Pro-apoptotic effects

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. 

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). 

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 precise mechanism of rituximab, as well as other monoclonal antibodies, is still incompletely understood despite extensive investigations. To our current knowledge, the mechanism of rituximab activity includes antibody-dependent cellular cytotoxicity (ADCC), complement dependent C5Totoxicity (CDC). and a direct pro-apoptotic effect (3,4). 

Aspirin, now commonly used for prevention of CHD and colon cancer, combined with butyrate exerted stronger anti-proliferate and pro-apoptotic effects than either alone. 

R. Lupi, F. Dotta, and L. Marselli, et al.. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets evidence that / -cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2, Diabetes, 2002, 53, 1437-1442. 

In a second way in which Akt kinase controls apoptosis, Akt kinase directly phosphorylates key regulators of apoptosis. The best-studied example of this type of control involves the Bad protein, which is a proapoptotic member of the Bcl-2 family. The Bad protein is phosphorylated by Akt kinase at Ser residues, and this modification promotes translocation of Bad to the cytosol, where it is found complexed with 14-3-3 proteins. By this mechanism, the pro-apoptotic effect of Bad can be inhibited. The effect on Bad is, however, not universal and is observed only in some cell types. Another pro-apoptotic substrate of Akt kinase is procaspase-9, which is inhibited upon phosphorylation by Akt. Dysregulation of the PI3-kinase/Akt kinase pathway, e. g., by inactivation of the PTEN tumor suppressor, has an anti-apoptotic effect and will favor tumor formation by preventing the death of cells that would be channeled to apoptosis under normal circumstances. 

Interestingly, the pro-apoptotic effects of Bad are blocked by the immunosuppressants cyclosporin (CsA) and FK506. In a model of transient ischemia/reperfusion following middle cerebral artery occlusion, both compounds reduced cerebral infarct volume to 30% of control (49). Blockade of calcineurin-mediated dephosphorylation of Bad is a potential mechanism for this effect. Thus phosphorylated, Bad remains sequestered in the cytoplasm and is unable to bind to Bcl-2 (or Bcl-XL), thereby allowing Bcl-2 to exert its protective effect. Regulating expression of specific members of the Bcl-2 family by targeted gene expression is another potential therapeutic tool. This approach is covered in Chapter 11. 

The above described pro-apoptotic effects were observed when cells were exposed to chemically defined phospholipids. However, it has to be taken into account that the respective 2-acyl-glycerophospholipids may be subject to hydrolysis by phospholipases inside and outside cells. As a consequence, the apoptotic oxidized phospholipids are degraded leading to harmless compounds or lipids of even higher toxicity. We found that POV-PCand PG-PC were inactivated in serum (Fruhwirth et al., 2006) and that this effect was due to hydrolysis by serum phospholipases since the main degradation product was lysophosphatidylcholine (Bjorkerud and Bjorkerud, 1996 Matsuzawa... 

In addition to cytochrome c, other factors such as apoptosis inducing factor (AIF), endonuclease G, and second mitochondria-derived activator of caspases (Smac/DIABLO) may also be released from the inter-mitochondrial membrane space to exert their pro-apoptotic effects (see later). Recently, the endoplasmic reticulum (ER) has been identified as another organelle that can initiate the intrinsic apoptotic cascade in response to cellular stress. The ER is essential for proper... 

Recent research seems to single out phenolics as being those natural products with the most potential for use as anti-inflammatory and pro-apoptotic agents. Many of these compounds are proven antioxidants that have been found to inhibit the enzymes implicated in the inflammatory process as well. Some of the mechanisms in question may be related to their pro-apoptotic effects and as such may provide ways to potentiate the compound s actual pharmacological effects. Alkaloids and terpenoids may also be of interest, but the research on them to date has focused more on their use as anticancer agents. 

This family of proteins plays a central role in the early life/death decisions of cells. The first family member discovered was Bcl-2 itself (identified as being overexpressed in B cell lymphoma) but since its discovery many other family members have been identified on the basis of the presence of conserved sequence motifs or BH domains (Bcl-2 homology domains) within their structures [66, 67]. Curiously, members belonging to this family can have anti-apoptotic effects (e.g. Bcl-2, Bc1-Xl) or pro-apoptotic effects (e.g. Bax, Bak, Bid, Bak) [68]. The niunber and types of BH domains present within these family members dictate their properties and function in the apoptotic process. Some family members possess 4 domains, whereas others contain only one. 

MODULATION OF CELL SIGNALING RESULTING IN ANTIPROLIFERATIVE AND PRO-APOPTOTIC EFFECTS... 

Feger F, Ferry-Dumazet H et al (2001) Role of iron in timior cell protection frinn the pro-apoptotic effect of nitric oxide. Cancer Res 61 5289-5294... 

Crimi, M. Astegno, A. ZoccatelU, G. Esposti, M. D., Pro-apoptotic effect of maize Upid transfer protein on mammalian mitochondria. Arch Biochem Biovhvs 2006,445(1), 65-71. 

Until very recently, research into the involvement of cholesterol oxidation products in the pathogenesis of atherosclerosis was mainly driven by the marked pro-inflammatory and pro-apoptotic effects that some members of this class of compounds exhibit (Poli et al. 2009 Vejux and Lizard 2009), whereas no attention was paid to possible anti-inflammatory or antiapoptotic signals generated by oxysterols. Nevertheless, an increased body of literature confirms the capability of oxysterols to interact with different nuclear receptors, which are known to play a main role in driving the anti-inflammatory and antiapoptotic cellnlar responses, thus suggesting a possible involvement of oxysterols even in these pathways. 

Figure 7.12 (a) Histograms illustrating the lack of effect of DNIC with glutathione (1 20 DNIC) on the state of DNA in HeLa cells, the lack of the HeLa subpopulation with the DNA content less than the diploid level (<2c, late apoptosis) on the fluorescence channels with the channel numbers <75. DNIC concentration - 100 pM (i), 200 pM (ii), and 500 pM (iii). The cells were incubated for 22 h in Eagle s medium supplemented with fetal calf serum. Solid line Control. Dotted line Incubation with DNIC. -2c- and —4c- Subpopulations of cells with the diploid and tetraploid content of DNA, respectively, (b) Histograms illustrating the pro-apoptotic effect of DNIC with... 

Choi EJ, Kim T, Lee MS (2007) Pro-apoptotic effect and cytotoxicity of genistein and genistin in human ovarian cancer SK-OV-3 cells. Life Sci 80 1403-1408... 

Yin QH, Yan EX, Zu XY, Wu YH, Wu XP, Liao MC, Deng SW, Yin LL, Zhuang YZ (2012) Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology 64(1) 43-51... 

---