Apoptotic effects

Glucocorticoids have inhibitory (apoptotic) effects on lymphocyte proliferation and are used to treat leukemias and lymphomas. Estrogens (fosfestrol) are used to block the effect of androgens in prostate cancer. Progestogens (megestrol, medroxyprogesteroneacetate) have been useful for treating endometrial carcinoma, renal tumors, and breast cancer. 

Chor SY, Hui AY, To KF, et al. Anti-proliferative and pro-apoptotic effects of herbal medicine on hepatic stellate cell. J Ethnopharmacol 2005 100 180-186. 

Kampa M, Alexaki VI, Notas G, et al. Apoptotic effects of selective phenolic acids on T47D human breast cancer cells potential mechanisms of action. Breast Cancer Res 2004 6 R63-R74. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

The involvement of mitochondria in the pro-apoptotic effects of carotenoids has been clearly demonstrated by the fact that P-carotene induces the release of cytochrome c from mitochondria and alters the mitochondrial membrane potential (Aym) in different tumor cells (Palozza et al., 2003a). Moreover, the highly polar xanthophyll neoxanthin has been reported to induce apoptosis in colon cancer cells by a mechanism that involves its accumulation into the mitochondria and a consequent loss of mitochondrial transmembrane potential and releas of cytochrome c and apoptosis-inducing factor (Terasaki et al., 2007). 

Andrabi, S. A., Sayeed, I., Siemen, D., Wolf, G. Horn, T. F. (2004). Direct inhibition of the mitochondrial permeability transition pore a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 18, 869-71. 

Palomba S, Orio F Jr, Russo T, Falbo A, Tolino A, Lombardi G, Cimini V, Zullo F (2005b) Anti-proliferative and pro-apoptotic effects of raloxifene on uterine leiomyomas in postmenopausal women. Fertil Steril (in press)... 

Although cadmium is not strongly mutagenic, it is known that it causes increased oxidative DNA damage and that it inhibits the DNA repair systems. It has also been found to induce cell death both by necrosis and apoptosis. Since the latter is extremely calcium-dependent, it seems likely that the pro-apoptotic effects of cadmium are due to its interference with calcium homeostasis. 

The apoptotic effect of 4-HNE and related aldehydes occitts at concentrations over 10 to 20 pM and depends on the ceU type, endothelial cells and fibroblasts being very sensitive to low 4-HNE concentrations (Esterbauer et al, 1991). Oxidized LDL exhibit certain amoimts of 4-HNE (range between 10 to 50 pM depending on the oxidation stage) which are compatible with an involvement of this aldehyde in the cytotoxicity (Jurgens et al, 1987). Moreover, local tissue concentrations of 4-HNE may reach concentrations higher than 100 pM, in particular in membranes because of its high hydrophobicity (Benedetti et al, 1986). 

SMase activity (Mansat et al 1997) and downstream (by blocking the apoptotic effect of ceramide). However, the cross-talk between ceramides and DAG opens new intriguing avenues of research and may lead to better pharmacological maiupulation of key steps in the apoptosis/survival signaling cascade resulting in an increased chemosensitivity of neoplastic cells. 

This chapter describes the metabohsm of sphingosine and SIP, evidence to support their pro- and anti-apoptotic effects and their proposed sites of action on signaling processes that contribute to apoptosis and proliferation. 

The effect of sphingosine on other enzymes may also contribute to its apoptotic effect. These include the inhibition of calcium/calmodulin-requiring enzymes and DNA primase and the stimulation of casein kinase II and several unidentified kinases (Alessenko, 2000). In addition, sphingosine can increase the cellular concentration of cyclic AMP, which is inhibitory for proliferation in many cell types (Pyne and Pyne, 1996). 

MiravaUe, L., Tokuda, T., Chiarle, R., et al. (2000) Substitutions at codon 22 of Alzheimer s A-beta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J. Biol. Chem., 275, 27110-27116. 

The mechanistic basis of the anti-neoplastic activity of UDCA and the explanation for the significant difference in bioactivity of UDCA compared with DCA despite marked similarity in chemical structure remain unresolved. UDCA administration in healthy volunteers and colorectal adenoma patients has been demonstrated to decrease the proportion of DCA in aqueous phase stool. Therefore, one possible mechanism of the chemopreventative activity of UDCA is reduction of mucosal secondary bile acid exposure. Consistent with this idea, UDCA administration has been demonstrated to reduce the incidence of K-ras mutations and decrease Cox-2 expression in AOM-induced tumors, which is the opposite of the reported effects of DCA in the same model. However, it is clear that exogenous administration of UDCA has direct anti-neoplastic activity on human CRC cells in vitro, either alone or in combination with DCA, including anti-proliferative and anti-apoptotic effects, as well as induction of cell senescence. " ... 

A detailed analysis of p53-activated genes has shown that this includes many genes that can generate or respond to oxidative stress (Polyak et al., 1997). The hnk between oxidative stress and p53 may be explained by the apoptotic effect of p53. It is plausible that formation of activated oxygen is involved in triggering of p53-mediated apoptosis. 

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