Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with intravenous heroin addiction are prone to recurrent infections and at times these infections are fatal. We evaluated the effect of morphine on the apoptosis of Jurkat cells and freshly isolated human T lymphocytes. Morphine promoted apoptosis of both the Jurkat cells and the freshly isolated T lymphocytes in a dose-dependent manner. DAGO, a specific mu receptor agonist, also promoted Jurkat cell apoptosis. DNA isolated from morphine-treated Jurkat cells and T lymphocytes also showed integer multiples of 200 base pairs. Superoxide dismutase (SOD) enhanced lymphocyte apoptosis; whereas catalase attenuated the morphine-induced apoptosis of Jurkat cells as well as of T lymphocytes. Morphine-treated Jurkat cells also showed a decreased expression of bcl-2 and an enhanced expression of bax. In addition, morphine-treated Jurkat cells showed activation of caspase-3. These results indicate that morphine-induced T lymphocyte apoptosis may be mediated through the generation of reactive oxygen species. The change in ratio of bax and bcl-2 seems to tilt the balance toward apoptosis, leading to the activation of caspase-3. This study provides further support for the hypothesis that morphine may be directly compromising immune function by enhancing apoptosis of T lymphocytes in patients with heroin addiction.
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PMID:Morphine promotes apoptosis in Jurkat cells. 1053 22

We have previously shown that generation of sublytic C5b-9, the membrane attack complex of complement, induces oligodendrocytes to enter cell cycle and reduces apoptotic cell death in vitro. In the present study, the cellular factors involved in apoptosis of oligodendrocyte progenitor cells and oligodendrocytes, and the inhibitory effect of C5b-9 on apoptotic process were investigated. Oligodendrocyte progenitor cells identified by mAb A2B5 that were isolated from neonatal rat brains were differentiated into oligodendrocytes in serum-free defined medium. The differentiation, which occurs simultaneously with apoptotic cell death, was associated with a rapid loss of bcl-2 mRNA and increased expression of caspase-3 mRNA. Activation of caspase-3 in differentiating cells was demonstrated by the generation of 17- and 12-kDa fragments of caspase-3 proenzyme and by cleavage of poly(ADP-ribose) polymerase, a specific caspase-3 substrate. Cell death associated with differentiation was inhibited by the caspase-3 inhibitor DEVD-CHO in a dose-dependent manner. Assembly of sublytic C5b-9 resulted in inhibition of caspase-3 activation. In addition, synthesis of BCL-2 protein in oligodendrocytes was significantly increased by C5b-9. The TNF-alpha-induced apoptosis of oligodendrocytes was also inhibited by C5b-9. These results indicate that up-regulation of BCL-2 protein and inhibition of caspase-3 activation are potential mechanisms by which C5b-9 increases survival of oligodendrocyte in vitro and possibly in vivo during inflammation and immune-mediated demyelination affecting the CNS.
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PMID:Inhibition of oligodendrocyte apoptosis by sublytic C5b-9 is associated with enhanced synthesis of bcl-2 and mediated by inhibition of caspase-3 activation. 1057 Mar 3

bcl-2 has been shown to enhance cell survival by inhibiting apoptosis. The present study investigates the potential role of bcl-2 on apoptosis in HL-60 cells induced by different agents. HL-60/bcl-2 and control HL-60/neo cells were obtained by transfection of bcl-2 cDNA or the neomycin-resistant gene, respectively. Staurosporine (STS) promoted DNA fragmentation dose-dependently in the 6 h exposure assay while C2-ceramide was relatively slow in the induction of apoptosis (approximately 40% after 24 h) and required higher concentrations (> 20 microM). Caspases inhibitors, Ac-YVAD-cmk (100 microM) and zVAD-fmk (20 microM) had no effect on DNA fragmentation themselves. However, they blocked C2-ceramide-induced caspase-3 cleavage and apoptosis, but not the release of cytochrome c from the mitochondria. In addition, we found that both Ac-YVAD-cmk and zVAD-fmk failed to protect STS-induced apoptosis in HL-60 cells. Overexpression of bcl-2 inhibited STS and C2-ceramide induced cytochrome c redistribution, caspase-3 activation and apoptosis. These results suggest a protective role of bcl-2 in the regulation of apoptosis and cytochrome c release is unlikely to be involved in the final common pathway in apoptosis.
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PMID:Redistribution of cytochrome c is not an essential requirement in C2-ceramide induced apoptosis in HL-60 cells. 1057 89

The realization that chemotherapeutic agents induce apoptosis raises the concern that tumors resistant to chemotherapy are unable to initiate the apoptotic program. In the present study, we examined the apoptosis-resistance mechanism of a multidrug-resistant cell line, A549/CPT, which was established from the human lung-cancer cell line A549 by in vitro selection with gradually increased camptothecin (CPT) concentrations. We found that A549/CPT cells were resistant to anti-cancer drug-induced apoptosis in which caspase-3-like protease activity was attenuated remarkably, compared with parental A549 cells. We observed 2 mechanisms associated with apoptosis resistance in A549/CPT cells: over-expression of anti-apoptotic bcl-2 and elevated expression of p21Waf1/Cip1. Transfection of either bcl-2 or p21Waf1/Cip1 cDNA into parental A549 cells resulted in resistance to apoptosis. Furthermore, the co-treatment of p21Waf1/Cip1 and bcl-2 anti-sense oligodeoxy-nucleotides restored drug susceptibility in A549/CPT cells more effectively than either one of them alone. These results indicate that co-induction of bcl-2 and p21Waf1/Cip1 in A549/CPT cells may be involved in acquired drug resistance by inhibiting caspase-mediated apoptosis. Agents aimed at preventing both bcl-2 and p21Waf1/Cip1 expression may increase the efficiency of chemotherapy.
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PMID:p21Waf1/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a camptothecin-selected human lung-cancer cell line. 1059 96

The kidney is a target for toxicants including cisplatin and S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a metabolite of the environmental contaminant, trichloroethylene. Necrosis is well characterized in kidney cells, but pathways leading to apoptosis are less clear. Cysteine conjugates are useful toxicants because they induce either necrosis or apoptosis depending on chemical structure or antioxidant status. Herein, we show that in the renal epithelial cell line LLC-PK1, activation of caspase-3 (CPP32/Yama/apopain) is crucial for apoptosis, but not necrosis. Apoptosis was blocked by zVAD.fmk, and partially by a cathepsin inhibitor. Caspase-3 activity and cleavage of poly(ADP-ribose) polymerase (PARP) was detected only during apoptosis. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC), a metabolite of tetrafluoroethylene, kills cells only by necrosis, and did not activate caspases under any conditions. Apoptosis and activation of caspase-3 by cisplatin, but not DCVC, was prevented by bcl-2. Thus, caspase-3 activation by bcl-2-dependent and -independent mechanisms is a terminal event in chemical-apoptosis of renal epithelial cells.
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PMID:The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis of renal epithelial cells. 1059 53

Apoptosis is an important mechanism of physiological and pathological cell death. It is regulated by several gene products, including caspases and the bcl-2-like proteins, whose roles have been demonstrated in numerous systems. One of these is a model of cerebellar granule cells (CGCs) in which apoptosis is induced by acute removal of serum and depolarizing concentrations of potassium. Previous work by several authors showed that benzyloxycarbonyl-DEVD-fluoromethylketone, a somewhat selective caspase inhibitor, significantly protected CGCs from apoptosis; however, because this molecule targets multiple caspases, it is not known whether a single caspase is primarily responsible for effecting cell death in this model. We attempted to answer this question by cotransfecting CGCs with green fluorescent protein reporter and a hammerhead ribozyme directed against caspase-3 mRNA. Maximal protection by this ribozyme was observed after 24 hr of deprivation, at which time apoptosis was 18 +/- 0.7% compared with 32 +/- 2% in control cells. Significant protection was also observed with human inhibitor of apoptosis (IAP)-like protein-X-linked IAP, a specific inhibitor of caspase-3, -7, and -9, and with p35, a general caspase inhibitor. Overexpression of bcl-2 produced almost complete protection from apoptosis after 24 hr of serum-K(+) deprivation (5 +/- 2 vs 44 +/- 2% in control cells). These results confirm that caspases play an important role in CGC apoptosis and indicate that caspase-3 itself is a significant mediator of this process.
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PMID:Ribozyme-mediated inhibition of caspase-3 protects cerebellar granule cells from apoptosis induced by serum-potassium deprivation. 1062 95

Dibutyryl cyclic AMP (DBcAMP) was previously reported to enhance the down-regulation of the retinoblastoma (RB) protein during G1 phase in proliferating primary rat hepatocytes, but to inhibit their entry into S phase and RB phosphorylation. In the present study, DBcAMP was also found to enhance the down-regulation of RB protein in the human hepatoma cells PLC/PRF/5 after hydroxyurea-induced synchronization at G1/S phase. One hour after synchronization, CPP32 activity was detected in the cells and was further enhanced in the presence of DBcAMP. CPP32-specific cleavage of the RB protein was also detected and enhanced by the addition of DBcAMP in a dose-dependent manner. DNA analysis by flow cytometry after serum starvation-induced synchronization at G0/G1 phase revealed that DBcAMP elicited an apoptotic peak after the S phase. Based on these findings, DBcAMP was suspected of inducing apoptosis by RB protein degradation during G1/S transition and thereby inhibit the growth of PLC/PRF/5 cells. Under serum-deficient culture conditions, addition of the CPP32 inhibitor DEVD or the ICE inhibitor YVAD enhanced cell growth but did not abolish the DBcAMP-induced growth inhibition. On the other hand, antisense oligodeoxynucleotides against Bcl-2 mRNA showed a growth inhibitory effect on PLC/PRF/5 cells, but did not show an additive effect on the DBcAMP-induced growth inhibition. DBcAMP itself inhibited bcl-2 protein expression. DBcAMP-induced growth inhibition may be mediated by different mechanisms, including apoptosis.
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PMID:Dibutyryl cyclic AMP-induced enhancement of RB protein degradation in human hepatoma cells. 1069 31

The efficacy of taxanes on human leukemia cells is the object of intensive in vitro investigation concerning the influence of cell-type-specific characteristics on cytotoxic response to drugs. The present study dissects the response to taxanes of HL60 acute myelomonocytic leukemia and of K562 chronic myelogenous leukemia, in parallel over a 72-hr time-span. The kinetics of cytotoxicity following pulsed and continuous exposure to either taxol or taxotere showed a delayed response of K562 cells independently of dose and type of exposure. In K562 cells, apoptosis became evident at 48 hr and prominent at 72 hr of treatment. These events were mirrored by delayed kinetics of caspase-3 activation. Comparable microtubule targeting was demonstrated in HL60 and in K562 cell lines, as bcl-2 and raf-1 were phosphorylated following treatment with taxanes. These observations indicate that early activation processes were responsible for apoptosis, but that the delay was determined by other factors. In addition, cell-free-system experiments excluded the presence of excess nuclear and/or cytoplasmic inhibitory factors and demonstrated that K562 cells possess a fully competent caspase system which can be readily activated. Processing of caspase-3 pro-enzyme was in fact increased by addition of cytochrome c. These results extend to taxol and taxotere the notion that drug-induced apoptosis is delayed upstream of caspase-3 activation in K562 cells, that such kinetics is independent of drug concentration and exposure time, and that it is linked to intrinsic cellular characteristics mapping between bcl-2 phosphorylation and cytochrome c release.
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PMID:Late apoptotic effects of taxanes on K562 erythroleukemia cells: apoptosis is delayed upstream of caspase-3 activation. 1069 26

The induction of cell death in leukemic HL-60 cells by the ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3); edelfosine) followed the typical apoptotic changes in ultrastructural morphology, including blebbing, chromatin condensation, nuclear membrane breakdown and extensive vacuolation. Using a cytofluorimetric approach, we found that ET-18-OCH(3) induced disruption of the mitochondrial transmembrane potential (DeltaPsi(m)) followed by production of reactive oxygen species (ROS) and DNA fragmentation in leukemic cells. ET-18-OCH(3) also induced caspase-3 activation in human leukemic cells, as assessed by cleavage of caspase-3 into the p17 active form and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP). ET-18-OCH(3) analogues unable to induce apoptosis failed to disrupt DeltaPsi(m) and to activate caspase-3. ET-18-OCH(3)-resistant Jurkat cells generated from sensitive Jurkat cells showed no caspase-3 activation and did not undergo DeltaPsi(m) disruption upon ET-18-OCH(3) incubation. Cyclosporin A partially inhibited DeltaPsi(m) dissipation, caspase activation and apoptosis in ET-18-OCH(3)-treated leukemic cells. Overexpression of bcl-2 by gene transfer prevented DeltaPsi(m) collapse, ROS generation, caspase activation and apoptosis in ET-18-OCH(3)-treated leukemic T cells. Pretreatment with the caspase inhibitor Z-Asp-2, 6-dichlorobenzoyloxymethylketone prevented ET-18-OCH(3)-induced PARP proteolysis and DNA fragmentation, but not DeltaPsi(m) dissipation. ET-18-OCH(3) did not affect the expression of caspases and bcl-2-related genes. ET-18-OCH(3)-induced apoptosis did not require protein synthesis. Our data indicate that DeltaPsi(m) dissipation and caspase-3 activation are critical events of the apoptotic cascade triggered by the antitumor ether lipid ET-18-OCH(3), and that the sequence of events in the apoptotic action of ET-18-OCH(3) on human leukemic cells is: DeltaPsi(m) disruption, caspase-3 activation and internucleosomal DNA degradation.
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PMID:Involvement of mitochondria and caspase-3 in ET-18-OCH(3)-induced apoptosis of human leukemic cells. 1073 48

We investigated the possible roles of mitochondrial manganese superoxide dismutase (MnSOD) and bcl-2 in etoposide-induced cell death in acute myeloblastic leukaemia (AML) using two subclones of the OCI/AML-2 cell line, the etoposide-sensitive (ES) and the etoposide-resistant (ER), as models. Cell death after 24 h exposure to 10 micromol/l etoposide was about 60% and 70% in the ES subclone and about 20% and 25% in the ER subclone, when analysed by trypan blue and annexin V respectively. Cytochrome c efflux from mitochondria to cytosol was observed after 4 h of exposure in both subclones, whereas the activation of caspase-3 was not detectable until after 12 h of exposure in the ES subclone and 24 h of exposure in the ER subclone, using Western blotting. The decrease in mitochondrial membrane potential, when analysed by the JC-1 probe fluorocytometrically, also appeared to take place later in the ER than in the ES subclone. Both subclones showed evident basal expression of MnSOD and bcl-2 by Western blotting. Etoposide caused a potent induction of MnSOD, more than 400% at 12 h, in the ER but not in the ES subclone. No significant change in bcl-2 expression could be observed in either of the subclones during exposure to etoposide when analysed by Western blotting or flow cytometry. In conclusion, we suggest that MnSOD might have a special role in the protection of AML cells against etoposide-induced cell death. Although unable to influence the cytochrome c efflux to cytosol, MnSOD might prevent the disruption of mitochondrial membrane potential, which evidently leads to cell death by releasing various activators of apoptosis.
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PMID:Induction of mitochondrial manganese superoxide dismutase confers resistance to apoptosis in acute myeloblastic leukaemia cells exposed to etoposide. 1075 16


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