Apoptosis antiapoptotic proteins

Oblimersen sodium is a DNA antisense oligonucleotide designed to specifically bind to human bcl-2 mRNA, resulting in catalytic degradation of bcl-2. This results in decreased translation of the protein Bcl-2, which is a cellular antiapoptotic protein. Thus, oblimersen enhances sensitivity to chemotherapy by shifting the intracellular balance to a state in which the cells are more likely to be killed by apoptosis. Currently, it is used in combination chemotherapy for treating advanced melanoma. 

Antiapoptotic proteins. There are many different intracellular proteins that can prevent apoptosis by inhibiting specific steps in the cell death process. These include Bcl-2 family members such as Bcl-2 and Bcl-xL which can stabilize (mitochondrial, ER and plasma) membranes (Bcl-2 may also have intrinsic antioxidant activity). Other proteins, IAPs such as XIAP (X-linked) and NIAP (neuronal), which can directly inhibit caspases [31]. Additional examples of antiapoptotic proteins include protease inhibitors such as calpastatin, and protein chaperones such as GRP-78 and heat shock protein (HSP)-70. 

The mechanism of biological action of 281 has been thoroughly investigated (04MI4, 04MI5). These 2-aminochromenes reveal anticancer activity as the result of caspase activation, and, consequently, starting the apoptosis mechanism. However, somewhat different 2-amino-4H-chromenes 161 show antitumor activity by another mechanism, which involves inactivation of antiapoptotic proteins of the Bcl-2 series. 

The biochemical basis of the various activities of the Bcl-2 family members is only partially imderstood. The antiapoptotic Bcl-2 proteins may function by directly inhibiting the activation of the caspases (see 15.3.3). It is assumed that proapoptotic proteins interact with antiapoptotic proteins and halt their inhibition of apoptosis. 

The target of the caspase proteins are nuclear, regulatory, and cytoskeleton proteins, whose degradation triggers the apoptotic response. The proteins of the bcl gene family modulate caspase activity and are divided into proapoptotic and anti-apoptotic fractions (see Figure 11.3). The BCL-associated death (BAD) protein is one of the proapoptotic proteins, whereas BCL-2 is one of the antiapoptotic proteins. The BCL proteins that interact with the caspases to determine whether apoptosis occurs are themselves phosphorylated by PI-3K. 

Furthermore, these researchers have found that compound 51 induces growth inhibition in T-84 cells due to its ability to induce cell-cycle arrest and/or apoptosis, while compound 18 blocked more than 60% of cells at the G2/M phase without inducing apoptosis [149]. Compound 50 (Fig. 13) also produced G2/M cell-cycle arrest and induction of apoptosis. Studying the QDO effects on molecules that regulate apoptosis and the G2 to M transition, 18 and 50 inhibited the expression of cyclin B while 51 decreased the levels of Bcl-2, gene that codifies for the antiapoptotic protein bcl-2, and increased Bax expression, gene with proapoptotic functions. 

The mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (for example mercury), cisplatin can accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (for example bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (146,195-197). 

Fig. 15.3 The major pathways of apoptosis. The extrinsic pathway uses extracellular death ligands (Fas ligand, tumor necrosis factor (TNF)) to activate death receptors which pass the apoptotic signal to initiator caspases (e. g. capsase 8) and to the executioner caspases (e. g. caspase 3 caspase 7). In the execution phase of apoptosis, various cellular substrates are degraded leading to cellular collapse. The intrinsic pathway uses the mitochondria as a central component for activation of apoptosis. In this pathway, a multitude of intracellular signals including various stresses, DNA damage and inappropriate cell signaling lead to activation of the pro-apoptotic protein Bax which induces release of cytochrome c from mitochindria, formation of the apoptosome and activation of the initiator caspase 9. Finally, the executioner caspases are activated and cells are destructed by proteolysis. Apoptosis via this pathway can be controlled by various antiapoptotic proteins including the Bcl-2 protein and inhibitors of apoptosis.

A singular characteristic of neutrophils is that they undergo spontaneous apoptosis. Whereas this process and its modulation by various agents have been extensively studied in neutrophils [as recently reviewed in 100 and in this book], the molecular events involved remain poorly understood. Given its central role in the induction of various antiapoptotic proteins, the NF-kB pathway could represent an important mechanism whereby neutrophil apoptosis is regulated, as described in many other cellular models [reviewed in 101]. 

Because apoptosis is pivotal in tissue turnover, we evaluated the expression of Bcl-2 (antiapoptotic protein) and cas-pase-3 (proapoptotic protein) before and after DHA treatment of skin. We observed that DHA treatment of normal skin increased the expression of Bcl-2 and decreased the expression of caspase-3. The topical application of 135-HODE and/or 155-HETrE to the DHA-induced epidermal hyperplasia suppressed DHA-induced expression of Bcl-2 and enhanced the expression of caspase-3. Although the mecha-... 

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