Apoptosis induction pathways

Herman-Antosiewicz A and Singh S V (2004), Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds a review , Mutation Res, 555, 121-131. 

In summary, the binding of oxLDL and/or lipids to several SC receptors (SRAI/II, CD36, CD68) has been clearly demonstrated. Most of other receptors may potentially bind oxLDL or lipids. Consequently, the cellular internalization of oxidized lipids by the SC receptor pathways may be involved in the biological effect of oxLDL, such as apoptosis induction. As a likely major ligand and because of their oxidized lipid contents, oxLDL may have many putative effects on different cells, such as alteration of cell signaling and gene expression. 

The second important function of the p53 protein is initiation of apoptosis. This pathway involves induction of the Bax protein, which is a part of the apoptotic program of the cell. 

Figure 15.4 Mechanisms of apoptosis induction by resveratrol. Resveratrol selectively induces apoptosis in various cancer cells in culture by several mechanisms including activation of death receptor-mediated signaling, mitochondria-dependent cytochrome c release and caspase activation, induction of p53 and p53-regulated proapototic genes, activation of MAP kinase-mediated p53 phosphorylation, blockade of Akt-mediated cell survival pathways, and accumulation of intracellular ceramide level.

A common feature of many animal viruses is their capacity to induce programmed cell death (apoptosis), a process characterized by cell shrinkage, nuclear condensation, and DNA fragmentation (Shen and Shenk, 1995). Apoptosis may serve as a host defense to limit virus growth, or it may promote virus spread or enhance viral replication via activation of one or more signaling pathways involved in apoptosis induction (Teodoro and Branton, 1997). 

Pan et al. have studied the induction of apoptosis signaling pathway by garcinol in human leukemia cell line, HL-60. Their results clearly demonstrate that garcinol strongly induced apoptosis in a dose-dependent manner in HL-60 cells [61]. 

To confirm the noninvolvement of the caspase pathway, cytotoxicity and apoptosis induction were studied in the presence of a caspase-3 inhibitor (Z-DEVD-FMK) and a negative control for the caspase-3 inhibitor (Z-FA-FMK). The negative control only inhibited cysteine protease and had no inhibitory effect on caspase-mediated apoptosis. The presence of a caspase-3 inhibitor, as well as a negative control, did not alleviate the cytotoxicity of 13-MTD and did not prevent induction of apoptosis. 

The most notorious apoptotic factors released from permeabilized mitochondria are cytochrome C and AIF, However, the results of the foregoing studies may rule out involvement of cytochrome C in the death pathway of 13-MTD-dependent apoptosis, AIF is therefore the most plausible candidate for death signal transducer for apoptosis induction by 13-MTD, The percentage of AlF-punctuated apoptotic nuclei was significantly increased by 13-MTD treatment. This percentage was increased to some extent by treatment with myristic acid. However, the difference between control and myristic acid treatment was statistically insignificant. Treatment of cells with vehicle buffer (control) resulted in little nuclear staining of AIF,... 

Apple juice phenolic compound extracts have the property to induce apoptosis in HT-29 cells [147]. Quercetin and phloretin dose-dependently induced both caspase-3 activity and DNA cleavage under serum-free conditions. Phloretin at 100 pM induced both the death receptor as well as the mitochondrial pathway of apoptosis induction, detected by activation of the initiator caspases-8 and -9 and the effector caspases-3 and -7 as well as by PARP cleavage. Activation of caspase-9 was accompanied by release of cytochrome c and the mitochondrial protein Smac/DIABLO from the mitochondria to the cytoplasm, and upregulation of proapoptotic Bax levels [43,44,148]. In general, berry extracts have the ability to stimulate apoptosis of the HT-29, COX-2-expressing colon cancer cells. Black raspberry and strawberry extracts showed the most significant proapoptotic effects against this cell line [43] (Tables 1 and 6). 

Extensive literature has been dedicated to define the types of cell death, considering morphological and biochemical aspects [86, 87, 88], Induction of death of cancer cells by alterations of mitochondrial bioenergetics have been proposed as promising approach for synthetic and natural compoimd s [23], Mitochondria participate in different types of cellular death, specially apoptosis (intrinsic pathway), programmed necrosis and autophagy [15, 16, 89], which can be triggered by anti-cancer alkaloids. 

Palozza et al. [20] Prostate cancer Colon cancer Apoptosis and cell growth inhibition by altering mevalonate pathway and Ras signaling Lycopene may alter mevalonate pathway through inhibition of HMG-CoA reductase. This may induce a decreased prenylation of Ras, which, in turn, may modulate redox-sensitive molecular pathways responsible for NF-kB activation and consequently, for cell cycle arrest and apoptosis induction, as evidenced by decreased cyclin D1 and pAKT levels increased p21, p27, and p53 levels and changes in Bax Bcl-2 ratio... 

Finally, when we evaluate ER cells, RA and 13-cw retinoic acid (13cRA) seem to be generally less effective, except when used at very high concentrations, than in ER cells, both in terms of proliferation inhibition and apoptosis induction, and modulation of cellular differentiation fails to occur under any experimental condition (see also Figs. 1 and 2). Probably one or more alterations in the complex pathway of retinoid action occurs in these cells, and these anomalies make it difficult for the retinoids to exert their effects (e.g. low levels of RARa, low levels or altered forms of RARp). 

Many anticancer agents currently in use, including chemotherapeutic drugs and radiation, are potent inducers of apoptosis and cell-cycle arrest. It is believed that induction of these molecular pathways is central to the efficacy of such agents [1]. Genetic and epigenetic alterations that contribute to tumorigenesis... 

A substantial amount of indirect evidence supports the contention that the induction of apoptosis in tumor cells is critical to successful therapy. Cancer therapy might therefore be viewed as an attempt to induce apoptosis in a population of cells that have undergone selection for apoptotic defects. If correct, this hypothesis would suggest why cancer therapy is in many cases unsuccessful. However, recent studies indicate that this fundamental problem can be circumvented. Progress in the identification of molecules key to the cell death pathways has led to a growing understanding of how apoptosis occurs [3]. It has become clear that pathways to apoptosis are numerous and often interconnected. A solution to the clinical problem of therapeutic resistance, then, may lie in the fact that there appears to be multiple ways that a cell death program can be implemented. 

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