In some cells, drug treatment and other stimuli can trigger a series of complex cyto-plasmic biochemical reactions that appear to constitute a cellular suicide program, culminating in the degradation and compaction of chromatin. This programmed mode of cell death is known as apoptosis, and in normal cellular conditions, it plays a considerable role in the early development of homeostasis of adult tissues. Apoptosis or literally "programmed cell death," is so far known to be triggered by three major stimuli: cell surface receptors such as FAS, mitochondrial response to stress, and cytotoxic T-cells.

The Fas receptor (CD95) mediates apoptotic signaling by Fas ligand expressed on the surface of other cells. Binding of FAS to Fas ligand activates apoptotic signaling through activation of a series of cytoplasmic enzymes called caspases. Caspases are cys-teine proteases that convey the apoptotic signal by cleaving and activating other cas-pases, which then degrade DNA. Caspase-8 is the initial caspase involved in response to receptors with a death domain such as FAS. The mitochondrial stress pathway begins with the release of cytochrome c from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9, which activates caspase-3, -6 and -7, which act themselves to cleave cellular targets. One mechanism used by cytotoxic T-cells to kill tumor cells and virus-infected cells is the release of perforin and granzyme proteins. Granzyme B and perforin proteins released by cytotoxic T-cells induce apoptosis in targeted cells, forming transmembrane pores, and trigge apoptosis through cleavage of caspases. For the past two decades, there has been a considerable amount of research of agents that interfere with apoptosis, and natural products, most of which are elaborated in Asian plant species, are being scheduled for clinical trials, such as theaflavins from tea, flavonoid derivative flavopiridol, epigallocatechin gallate, gossypol, and embelin (Figs. 99, 100) (56-60).

Embelin, which is common in the family Myrsinaceae in plants such as Embelia ribes Burm f., is of particular interest because it binds to the BIR3 domain of X-linked mammalian inhibitor of apoptosis protein (XIAP) and competes with caspase-9. Embelin inhibits cell growth, induces apoptosis, and activates caspase-9 in prostate cancer cells with high levels of XIAP, but has a minimal effect on normal prostate epithelial and fibroblast cells with low levels of XIAP and represents a promising lead compound for designing an entirely new class of anticancer agents that target the BIR3 domain of XIAP.

Fig. 101. Typical flower of Goniothalamus (Goniothalamus scortechinii King). The figure shows the veined petals and sepals.

Fig. 101. Typical flower of Goniothalamus (Goniothalamus scortechinii King). The figure shows the veined petals and sepals.

One might have noticed that most of these natural products are of a phenolic nature and we can reasonably expect, in light of the complexity of apoptosis and the broad spectrum of cytotoxic agents elaborated from flowering plants, the discovery of lead apoptotic-antineoplastic agents in the relatively near future. When looking for such agents, one could investigate the medicinal flora of the Asia-Pacific region.

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