Apoptosis, apoptotic effect

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

The involvement of mitochondria in the pro-apoptotic effects of carotenoids has been clearly demonstrated by the fact that P-carotene induces the release of cytochrome c from mitochondria and alters the mitochondrial membrane potential (Aym) in different tumor cells (Palozza et al., 2003a). Moreover, the highly polar xanthophyll neoxanthin has been reported to induce apoptosis in colon cancer cells by a mechanism that involves its accumulation into the mitochondria and a consequent loss of mitochondrial transmembrane potential and releas of cytochrome c and apoptosis-inducing factor (Terasaki et al., 2007). 

Although cadmium is not strongly mutagenic, it is known that it causes increased oxidative DNA damage and that it inhibits the DNA repair systems. It has also been found to induce cell death both by necrosis and apoptosis. Since the latter is extremely calcium-dependent, it seems likely that the pro-apoptotic effects of cadmium are due to its interference with calcium homeostasis. 

SMase activity (Mansat et al 1997) and downstream (by blocking the apoptotic effect of ceramide). However, the cross-talk between ceramides and DAG opens new intriguing avenues of research and may lead to better pharmacological maiupulation of key steps in the apoptosis/survival signaling cascade resulting in an increased chemosensitivity of neoplastic cells. 

This chapter describes the metabohsm of sphingosine and SIP, evidence to support their pro- and anti-apoptotic effects and their proposed sites of action on signaling processes that contribute to apoptosis and proliferation. 

A detailed analysis of p53-activated genes has shown that this includes many genes that can generate or respond to oxidative stress (Polyak et al., 1997). The hnk between oxidative stress and p53 may be explained by the apoptotic effect of p53. It is plausible that formation of activated oxygen is involved in triggering of p53-mediated apoptosis. 

In contrast to catechol and hydroquinone, phenol was a weak inducer of apoptosis in HL60 human promyelocytic leukaemia cells, and had an apoptotic effect only at the highest concentration tested (0.75 mmol/L) (Moran et al., 1996). Phenol (< 10 mmol/L) had no effect on the colony formation of granulocytes/macrophages induced by a recombinant granulocyte/macrophage colony-stimulating factor of murine bone-marrow cells (Irons et al., 1992). 

Mechanisms of oxLDL-induced apoptosis have been studied in numerous in vitro models, such as SMC, EC, macrophages and lymphocytes, for which cytotoxic and apoptotic effect of oxidized lipids were demonstrated. In vitro experiments have shown that slightly or strongly oxidized LDL may have dual effect on vascular cells. For instance slightly oxidized LDL have a proliferative effect on SMC and macrophages (Auge et al 1999 Heery et al., 1995), whereas strongly oxidized LDL promote apoptosis (Hsieh et al. 2001, Siow et al., 1999 Bjorkerud and Bjorkerud, 19961 ). These opposite effects are probably related to the concentration and the quality of oxidized lipids internalized by the cells, but could also result from biochemical differences between cellular pathways of oxLDL uptake. 

The anti-apoptotic effect of dysbindin-1 is due in part to increased Akt signaling, which is well known for its ability to suppress apoptosis (see Manning and Cantley, 2007). As shown by Numakawa et al. (2004), overexpression of dysbindin-1 in immature cerebrocortical neurons increases phosphorylation of Akt (O Figure 2.2-22a), whereas dysbindin-1 knockdown had the opposite effect ( Figure 2.2-22b). 

It is also unclear what role the predicted DNA-PK site in dysbindin-1 may have in enabling or mediating its anti-apoptotic effect. As explained earlier (see Section 2.2.3.3.1), DNA-PK, which phosphorylates dysbindin-1 (Oyama et al., 2009), helps repair double-strand DNA breaks and suppresses apoptosis in developing and adult neurons (cf., Chechlacz et al., 2001, Culmsee et al., 2001, Vermuri et al., 2001, and Neema et al., 2005). Anti-apoptotic effects of DNA-PK on prenatal neurons (Vermuri et al., 2001) presumably have a major impact on brain development, especially given that the highest levels of DNA-PK are found in fetal tissue (Oka et al., 2000). It will thus be important to test if DNA-PK phosphorylation of nuclear dysbindin-1 in developing neurons contributes to the survival of those cells. 

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