Death, programmed

Active caspases 8, 9 and 10 can convert caspase-3, the most abundant effector caspase from its pro-form to its active cleaved form. Cleavage of a number of different substrates by caspase-3 and also by caspase-6 and -7 which are two other executioner caspases besides caspase-3 then results in the typical morphology which is characteristic of apoptosis. Yet, the activation of caspase-3 and also of caspase-9 can be counteracted by IAPs, so called inhibitor of apoptosis proteins. However, concomitantly with cytochrome C also other proteins are released from mitochondria, including Smac/DIABLO. Smac/DIABLO and potentially other factors can interact with IAPs and thereby neutralize their caspase-inhibitory activity. This releases the breaks on the cell death program and allows apoptosis to ensue. 

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. 

Parallel to our group, a few other researchers also performed significant studies on anticancer (3-lactams. For example, (3-lactam derivatives (Fig. 2) induced DNA damage, inhibited DNA replication, and activated the apoptotic death program in human leukemic Jurkat T cells in a time and concentration-dependent manner. Importantly, (3-lactam 69 also inhibited proliferation and induced apoptosis in other human solid tumor cell lines (breast, prostate, and head-and-neck). It was believed that induction of apoptosis by 69 is associated with activation of p38 mitogen-activated protein (MAP) kinase, release of mitochondrial cytochrome c, and activation of the caspases. It was reported that apoptosis is blocked by a specific inhibitor to p38 kinase, implicating p38 MAP kinase as the major factor in (3-lactam-induced apoptosis [154]. This study was very significant. 

Nylandsted, J., Rohde, M., Brand, K., Bastholm, L., Elling, F. and Jaattela, M. (2000) Selective depletion of heat shock protein 70 (HSP70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc. Natl. Acad. Sci. USA, 97,7871-7876. 

Rao RV, Ellerby HM, Bredesen DE (2004), Coupling endoplasmic reticulum stress to the cell death program, Cell Death Differ. 11 372-380. 

It remains to be determined why apoptotic features are rarely, if ever, found in MI. It is possible that in acute MI, cardiomyocytes begin to die from apoptotic mechanism, but as cellular energy declines the cells continue to die of necrosis [22,23]. Another possibility is that complex and large cells such as cardiomyocytes may not be able to show the classical morphological characteristics of apoptosis as originally described by Wyllie et al. [6], despite the activation of the cell death program [124]. 

Chi S, et al. Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. Oncogene 1999 18 2281-2290. 

Cefxil. See Cefprozil Celebrex. See Celecoxib Ceiccoxib. 760. 822-823 metabolism of. 77 Celexa. See Citolopram Cell cycle.. 391. 39lf Cell death, programmed.. 390-391 Cell-mediated immunity. 202-203 Cell membrane. See Membraoe(s)... 

Inhibition of cell death. Programmed cell death (apoptosis) is used by organisms to eliminate damaged cells. Inhibition of this process can allow cells with damage to the cell cycle control system to proliferate. 

DrexlerHC. 1997. Activation of the cell death program by inhibition of proteasome function. Proc. Natl. Acad. Sci. USA 94 855-60... 

---