Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Magnolol, isolated from the stem bark of Magnolia officnalis, was found to inhibit proliferation of human HL-60 cells and Jurkat T leukemia cells via inducing apoptosis in a dose- and time-dependent manner. By contrast, magnolol did not cause apoptosis in neutrophils and peripheral blood mononuclear cells of healthy donors. Apoptosis was determined by detection of DNA fragmentation in gel electrophoresis, morphological alternations by flow cytometry, quantification of phosphatidylserine externalization by Annexin V labeling and oligonucleosomal DNA content by TUNEL labeling. Activation of caspase-9, -3 and -2, and the proteolytic cleavage of poly(ADP-ribose) polymerase were found during apoptosis induced by magnolol. In addition, both pan-caspase and selective caspase-9 inhibitor blocked magnolol-induced apoptosis. The apoptosis could also be partially attenuated by caspase-3 and -2 inhibitors. Magnolol induced the reduction of mitochondrial transmembrane potential and the release of cytochrome c into cytoplasm. In conclusion, our findings indicate that magnolol-induced apoptotic signaling is carried out through mitochondria alternations to caspase-9 and that then the downstream effector caspases are activated sequentially. Magnolol could be a potentially effective drug for leukemia with low toxicity to normal blood cells and it merits further investigation.
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PMID:Magnolol induces apoptosis in human leukemia cells via cytochrome c release and caspase activation. 1263 15

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.
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PMID:Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. 1264 85

Leptin, the Ob gene product, has emerged recently as a key regulator of bone mass. However, the mechanism mediating leptin effect remains controversial. Because the action of leptin is dependent on its receptors, we analyzed their expression in osteoblast-lineage primary human bone marrow stromal cells (hBMSC). Both the short and long forms of leptin receptors were detected in hBMSC. Leptin significantly decreased the viability of hBMSC. This cytotoxic effect was prevented by Z-Val-Ala-Asp-fluoromethylketone, a pan-caspase inhibitor, implicating that leptin-induced hBMSC death was caspase-dependent. Further investigation demonstrated that leptin activated caspase-3 and caspase-9, but not caspase-8, and increased the cleavage of poly-(ADP-ribose) polymerase and cytochrome c release into cytosol. Leptin activated ERK, but not p38 and JNK, and up-regulated cPLA2 activity; the latter was abolished by pre-treatment of cells with the MEK inhibitor (PD98059 or U0126) or cPLA2 inhibitor (AACOCF3). PD98059, U0126, and AACOCF3 also diminished the leptin-induced cytochrome c release into cytosol, cell death, and caspase-3 activation. These data indicated that leptin induced hBMSC apoptosis via ERK/cPLA2/cytochrome c pathway with activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. To our knowledge, this is the first study demonstrating the direct detrimental effect of leptin on bone cells.
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PMID:Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. 1266 5

The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. Initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Pre-incubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting.
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PMID:Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential. 1266 10

Hairy-cell leukaemia cells have a low rate of growth but an even lower rate of apoptosis. Accordingly, this malignancy is an excellent model for studying the effects of drugs on the pathways of apoptosis independently of cell proliferation. The remarkable effectiveness of 2-chlorodeoxyadenosine in hairy-cell leukaemia affirms the feasibility of developing drugs that can destroy even non-proliferating malignant cells. The major nucleotide metabolite of 2-chlorodeoxyadenosine accumulates selectively in lymphocytes and co-activates two key apoptosis-regulating enzymes: poly(ADP-ribose) polymerase and Apaf-1/caspase-9. The ability of 2-chlorodeoxyadenosine to induce durable remissions in hairy-cell leukaemia may also be attributable to its effects on lymphocytes and monocytes in the microenvironment, although this latter effect remains to be proven experimentally.
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PMID:Hairy-cell leukaemia as a model for drug development. 1267 Apr 67

Pseudomonas aeruginosa is a gram-negative facultative opportunistic pathogen associated with severe infections in immunocompromised hosts and in patients with cystic fibrosis. P. aeruginosa strains show divergent pathogenicity in vivo and trigger apoptosis of and/or are internalized into human host cells. In the present study, we studied the molecular ordering of apoptosis signaling upon infection of human conjunctiva epithelial Chang cells with P. aeruginosa PAK as well as the role of bacterial pili in the response to the infection. Our results show that CD95 up-regulation is followed by early activation of caspase-8 and -3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase. The data also demonstrate release of apoptosis inducing factor into the cytosol of infected cells. Induction of mitochondrial alterations, i.e., mitochondrial depolarization and release of cytochrome c, as well as cleavage of caspase-9, -7, and -1 occurred only at later time points. In addition, our results demonstrate that pili are required for P. aeruginosa-induced apoptosis of human epithelial cells. While the two piliated P. aeruginosa strains, PAO-I and PAK, induced apoptosis of Chang cells within 3 h of infection, the pilus-deficient P. aeruginosa mutants PAK Delta pilA and PAK Delta pilA Delta all were without effect. The pilus-deficient mutants failed to induce a significant up-regulation of CD95 on the cell surface and to trigger mitochondrial alterations or activation of caspase-8, -3, and -7. In addition, only the piliated wild-type strains induced caspase-1-mediated activation of interleukin-1 beta. Thus, pili are necessary for distinct infection-induced cellular responses of human epithelial cells.
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PMID:Apoptotic response of Chang cells to infection with Pseudomonas aeruginosa strains PAK and PAO-I: molecular ordering of the apoptosis signaling cascade and role of type IV pili. 1270 41

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.
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PMID:Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. 1272 25

Disintegrins, the snake venom-derived arginine-glycine-aspartic acid-containing peptides, have been demonstrated to inhibit angiogenesis through induction of endothelial cell apoptosis. However, it is not clear how a disintegrin causes endothelial apoptosis. In this study, we elucidated the action mechanism of disintegrin in causing endothelial apoptosis by using rhodostomin as a tool. We showed that cell detachment was observed at the early stage of rhodostomin treatment. It was initiated through the blockade by integrin alphanubeta3 and was accelerated by a mechanical stretch from neighboring cells. Both rhodostomin and poly(HEME) induced a higher percentage of cells at G2-M phase, the cleavage of beta-catenin and poly(ADP-ribose) polymerase during apoptosis, indicating that cell detachment is a prerequisite for rhodostomin-induced apoptosis. Moreover, pp125(FAK) phosphorylation and actin cytoskeleton were affected upon rhodostomin treatment. The activation of caspase-3 but not that of caspase-9 was detected after rhodostomin treatment. In addition, general caspase inhibitors inhibited the cleavage of beta-catenin and poly(ADP-ribose) polymerase, and DNA fragmentation, whereas they did not prevent cell shape change or detachment. According to these results, we concluded that disintegrin-induced endothelial apoptosis is a complex process, not merely caused by a blockade of endothelial integrin alphanubeta3 but also by an accompanied shape change and mechanical stretches among cells.
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PMID:Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability. 1272

Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. 1275 Feb 70

Apoptotic host cell death is a critical determinant in the progression of microbial infections and outcome of resultant diseases. The potentially fatal human infection caused by Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, involves the vascular endothelium of various organ systems of the host. Earlier studies have shown that survival of endothelial cells (EC) during this infection depends on their ability to activate the transcription factor nuclear factor kappa B (NF-kappa B). Here, we investigated the involvement of caspase cascades and associated signaling pathways in regulation of host cell apoptosis by NF-kappa B. Infection of cultured human EC with R. rickettsii with simultaneous inhibition of NF-kappa B induced the activation of apical caspases 8 and 9 and also the executioner enzyme, caspase 3, whereas infection alone had no significant effect. Inhibition of either caspase-8 or caspase-9 with specific cell-permeating peptide inhibitors caused a significant decline in the extent of apoptosis, confirming their importance. The peak caspase-3 activity occurred at 12 h postinfection and led to cleavage of poly(ADP-ribose) polymerase, followed by DNA fragmentation and apoptosis. However, the activities of caspases 6 and 7, other important downstream executioners, remained unchanged. Caspase-9 activation was mediated through the mitochondrial pathway of apoptosis, as evidenced by loss of transmembrane potential and cytoplasmic release of cytochrome c. These findings suggest that activation of NF-kappa B is required for maintenance of mitochondrial integrity of host cells and protection against infection-induced apoptotic death by preventing activation of caspase-9- and caspase-8-mediated pathways. Targeted inhibition of NF-kappa B may therefore be exploited to enhance the clearance of infections with R. rickettsii and other intracellular pathogens with similar survival strategies.
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PMID:Nuclear factor kappa B protects against host cell apoptosis during Rickettsia rickettsii infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity. 1281 4


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