several possible ways for cells to die. These two types of demise can o ccur simultaneously in tissues or cell cultures exposed to the same stimulu s, and often local metabolic conditions and the intensity of the same initi al insult decide the prevalence of either apoptosis or necrosis. Recent wor k has shown that execution of the apoptotic programme involves a relatively limited number of pathways. According to a general view, these would conve rge to activate the caspase family of proteases. However, there is increasi ng evidence that apoptotic-like features can be observed also in cells wher e caspases are inhibited by cell-permeable tripeptides, such as z-VaD-Ala-A sp-fluoromethyl ketone (z-VAD-fmk), or analogous compounds. This has posed the question as to whether apoptosis may or may not occur in a caspase inde pendent way, and whether caspase inhibitors may be effective in the treatme nt of disease. Also relevant is the understanding that low intracellular en ergy levels during apoptosis can preclude caspase activation, and consequen tly decide the occurrence and mode of demise in damaged cells. In viva, inc omplete execution of damaged cells by apoptosis may have profound implicati ons, as their persistence within a tissue, followed by delayed lysis, may e licit delayed pro-inflammatory reactions. In this minireview, we discuss so me recent findings suggesting that cells may use diverging execution pathwa ys, with different implications in pathology and therapy.