Proteins, antiapoptotic

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. 

Tran J, Rak J, Sheehan C, et al. Marked induction of the IAP family antiapoptotic proteins surviving and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999 264(3) 781-788. 

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. 

On astroglial cell lines (human astrocytoma ADF cells) low (nM) concentrations of the selective A3AR agonist Cl-IB-MECA induced a marked reorganization of cell cytoskeleton accompanied by induction of expression of small GTP-binding protein of the Rho family that is involved in control of actin cytoskeleton and by changes of intracellular distribution of the antiapoptotic protein Bcl-XL (Abbracchio et al. 1997, 2001). 

Gerber, H.P., Dixit, V. and Ferrara, N. (1998a) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and Al in vascular endothelial cellsJ. Biol. Chem., 273, 13313-13316. 

Hotta, M., Tashiro, F., Ikegami, H., Niwa, H., Ogihara, T., Yodoi, J. and Miyazaki, J. (1998). Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and Streptozotocin-induced diabetes. J. Exp. Med. 188, 1445-1451. 

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. 

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