Cell death pathways

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. 

Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M. Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 2007 Epub Feb 21. 

Barnard, P.J. and Berners-Price, S.J. (2007) Targeting the mitochondrial cell death pathway with gold compounds. Coordination Chemistry Reviews, 251, 1889-1902. 

Peg3 (7) Paternal Unknown (implicated in TNF signalling pathway and in p53-mediated cell death pathway) GR BW 81%N Li et al 1999 4 weeks 65% N reduced postnatal survival rates impairment of maternal behaviour... 

Pharmacogenomics of Cell Death Pathways Mechanisms from Cell to Brain... 

Both PAF [57] and COX-2 are potent mediators of the injury/inflammatory response (Fig. 33-5). PAF and COX-2 are also interrelated in neuronal plasticity. The PAF transcriptional activation of COX-2 may provide clues about novel neuronal cell-death pathways. In fact, the delayed induction of COX-2 by kainic acid precedes selective neuronal apoptosis by this agonist in the hippocampus [42,58]. 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

A wide array of growth factors, proinflammatory molecules, including cytokines, prostanoids, and neuropeptides, contributes to the manifestation of inflammatory, neuro-degenerative, and metabolic consequences, including increased risk for triggering cell death pathways (Fig. 17.3). 

Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bommann WG Gao J, Boothman DA. (2007) An NQOl- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci USA 104 11832-11837. 

Cell death pathways may be counteracted by survival signaling cascades in the early stages of intoxication or in cells that are resistant to the toxic actions of the drugs. Signaling via the transcription factor NF-kB may constitute such a homeostatic mechanism in the cochlea. Cells that survived aminoglycoside treatment in a model of chronic ototoxicity were marked by NF-kB activation. ... 

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

FedorovaN, Badger], Robson G, Wortman J, Merman W, Gomparative analysis of programmed cell death pathways in filamentous fungi, BMC Genomics 6 177,... 

Figure 1. Model-1. Loss-of-function of parkin specifically causes AR-JP. Ub, ubiquitin SN, substantia nigra AR-JP, autosomal recessive juvenile parkinsonism. X(s) is a SN-specific substrate(s) whose accumulation in non-ubiquitinated form could activate directly the cell death pathway.

Degeneration Mitochondrial permeability transition with membrane depolarization, cytochrome c release, and mitochondrial swelling and fragmentation activation of caspases and cell death pathway, endonuclease fragmentation of DNA with chromatin and nuclear condensation phosphatidyserine exposure on cell surface cytoskeletal disruption with membrane blebbing... 

Ferri K.F., and Kroemer G. 2001 Organelle-specific initiation of cell death pathways. Nat Cell Biol 3, E255-263. 

Perrin FE, Boisset G, Lathuiliere A, Kato AC. Cell death pathways differ in several mouse models with motoneurone disease Analysis of pure motoneurone populations at a presymptomatic age. J Neurochem 2006 98(6) 1959-1972. 

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