Mechanisms of Cell Death Apoptosis and Necrosis

Apoptosis or programmed cell death is the mechanism by which superfluous or damaged cells are removed in most organ systems. This applies to embryogenesis, organogenesis, maintenance of normal tissue structure, responses to mild chemical or physical damage, neutrophils following ingestion of bacteria, and AIDS pathogenesis. Apoptotic cells are driven into death by an active process that involves activation of several calcium-dependent endonucleases which bind to the internucleosomal spacer, resulting in the fragmentation of the DNA. These cells are morphologically characterised by condensation and fragmentation of cell nuclei, cytoplasmic densification, nuclear membrane blebbing, and breakdown of the nucleus into discrete fragments; however, integrity of cytoplasmic membranes and organelles is preserved. On the other hand, necrosis is a "non-specific" mode of cell death induced by cell membrane affections (complement attack, severe hypoxia, hyperthermia, lytic viral infection, and several toxic chemicals) which cause ions and water efflux, resulting in disruption of cytoplasmic and nuclear membranes, swelling of mitochondria, and floculation of chromatin (for review see Schwartz and Osborn, 1993).

A wide variety of stimuli can trigger cell death, such as T cell receptor signalling, binding of the APO-1/Fas ligand, glucocorticoides, TNF-a or transforming growth factor-^ to their receptors on appropriate cells, DNA strand breakage etc. (reviewed by Schwartz and Osborn, 1993; Green and Scott, 1995; Green and Martin, 1995). The "decision" of a cell to die is under the control of a number of different pathways considered as cellular "sensors" of apoptosis-inducing signals (such as p53 and others), which in turn trigger the central mechanisms leading to cell death (for review see Green and Martin, 1995). Most of the defects in apoptosis,' which may contribute to the transformed state of a cell, are suggested to focus on the triggering or sensing of apoptosis-inducing signals (Green and Martin, 1995).

There is growing evidence that the susceptibility of malignant neoplasms to undergo apoptosis in response to different therapeutic modalities may be used in predicting clinical response. Arends et al. (1994) observed that high apoptotic rates in immortalised rat fibroblasts injected subcutaneously into immunosuppressed mice resulted in slowly growing fibrosarcomas with high ratios of apoptosis to mitosis and little necrosis, while lines with low apoptotic rates in vitro generated rapidly expanding tumours with high mitotic rates, extensive necrosis, and little apoptosis relative to mitosis. Thus, any treatment or condition that favour apoptosis may have desirable effects.

Whole plant extracts

VA-E differ in regard of their cytotoxic activity (Büssing et al., 1996d; Büssing and Schietzel, 1999). This effect is probably not host tree-specific but dependent on the manufacturing process and thus, on biologically active compounds which in turns may depend on the host tree and time of harvest. VA-E were recognized to induce apoptosis of cultured cell lines within 24 to 72 h (Janssen et al., 1993; Büssing et al., 1996c, d, 1997, 1998a, b; Büssing and Schietzel, 1999). In human lymphocytes, the apoptosis-inducing property of the Iscador extracts and ABNOBAviscum extracts strongly correlated with their ML content, while, however, the ML-rich Helixor extracts did not (Büssing and Schietzel, 1999). Although Koch (1938a) observed the VA-E from winter harvests to possess a higher cytotoxic potential (probably due to a higher ML content) than those from summer harvests, however, no clear-cut correlation between defined components and the apoptosis-inducing potential of the aqueous extracts from the winter and summer harvest was found (Büssing and Schietzel, 1999). In fact, the winter extract from pine tree contained significantly higher amounts of ML but was the same effective the summer extract containing a lower amount of ML. It is tempting to speculate the involvement of other components which may modulate the activity of ML.

Defined components

During the 1960s, Vester and co-workers isolated and purified carcinostatic protein fractions from Viscum album (Vester and Nienhaus, 1965), which were recognised, in part, later on as ML and other proteins (Franz, 1986). The ML differ in molecular weight and carbohydrate specificity (Franz et al., 1981; Franz, 1986). The ML were found to be potent inducer of apoptosis (Janssen et al., 1993; Büssing et al., 1996c, 1997, 1998a, b, 1999b, f; Hostanska et al., 1996-1997; Möckel et al., 1997; Bantel et al., 1999), while the viscotoxins were found to affect cell membranes and thus induce accidental (necrotic) cell death with membrane permeabilisation, degradation of cytoplasm and chromatin, swelling of mitochondria with loss of their cristae, and generation of reactive oxygen intermediates (ROI) within 1 to 2 h, followed by secondary apoptosis-associated events (Büssing et al., 1998c, 1999b, c, f).

Whatever the underlying mechanisms are, there may be at least two distinct pathways of ML-mediated cell death: (1) direct induction of apoptosis in response to an inhibition of protein synthesis by the enzymic ML A chain (reviewed by Büssing, 1996e), and (2) indirect induction of apoptosis in Fas+ tumour cells by ML-activated FasL+ T cells (Büssing et al., 1999e).

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