Apoptosis resistance

The importance of NF-kB to inflammation, apoptosis resistance and tumour progression has resulted in the development of unique NF-kB inhibitors as part of cancer therapeutic regimens for GI and other cancers. Efforts are also being made to understand the efficacy of using natural substances obtained from plants, such as feverfew (e.g. parthenolide), bee glue (e.g. caffeic acid phenylethyl ester), tea (e.g. EGCG), spices (e.g. curcumin from turmeric) and mulberry figs (e.g. morin, a flavone) for the prevention both of persistent NF-kB activation and of the development of inflammatory pre-neoplastic lesions. 

Repeated Exposure to High Concentrations of Bile Acids Probably Selects for Apoptosis Resistance in Cells of the GI Tract... 

A number of observations (Table 3.6) indicate that tumours arise in an apoptosis-resistant pre-malignant cell population. Barrett s esophagus (BE) is a pre-malignant lesion of the distal esophagus in which squamous epithelial cells... 

Table 3.6 Observations indicating that development of apoptosis resistance often occurs early in cancer progression in the GI tract.

Target organjtissuejcell Evidence for apoptosis resistance in pre-malignant tissue References... 

Table 3.6) suggesting that areas of apoptosis-resistant epi-... 

H. Bernstein, H. Holubec, J. A. Warneke, H. Garewal, D. L. Earnest, C. M. Payne, D. J. Roe, H. Cui, E. L. Jacobson and C. Bernstein, Patchy field defects of apoptosis resistance and dedifferentiation in flat mucosa of colon resections from colon cancer patients, Ann. Surg. Oncol., 2002, 9(5), 505. 

C. M. Payne, C. Bernstein and H. Bernstein, Field change of apoptosis resistance in colonic mucosa of patients with colorectal carcinoma, J. Clin. Path., 2007, Electronic letters published (5 February, 2007). 

K. Dvorakova, C. M. Payne, L. Ramsey, H. Bernstein, H. Holubec, M. Chavarria, C. Bernstein, R. E. Sampliner, C. Riley, A. Prasad and H. Garewal, Apoptosis resistance in Barrett s esophagus ex vivo bioassay of live stressed tissues. Am. J. Gastroenterol, 2005, 100(2), 424. 

In addition to be a direct target of antitumor treatment, PKC has been shown to be involved in the resistance to antitumor treatment and in the modulation of apoptosis. Resistance to cancer chemotherapy is a major... 

In vivo studies using mouse models have proved that curcumin modifies apoptosis resistance, leading to the inhibition of tumor formation and the prevention of adenoma development in the intestinal tract. The chemopreven-tive effect of curcumin for intestinal tumors in Min/+ mice was investigated. A dietary level of 0.15% curcumin decreased tumor formation in Min—/— mice by 63%. Examination of intestinal tissue from the treated animals showed the tumor prevention by curcumin was associated with increased enterocyte apoptosis and proliferation. Curcumin also decreased expression of the oncoprotein (S-catenin in the erythrocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. Curcumin enhanced PhlP-induced apoptosis and inhibited PhIP-induced tumorigenesis in the proximal small intestine of Ape (min) mice. Experiments performed on intestinal tumors in C57BL/6J-Min/+ (Min/+) mice demonstrated that curcumin has a regulatory role in lymphocyte-mediated immune function [Churchill et al., 2000]. Furthermore, levels of COX-2 protein expression have been found to reflect the retardation of adenoma development in mouse intestines after treatment with curcumin [Tunstall et al., 2006]. 

Wolanin K, Magalska A, Mosieniak G, Klinger R, McKenna S, Vejda S, Sikora E, Piwocka K. 2006. Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells. Mol Cancer Res 4 457-469. 

Caspase-1 Yes Normal development Defects in death receptor-mediated apoptosis, resistant to lipopolysaccaharide (LPS)-induced endotoxic shock Normal [57-59]... 

The implication of the SM-CER signaling pathway in MTR opens intriguing avenues of research. Indeed, it has been suggested, for example, that apoptosis-resistant cells are deficient in SMase activation or SM hydrolysable pools (Santana et al., 1996 Bettai eb et al., 1996 Wright et al., 1996). In fact, we have shown in some resistant myeloid leukemia cells that the incapacity to generate CER in the presence of effector was in relation to a deficit of (hydrolysable) SM pool (Bettai eb et al., 1996). Thus, it is possible that, in some AML cells, the activation of a yet undefined SM translocase results not only in modification of SM transverse asymmetry but also in reduced SM hydrolysable pool, decreased CER production, and inhibition of apoptosis (Bezombes et al. 1998). Hence one can conclude from these studies that SMase activation is substrate dependent and therefore it is conceivable that spacial SM organisation is essential in the initiation of a SMase dependent apoptotic pathway. If this hypothesis were valid, one could concede that by modifying SM transverse distribution it would be possible to restore an apoptotic pathway in MTR cells. 

Lefranc F, Facchini V, Kiss R (2007) Proautophagic drugs a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12 1395-1403... 

Pipalamycin was discovered by Uchihata et al. in 2002 as an apoptosis inducer in apoptosis-resistant human pancreatic adenocarcinoma AsPC-1 cells from Streptomyces sp. (Fig. 15). In this apoptotic pathway, both caspase-3 and -9 are activated. Pipalamycin shows strong cytotoxicity against tumor cells and antibacterial activity against gram-positive bacteria ... 

Polyoxypeptins A and B were discovered by Umezawa et al. in 1998 from Streptomyces sp. and were also isolated as apoptosis inducers in apoptosis-resistant human pancreatic adenocarcinoma AsPC-1 cells l Polyoxypeptin contains the novel amino acid, 2S, 3R)-3 -hydroxy-3 -methylproline l... 

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