Caspase-dependent apoptosis

Proteasomal inhibition represents a novel strategy in cancer treatment and the small molecule Bortezomid (PS-341, Velcade ) has been approved for the treatment of refractory and relapsed multiple myeloma, a proliferative disease of plasma cells. Bortezomid inhibits an active site in a proteasome subunit and remarkably shows selective cytotoxicity to cancer cells. Although the underlying mechanisms are not completely understood bortezomid apparently induces a cell stress response in these tumor cells followed by caspase-dependent apoptosis. Whether bortezomid is beneficial for the treatment of other proliferative disease is currently being tested in clinical trials. 

Figure 3. The many ways to lose a HAT. Decreased amounts of functional CBP protein and subsequent CBP s loss of function has been observed in different contexts of neurological disorders and neuronal apoptosis. RTS (Rubinstein-Taybi Syndrome) results from a mutation on one cbp gene allele. In several cases of polyQ diseases, CBP can be sequestred by the mutated polyQ proteins, forming aggregates in the cytoplasm or the nucleus. CBP proteasomal degradation was also shown to be favored by polyQ proteins. CBP is a caspase-6 substrate in cerebellar granule neurons (CGN) deprived of potassium modeling caspase-dependent apoptosis. Finally, cbp gene repression has been observed in oxidative stress-induced death of a motomeuronal cell line. The mechanisms by which CBP levels are reduced in motomeurons of ALS mice is still unknown...

Inhibits protein synthesis by interfering with endoplasmic reticulum and Golgi apparatus functions it also induces cell differentiation and caspase-dependent apoptosis Stabilizes protein structures and restores correct folding tiirough binding with tiiem... 

The group at Pharmacyclics developed a related phenyl hydroxamic add HDACi, PCI-34051 (27e) and demonstrated this to display greater than 200-fold selectivity for HDAC8 (IC5o = 10nM) over the other HDAC isoforms [40b]. Interestingly, this compound induced caspase-dependent apoptosis in T-cell lymphomas and leukemias at low micromolar concentrations, but not in other hematopoietic or solid tumor cell lines. Furthermore, PCI-34051 does not cause detectable tubulin or histone acetylation. 

Smyth MJ, Drasovskis E, Sutton VR, Johnstone RW (1998) The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sd USA 95 7024-7029... 

B12. Brancolini, C., Lazarevic, D., Rodriguez, J., and Schneider, C., Dismantling cell-cell contacts during apoptosis is coupled to a caspase-dependent proteolytic cleavage of beta-catenin. J. Cell Biol. 139, 759-771 (1997). 

In summary, the mechanism of monoclonal antibody activity for CLL might be different from that for lymphoma. Besides ADCC, other pathways such as caspase-dependent apoptosis or CDC are more likely to contribute to rituximab or alemtuzumab-induced clearance of CLL cells in vivo. 

Curcumin was found to inhibit cellular proliferation and enhance apoptosis in a variety of lymphoma cell lines in vitro [Skommer et al., 2006 Thompson et al., 2004 Wu et al., 2002]. The proposed mechanism of curcumin s action in the majority of these studies involves the suppression of the expression of NF-KB-regulated gene products. One study suggested a novel function for curcumin as a suppressor of JAK-1 and STAT3 activation in primary effusion lymphoma cells, a function that would lead to the inhibition of proliferation and the induction of caspase-dependent apoptosis [Uddin et al., 2005],... 

Chami, M., Ferrari, D., Nicotera, P., Paterlini-Brechot, P. and Rizzuto, R., 2003, Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J Biol Chem 278, 31745-55. 

Biochemical execution of cell death depends on three major components caspases, mitochondrial factors, and the Bcl-2 family of proteins (Green 2005 Yuan 2006). Caspases are a group of cysteine proteases acting as the central effectors of apoptosis. Caspases are normally suppressed by the inhibitor of apoptosis (IAP) in... 

Bannon JH, Fichtner I, O Neill A, Pampillon C, Sweeney NJ, Strohfeldt K, Watson RW, Tacke M, Me Gee MM (2007) Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo. Br J... 

Sourdeval, M., Lemaire, C., Deniaud, A., Taysse, L., Daulon, S., Breton, P., Brenner, C., Boisvieux-Ulrich, E., Marano, F. (2006). Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis. 11 1545-59. 

Cummings BS, Schnellmann RG. Cisplatin-induced renal cell apoptosis caspase 3-dependent and -independent pathways. J Pharmacol ExpTher 2002 302 8-17... 

Apoptotic cell death is regulated by NO and ONOO" in several cell types including myeloid-derived leukocytes such as neutrophils. The biological effects of NO and ONOO" have been recently reviewed [68]. GEA3162 is able to promote apoptotic cell death in human neutrophils in a caspase-dependent manner [69]. The tumor suppressor p53 is suggested to play a crucial role in apoptosis induced by oxidants. However, functional p53 is not a requirement for ONOO -mediated cell death, as GEA3162 induces mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. GEA3162 activates caspases 3 and 2 which are important for apoptosis to proceed, with roles for caspases 8 and 9, and p38 MAP kinase [70]. 

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