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

Several malignant cell lines are resistant to CD95-(Apo1/Fas)-mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95-induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti-CD95 monoclonal antibody, increases DNA fragmentation and caspase-3 activity in HPB-ALL cells. These cells have been selected for their known resistance to CD95-induced apoptosis. At molecular level, quercetin lowers the level of intracellular reactive oxygen species, reduces mitochondrial transmembrane potential, thereby leaving the expression of CD95 receptor unchanged.
FEBS Lett 1999 Dec 03
PMID:Quercetin and anti-CD95(Fas/Apo1) enhance apoptosis in HPB-ALL cell line. 1062 19

Treatment of U937 cells with various apoptosis-inducing agents, such as TNFalpha and beta-D-arabinofuranosylcytosine (ara-C) alone or in combination with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), bryostatin 1 or cycloheximide, causes proteolytic cleavage of protein kinase Cmu (PKCmu) between the regulatory and catalytic domain, generating a 62 kDa catalytic fragment of the kinase. The formation of this fragment is effectively suppressed by the caspase-3 inhibitor Z-DEVD-FMK. In accordance with these in vivo data, treatment of recombinant PKCmu with caspase-3 in vitro results also in the generation of a 62 kDa fragment (p62). Treatment of several aspartic acid to alanine mutants of PKCmu with caspase-3 resulted in an unexpected finding. PKCmu is not cleaved at one of the typical cleavage sites containing the motif DXXD but at the atypical site CQND378/S379. The respective fragment (amino acids 379-912) was expressed in bacteria as a GST fusion protein (GST-p62) and partially purified. In contrast to the intact kinase, the fragment does not respond to the activating cofactors TPA and phosphatidylserine and is thus unable to phosphorylate substrates effectively.
FEBS Lett 1999 Dec 03
PMID:Proteolytic cleavage of protein kinase Cmu upon induction of apoptosis in U937 cells. 1062 42

Apoptosis is a new therapeutic target of cancer research. Tanshinone IIA isolated from Salvia miltiorrhiza BUNGE, a traditional oriental medical herb, was observed to induce apoptosis in HL60 human premyelocytic leukemia cell line. Tanshinone IIA induced DNA fragmentation into the multiples of 180 bp and increased the percentage of hypodiploid cells in flow cytometry after propidium iodide (PI) staining. Tanshinone IIA-induced apoptosis is accompanied by the specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-3, a major component in apoptotic cell death mechanism.
J Ethnopharmacol 1999 Dec 15
PMID:Tanshinone IIA isolated from Salvia miltiorrhiza BUNGE induced apoptosis in HL60 human premyelocytic leukemia cell line. 1062 71

Recent results demonstrated that S-nitrosoglutathione (GSNO) and nitric oxide (*NO) protect brain dopamine neurons from hydroxyl radical (*OH)-induced oxidative stress in vivo because they are potent antioxidants. GSNO and *NO terminate oxidant stress in the brain by (i) inhibiting iron-stimulated hydroxyl radicals formation or the Fenton reaction, (ii) terminating lipid peroxidation, (iii) augmenting the antioxidative potency of glutathione (GSH), (iv) mediating neuroprotective action of brain-derived neurotrophin (BDNF), and (v) inhibiting cysteinyl proteases. In fact, GSNO--S-nitrosylated GSH--is approximately 100 times more potent than the classical antioxidant GSH. In addition, S-nitrosylation of cysteine residues by GSNO inactivates caspase-3 and HIV-1 protease, and prevents apoptosis and neurotoxicity. GSNO-induced antiplatelet aggregation is also mediated by S-nitrosylation of clotting factor XIII. Thus the elucidation of chemical reactions involved in this GSNO pathway (GSH GS* + *NO-->[GSNO]-->GSSG + *NO-->GSH) is necessary for understanding the biology of *NO, especially its beneficial antioxidative and neuroprotective effects in the CNS. GSNO is most likely generated in the endothelial and astroglial cells during oxidative stress because these cells contain mM GSH and nitric oxide synthase. Furthermore, the transfer of GSH and *NO to neurons via this GSNO pathway may facilitate cell to neuron communications, including not only the activation of guanylyl cyclase, but also the nitrosylation of iron complexes, iron containing enzymes, and cysteinyl proteases. GSNO annihilates free radicals and promotes neuroprotection via its c-GMP-independent nitrosylation actions. This putative pathway of GSNO/GSH/*NO may provide new molecular insights for the redox cycling of GSH and GSSG in the CNS.
Free Radic Res 1999 Dec
PMID:The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. 1063 Jun 87

Caspase-3 is a member of the cysteine protease family, which plays a crucial role in apoptosis. We applied the human caspase-3 gene as a novel form of anticancer gene therapy. Overexpression of human caspase-3 alone could not induce apoptosis of tumor cell lines, but apoptosis was markedly enhanced by the addition of etoposide. In an AH130 liver tumor model, transduction of human caspase- 3, but not the empty vector, induced extensive apoptosis and reduced tumor volume when combined with etoposide administration. However, this effect was not observed with a Bcl-2 overexpressing tumor. In conclusion, caspase-3 gene transduction accompanied by an additional death stimulus may be a useful method of anticancer gene therapy, except for Bcl-2 overexpressing tumors.
Gene Ther 1999 Dec
PMID:Cancer gene therapy using a pro-apoptotic gene, caspase-3. 1063 46

The present study was aimed at evaluating of the effects of dopamine (DA) toxicity on PC12 cells' calcium homeostasis, cellular viability, and free radical levels. Moreover, the effect of receptor inhibition, and DA metabolism and reuptake antagonism on all parameters was also evaluated. Acute treatment with DA impaired the ability of PC12 cells to buffer excess calcium after K+-depolarization, decreased cellular viability by approximately 35%, and increased free radical levels by about 10% in a dose dependent manner. Pretreatment with both active and inactive pargyl monoamine oxidase inhibitors (MAOi) protected PC12 cells from DA toxicity on cellular viability and free radical levels, regardless of the presence or absence of their target enzymes in PC12 cells. These results suggest a lack of specific involvement of DA metabolism by MAO in dopamine's effects on cellular viability and production of free radicals. However, DA-induced dysregulation of calcium homeostasis seems to be more specifically mediated by DA metabolism by MAO. Results indicate that, in order for toxicity to occur the DA must be taken up into the cells. DA receptors do not mediate dopamine cytoxicity, and the D2 receptor plays a modest role in DA-induced calcium dysregulation and generation of free radicals. Moreover, DA-induced cell viability loss is not mediated by calcium, nor by caspase-3 enzyme, but is prevented by inhibition of mitochondrial permeability transition pores.
Free Radic Biol Med 1999 Dec
PMID:Differential effect of dopamine catabolism and uptake inhibition on dopamine-induced calcium dysregulation and viability loss. 1064 34

We have demonstrated that clofilium, a potassium channel blocker, induces apoptosis on human promyelocytic leukemia (HL-60) cells. Cells treated with clofilium led to suppression of viability and proliferation in both time and concentration-dependent manners. Nuclear DAPI staining and electronmicroscopic examination revealed typical nuclear features of apoptosis in cells treated with clofilium that was further verified in DNA fragmentation analysis. Flow cytometry analysis with FITC-annexin V and propidium iodide (PI) revealed that apoptotic cell population with Annexin V+/PI- increased gradually from < 2% at 0 h, to 20% at 4 h and 29% at 16 h after exposure to 10 microM clofilium in HL-60 cells. Furthermore, fluorometric immunosorbent enzyme assay for activity of caspase-3 showed approximately a 10-fold increase of activity in cells treated with 10 microM of clofilium for 2-3 h compared with the basal level of its activity in untreated control cells. Immunoblotting analysis revealed proteolytic cleavage of caspase-3 and subsequent cleavage of PARP. However, there was no significant change of Bcl-2 and Bax proteins. These results indicate that clofilium exerts antiproliferative action and growth inhibition on HL-60 through induction of apoptosis which is mediated via Bcl-2-insensitive activation of caspase-3, and suggest chemotherapeutic and cytostatic potentials of this compound in human leukemias.
Cancer Lett 1999 Dec 01
PMID:Clofilium, a potassium channel blocker, induces apoptosis of human promyelocytic leukemia (HL-60) cells via Bcl-2-insensitive activation of caspase-3. 1066 93

Recently, we have demonstrated that ischemic preconditioning (IP) both limits infarct size and decreases internucleosomal DNA fragmentation in rat hearts in vivo, and that there was a direct correlation between myocardial infarct size and DNA fragmentation even after IP. In this study, we examined the ability of IP to attenuate processing and activation of caspase-1 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP), after prolonged ischemia and reperfusion using the same in vivo animal model. Rats that underwent IP and controls (Ctrl) were subjected to 30 min of left coronary artery occlusion followed by 180 min of reperfusion. IP was accomplished by five 5-min cycles of ischemia, each followed by 5 min of reperfusion. The amount of soluble nucleosomes was measured by enzyme-linked immunosorbent assay. Cleavage of caspases-1 and -3, and of one of their substrates PARP, was analyzed by Western blotting. Nucleosomal DNA fragmentation was significantly reduced in ischemic left ventricular (LV) tissue obtained from IP compared with Ctrl animals. The proforms of caspases-1 and -3, and the active form of PARP were not cleaved in the nonischemic LV region of both IP and Ctrl hearts. In contrast, the proform of caspase-3 and the active form of PARP were cleaved in the ischemic LV region of Ctrl hearts, while processing of caspase-1 was increased. Cleavages of caspases-1 and -3, and inactivation of PARP were prevented by IP. The results of this study indicate that IP attenuates both internucleosomal DNA fragmentation and caspases processing, and suggest that the prevention of caspases activation by IP may be important steps in protecting the heart against ischemia/reperfusion injury in vivo.
Cardiovasc Res 1999 Dec
PMID:Ischemic preconditioning attenuates ischemia/reperfusion-induced activation of caspases and subsequent cleavage of poly(ADP-ribose) polymerase in rat hearts in vivo. 1069 Feb 85

Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.
J Neuroimmunol 1999 Dec
PMID:Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. 1069 26

A previous paper from this laboratory reported the activation of a caspase-3-like protease by a digitonin-treated lysosomal fraction [FEBS Lett. 435, 233-236, 1998]. In this study, we examined the effects of specific inhibitors of lysosomal cysteine proteases, such as cathepsins B, S, and L, on the activation of caspase-3 to find out which cathepsin is responsible for the activation. Pro-caspase-3 in the cytosol was cleaved by a lysosomal protease(s) contained in the supernatant of a digitonin-treated crude mitochondrial fraction containing lysosomes (ML) and the cleaved product was detected by Western blotting using anti-caspase-3 antibody. The activation of caspase-3 by the lysosomal protease(s) was pH dependent and the optimum pH for activation was pH 6.6-6.8. This activation was not inhibited by CA-074, a specific inhibitor of cathepsin B, but was strongly inhibited by CLIK-066 and CLIK-181, specific inhibitors of cathepsin L. The inhibitory effect of CLIK-060, a specific inhibitor of cathepsin S, was very weak. Furthermore, the activation of caspase-3 was enhanced by addition of purified cathepsin L only in the presence of the supernatant of the digitonin-treated ML. These results suggested that a cathepsin L-type protease activity might participate in the activation mechanism of caspase-3 in the presence of the supernatnat from the ML.
Cell Struct Funct 1999 Dec
PMID:Participation of a cathepsin L-type protease in the activation of caspase-3. 1069 61


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