Apoptotic pathways

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Additionally, mechanisms of immunosuppression by organotins have also focused on the role of apoptosis versus proliferation arrest. The apoptotic pathway followed by organotin compormds such as dibutyltin dichloride and tributyltin chloride at high doses is... 

Wang HY, Cai B, Cui CB, Zhang DY, Yang BF. Vitexicarpin, a flavonoid from Vitex trifolia L, induces apoptosis in K562 cells via mitochondria-controlled apoptotic pathway. Yao Xue Xue Bao 2005 40 27-31. 

Carotenoids can strongly modulate apoptotic pathways (Palozza et al., 2006). For example, it has been demonstrated that lutein and zeaxanthin modulate the expression of anti-and pro-apoptotic factors and can selectively induce apoptosis in cancer cells but not in normal cells (Chew et al., 2003 Maccarrone et al., 2005). 

Ramos S. 2007. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem 18(7)427 142. 

In conclusion, it should be stressed that the competition between pro- and antiapoptotic effects of nitric oxide must probably depends on its relevant levels [137] the low physiological levels of NO principally suppress the apoptotic pathway by several mechanisms, whereas the higher rates of NO production may overcome cellar protective mechanisms and stimulate apoptosis. Furthermore, the simultaneous formation of nitric oxide and superoxide increases the possibility of apoptosis activation due to the formation of peroxynitrite. 

Guegan, C.,Vila,M.,Rosoldija,G.,Hays,A P. and Przedborski, S. Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. /. Neurosci. 21 6569-6576, 2001. 

Current hypotheses indicate that B-cell transcriptional processes are disrupted, which prevent expression of B-cell surface markers and production of immunoglobulin messenger RNA. Alterations in the normal apoptotic pathways favor cell survival and proliferation. 

Green, D.R., 1998, Apoptotic pathways The roads to ruin. Cell 34 695-698. 

Nomura, K., Imai, H., Koumura, T., Kobayashi, T., andNakagawa, Y., 2000, Mitochondrial phosphohpid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. Biochem. J., 351 183-193 Nunez, G., Benedict, M., Hu, Y., and Inohara, N., 1998, Caspases the proteases of the apoptotic pathway. Oncogene, 17 157-168... 

This ceramide-mediated apoptosis was shown to be inhibited by the simultaneous addition of PKC activators (Ni et at, 1994 Obeid et al, 1993), implying that PS may activate the ceramide-mediated apoptotic pathway. However, the inhibitors of interleukin-1 converting enzyme (ICE)-like proteases (Caspase), such as tosyl-L-lysine chloromethyl ketone (TLCK), and tosyl-L-phenylalanine chloromethyl ketone (TPCK) which inhibit ceramide-mediated apoptosis, had no effect on PS-induced apoptosis (Figure 4). Thus, PS-induced apoptotic pathway appears to be distinct from that mediated by ceramide. Further studies are required to clarify the molecular mechanisms underlying the PS-induced apoptosis. 

Dbaibo, G.S., Perry, D.K., Gamard, C.J., and Hannun, Y.A., 1997, Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-a CrmA and Bcl-2 target distinct components in the apoptotic pathway. J.Exp.Med. 185 481-490. 

Furthermore, an increasing body of circumstantial evidence is emerging for a role of diminished PC synthesis in apoptosis from observations, that a number of apoptosis-inducing comporuids can inhibit PC synthesis. However, it should be kept in mind that most of these compounds might not be completely specific and may also affect other pro-apoptotic pathways, besides PC synthesis. In the following section we will discuss some of the apoptotic compormd that affect PC synthesis in more detail. 

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