Induction of apoptosis

Apoptosis is caused by the release or activation of one or more BH3 domain-only proteins (Fig. 13.9c, step 1). These initiating B 13-only proteins bind to a cytosolic heterodimer containing a Bcl-2 protein (step 2) and displace a previously bound BH3-only protein, Bid, BIM or PUMA (step 3). In the case of Bid, dissociation from a partner such as Bcl-2 may be mediated by proteolysis of the Bid N-terminal 60 amino acid residues, creating truncated Bid (tBid), which activates an effector protein. The BH3-only proteins are therefore activators of apoptosis that displace effector proteins (BAK or BAX) from a non-Bcl-2 partner on the cytosolic surface of mitochondria and endoplasmic reticulum (step 4). For example, BAK is attached to an outer mitochondrial membrane channel protein in a healthy cell. An activating BH3-only protein displaces BAK, which then self-aggregates into homodimers that burrow a hole in the mitochondrial or endoplasmic reticular membrane, releasing the contents (step 5). 

Induction by interactions between Bcl-2 family proteins may be induced by cytokine-receptor binding extrinsic) or by intracellular changes (intrinsic). 

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PMURAR a Transcriptional regulator Inhibition of cell proliferation induction of apoptosis increase in sensitivity against ATRA... 

Telomerase Ribonucleoprotein Suppression of telomerase activity inhibition of cell proliferation change in morphology induction of apoptosis... 

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. 

Also nonkinase molecules might be important targets for anticancer drugs. For instance, the activity of the mitotic kinesin Eg5 (KSP, kinesin-5) can be inhibited by small molecules (e.g., monastrol, KSP-IA) resulting in mitotic defects associated with the induction of apoptosis. 

Induction of apoptosis has been reported in various mammalian cell lines. In previous studies, it has been reported that TBT induces apoptosis in isolated thymocytes at concentrations which are relevant to those causing thymus atrophy in vivo. TBT can also induce apoptosis in PC12 cells, and in human T-lymphoblastoid CEM cells. While the mechanism of TBT-induced apoptosis is still unknown, it has been reported that TBT stimulates thymocyte apoptosis by a mechanism independent of protein synthesis and under conditions where intracellular ATP levels are severely depleted. ... 

TSAI J-C, JAIN M, HSIEH C-M, LEE W-S, YOSHIZUMI M, PATTERSON C, PERRELLA M A, COOKE C, WANG H, HABER E, scHLEGEL R, and LEE M E (1996) Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells Journal Biological Chemistry 271, 3667-70. 

SMITH T K, LUND E K and JOHNSON I T (1998) Inhibition of dimethylhydrazine-induced aberrant crypt foci an induction of apoptosis in rat colon following oral administration of the glucosinolate sinigrin , Carcinogenesis, 19, 267-73. 

Like sulforaphane, however, PEITC-NAC (N-acetylcysteine) conjugate appears to block in Gl. Studies by Lund et al. show that in the case of the colorectal cell line HT29, which lacks wild type p53, treatment with AITC causes the cells to detach from the substratum but, at least in the short-term, they do not then enter apoptosis . Where it does occur, induction of apoptosis by isothiocyanate appears to be a p53-dependent process. However, this statement must also be qualified, because the effect appears to depend on which metabolite is considered. For example, sulforaphane does appear to be able to induce apoptosis in HT29 cells, which express a mutated form of the protein. 

KONG A N, YU R, CHEN c, MANDLEKAR s and PRIMIANO T (2000) Signal transduction events elicited by natural products role of M APK and caspase pathways in homeostatic response and induction of apoptosis . Arch Pharm Res, 23 1-16. 

FAN H, MORIOKA T, iTO E (2000) Induction of apoptosis and growth inhibition of cultured human endometrial adenocarcinoma cells (Sawano) by an anti-mmor lipoproteinfraction of rice bran. Gynacol, Oncol, 76(2) 170-75. 

Different types of apparently beneficial activities have been demonstrated in vitro for carotenoid oxidation products, including induction of gap-junctional communications, " growth inhibition of leukemia and cancer cells, induction of apoptosis... 

The plant is known to contain chelerythrine chloride, which inhibits the aggregation of rabbit platelet in vitro via inhibition on thromboxane formation and phosphoinosi-tides breakdown (30). Chelerythrine, which occurs in members of the family Papaver-aceae, has been reported to inhibit the enzymatic activity of protein kinase C and to exert cell-growth inhibitory effect via the induction of apoptosis in numerous cancer cell lines (31,32). What is the topoisomerase activity of chelerythrine ... 

Parker BW, Kaur G, Nieves-Neira W, et al. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 1998 91 458-465. 

Nakatani N, Ichimaru M, Moriyasu M, Kato A. Induction of apoptosis in human promyelocytic leukemia cell line HL-60 by C-benzylated dihydrochalcones, uvaretin, isouvaretin and diuvaretin. Biol Pharm Bull 2005 28 83-86. 

Rivero A, Quintana J, Eiroa JL, et al. Potent induction of apoptosis by germacrano-lide sesquiterpene lactones on human myeloid leukemia cells. Eur J Pharmacol... 

The ozonolysis of carotenoids was employed in order to obtain oxygenated cleavage products for biological tests, for example, for lycopene. In this case, among a series of products, one product formed by a double oxidative cleavage was purified and characterized as ( , ,/ )- 4 - methyl - 8 -oxo-2,4,6-nonatrienal, and it was shown to be active in the induction of apoptosis in HL-60 cells (Zhang et al. 2003). 

Chen, JY, Cheung, NH, Fung, MC, Wen, JM, Leung, WN, and Mak, NK, 2000. Subcellular localization of merocyanine 540 (MC540) and induction of apoptosis in murine myeloid leukemia cells. Photochem Photobiol 72, 114-120. 

Hwang, E. S. and P. E. Bowen. 2004. Cell cycle arrest and induction of apoptosis by lycopene in LNCaP human prostate cancer cells. J Med Food 7(3) 284-289. 

Elgrabli, D. et al. (2008) Induction of apoptosis and absence of inflammation in rat lung after intratracheal instillation of multiwalled carbon nanotubes. Toxicology, 253 (1-3), 131-136. 

Tietze N, Pelisek J, Philipp A, Roedl W, Merdan T, Tarcha P, Ogris M, Wagner E (2008) Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran. Oligonucleotides 18 161-174... 

These structurally diverse compounds exhibit a range of biological activities in vitro that may explain their potential health-promoting properties, including antioxidant and anti-inflammatory effects and the induction of apoptosis (Hooper and others 2008). Most of the recent interest in flavonoids as health-promoting compounds is related to their powerful antioxidant properties. The criteria to establish the antioxidant capacity of these compounds is based on several structural characteristics that include (a) the presence of o-dihydroxyl substituents in the B-ring (b) a double bond between positions 2 and 3 and (c) hydroxyl groups in positions 3 and 5. 

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