Anti-apoptotic properties

Oxidative stress appears to have a central role in the induction of apoptosis following the exposure of cells to a range of cytotoxic insults. Anti-apoptotic properties of the antioxidant, 4b,5,9b,10-tetrahydroindeno[l,2-b]indole, in Jurkat T cells subjected to a number of cytotoxic insults. Peroxide and superoxide anion production following UV treatment showed that indole derivative was found to only partially inhibit superoxide anion production and exhibited strong inhibition of caspase-3 activation in UV [115]. 

Minocycline is a tedacycline antibiotic with anti-inflammatory and anti-apoptotic properties. It has been shown to delay disease onset and prolong survival in dansgenic ALS mice (Zhu et al., 2002 Kiiz et al., 2002). Two early phase randomized condolled dials indicated that minocycline could be used safely in high doses and in conjunction withriluzole (Gordon et al., 2004). but minocycline caused a worsening of function in a recent phase III dial (Gordon et al., 2007). A separate efficacy dial is just underw ay in Europe, so that cumulative data may determine the due effect of minocycline in ALS. 

Selegiline may have anti-oxidant and anti-apoptotic properties in addition to inhibiting MAO, and has been reported to increase SOD activity in the basal ganglia of rats (Knoll, 1989). There have been several duals of selegiline 10mg per day in patients with ALS a randomized, placebo controlled, double blind trial (Lange et al., 1998), and a placebo-con trolled crossover trial (Mitchell et al., 1995). Neither showed improvement in functional or subjective rating scales, but both trials were underpowered due to insufficient sample size and so may be considered inconclusive. 

The anti-apoptotic properties of Bcl-2 family members have been used to protect industrially important cell lines, including GS-NSO and GS-CHO cells [44, 45], from insults typically experienced during cell culture operations. Interestingly, although Tey et al. [45] report that over-expression of Bcl-2 protects a GS-NSO cell line against... 

It has been reported that NO can have both pro- and anti-apoptotic properties (Li and Billiar 1999 Weller et al. 2002 Liu et al. 1998 Pervin et al. 2001a, b, 2003a, b). Inhibition of apoptosis by NO is reported in endothelial cells, hepatocytes, and other tumor cells (Li and Billiar 1999 Weller et al. 2002 Liu and Stamler 1999). NO induces S-nitrosylation of active site cysteines in caspases and other related proteins leading to inhibition of apoptosis and the formation of 5-nitrosothiols leading to the oxidation of thiol proteins, which might act as switches in cell survival and apoptotic signaling pathway (Mannick et al. 2001 Azad et al. 2006 Marshall et al. 2000). 

Mcl-l is a recognized major resistance factor in human cancer and Mcl-l over-expression has been linked to the pathogenesis of several cancers. Its anti-apoptotic properties are mechanistically related to its neutralizing interaction with BIM, BAK, NOXA and PUMA. ° Recently, a compelling Mcl-l BH3 stapled peptide has been reported to exhibit highly specificity and affinity to bind Mcl-l as well as effectively sensitizing cancer cells to caspase-dependent apoptosis in vitroJ An X-ray structure of Mcl-l complexed with this Mcl-l BH3 stapled peptide was also determined and showed inter-molecular contact of its hydrocarbon staple moiety with Mcl-l, accounting for the specificity versus other Bcl-2 family proteins. 

The structure of Bc1-Xl provides support for this idea (Plate 27). (Refs. 27—37 provide more information on the properties of pro- and anti-apoptotic proteins which control the fate of the cell). 

This family of proteins plays a central role in the early life/death decisions of cells. The first family member discovered was Bcl-2 itself (identified as being overexpressed in B cell lymphoma) but since its discovery many other family members have been identified on the basis of the presence of conserved sequence motifs or BH domains (Bcl-2 homology domains) within their structures [66, 67]. Curiously, members belonging to this family can have anti-apoptotic effects (e.g. Bcl-2, Bc1-Xl) or pro-apoptotic effects (e.g. Bax, Bak, Bid, Bak) [68]. The niunber and types of BH domains present within these family members dictate their properties and function in the apoptotic process. Some family members possess 4 domains, whereas others contain only one. 

The hallmark feature of the Bcl-2 proteins is their ability to form hetero-or homodimers [69-71], The BH domains are the key to this property and form a-helical structures that serve as protein protein interaction motifs. For example, the BH4 domain (found in most, but not all anti-apoptotic family members) may be responsible for molecular interactions with calcineurin and Raf-1 [72, 73], The importance of the BH4 domain is emphasised by the fact that in cells transfected with a mutant or truncated form of Bcl-2 (an anti-apoptotic protein) apoptosis is accelerated [74,75], There is also some evidence that this BH4 domain may be involved in control of the voltage-dependent anion channel of mitochondria [76], Some pro-apoptotic proteins (e.g. Bik, Bid and Bad) only possess the BH3 domain. Consequently, this has led to the idea that this domain is the minimal death domain required for the activity of some pro-apoptotic proteins. 

If neutrophils do express neither Bcl-2 nor Bc1-Xl, then how is their survival regulated The answer lies in the fact that they express Mcl-l [31, 100], an anti-apoptotic protein of the Bcl-2 family that has some unusual properties compared to other members of the family. These properties of Mcl-l make it ideally suited to its function in the survival of neutrophils, cells which must respond very quickly to either pro- or anti-inflammatory signals in their environment so that their role in infections and inflammation is tightly controlled. 

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