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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 - 100 microM significantly attenuated the H(2)O(2)-induced decrease in cell viability. Ibudilast inhibited the H(2)O(2)-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3',5'-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H(2)O(2)-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H(2)O(2)-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D(4) antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H(2)O(2)-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H(2)O(2)-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway.
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PMID:Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. 1145 57

To test the role of caspase 3 in apoptosis and in overall cell lethality caused by the protein kinase inhibitor staurosporine, we compared the responses of MCF-7c3 cells that express a stably transfected CASP-3 gene to parental MCF-7:WS8 cells transfected with vector alone and lacking procaspase-3 (MCF-7v). Cells were exposed to increasing doses (0.15-1 microM) of staurosporine for periods up to 19 h. Apoptosis was efficiently induced in MCF-7c3 cells, as demonstrated by cytochrome c release, processing of procaspase-3, procaspase-8, and Bid, increase in caspase-3-like DEVDase activity, cleavage of the enzyme poly(ADP-ribose) polymerase, DNA fragmentation, changes in nuclear morphology, and TUNEL assay and flow cytometry. For all of these measures except cytochrome c release, little or no activity was detected in MCF-7v cells, confirming that caspase-3 is essential for efficient induction of apoptosis by staurosporine, but not for mitochondrial steps that occur earlier in the pathway. MCF-7c3 cells were more sensitive to staurosporine than MCF-7v cells when assayed for loss of viability by reduction of a tetrazolium dye. However, the two cell lines were equally sensitive to killing by staurosporine when evaluated by a clonogenic assay. A similar distinction between apoptosis and loss of clonogenicity was observed for the cancer chemotherapeutic agent VP-16. These results support our previous conclusions with photodynamic therapy: (a) assessing overall reproductive death of cancer cells requires a proliferation-based assay, such as clonogenicity; and (b) the critical staurosporine-induced lethal event is independent of those mediated by caspase-3.
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PMID:Staurosporine-induced death of MCF-7 human breast cancer cells: a distinction between caspase-3-dependent steps of apoptosis and the critical lethal lesions. 1258 34

FK506, a calcineurin inhibitor, shows potent neuroprotective effects in animal models such as those of stroke and neurodegenerative diseases. However, the mechanism underlying these neuroprotective effects is unclear. In this study, an in vitro model, in which FK506 protected the cells against cell death, was established and analyzed in detail by pharmacological experiments. Thapsigargin (TG), an inhibitor of endoplasmic reticulum calcium-ATPase, induced SH-SY5Y cell death. FK506 concentration-dependently protected the cells from this type of death. In contrast, FK506 did not suppress SH-SY5Y cell death caused by the following molecules: tunicamycin (TM), an inhibitor of N-linked glycosylation; etoposide (Eto), a topoisomerase II inhibitor; and staurosporine (STS), a phospholipid/calcium-dependent protein kinase inhibitor. Additionally, FK506 did not inhibit TG-induced cell death in either SK-N-MC or HeLa cell lines. FK506 completely inhibited caspase-3 activation and apoptosis caused by TG in a concentration-dependent manner, but not that caused by TM, Eto, and STS. TG did not activate caspase-3 in SK-N-MC cells, although it slightly activated caspase-3 in HeLa cells. FK506 did not change caspase-3 activity in either SK-N-MC or HeLa cell lines. Cyclosporin A, another calcineurin inhibitor, showed the same results as FK506 in this study, whereas rapamycin, an immunosuppressant not associated with calcineurin activity, did not have any effect in this context. Thus, the suppressive effects of FK506 on cell death are specific to SH-SY5Y cells treated with TG and are caused by the inhibition of calcineurin and subsequent suppression of caspase-3 activation. Therefore, an in vitro system using SH-SY5Y cells treated with TG could provide a model reflective of certain aspects of the neuroprotective activity of FK506.
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PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56

Neuronal apoptosis may contribute to pathologic neuronal loss in certain disease states such as neurodegenerative diseases. Staurosporine (ST), a nonselective protein kinase inhibitor, has been shown to induce apoptosis in a variety of cells including nerve cell lines. In this study, we investigated the neuroprotective effect of sauchinone, which is a unique lignan from Saururus chinensis, on ST-induced apoptosis in C6 rat glioma cells. Sauchinone attenuated ST-induced apoptosis of C6 glioma cells as evidenced by DNA fragmentation. We also provide evidence that the inhibitory effect of sauchinone on ST-induced apoptosis involves a dose-dependent upregulation of an antiapoptotic protein, Bcl-2. Mounting evidence shows that the activation of caspases, especially caspase-3, triggers the apoptotic process. The activity of caspase-3 of ST-pretreated cells was significantly decreased upon sauchinone treatment in a dose-dependent manner. Taken together, the data demonstrate that sauchinone protects C6 glioma cells from ST-induced apoptosis in a caspase-3 dependent manner. Our findings may be critical for developing a strategy to protect nerve cells from apoptosis, suggesting the potential development of sauchinone as a neuroprotective agent.
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PMID:Sauchinone, a lignan from Saururus chinensis, inhibits staurosporine-induced apoptosis in C6 rat glioma cells. 1451 49

The effects of soluble Nef protein on CD4(+) T cells were examined. CD4(+)-T-cell cultures exposed to soluble Nef were analyzed for apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and hallmarks of apoptosis including cytoplasmic shrinkage, nuclear fragmentation, DNA laddering, and caspase activation. We observed dose- and time-dependent inductions of apoptosis. DNA laddering and activated caspase 3 were also evident. Cells treated with Nef/protein kinase inhibitor complexes were protected from Nef-induced apoptosis, suggesting possible roles for protein kinases in the apoptosis pathway. Similarly, cells treated with Nef/anti-Nef antibody complexes were protected from Nef-induced apoptosis. The cellular receptor responsible for Nef-induced apoptosis was identified through antibody- and ligand-blocking experiments as a receptor commonly involved in viral entry. CXCR4 antibodies, as well as the endogenous ligand SDF-1alpha, were effective in blocking Nef-induced apoptosis, while CCR5 and CD4 antibodies were ineffective. Moreover, a CXCR4-deficient cell line, MDA-MB-468, which was resistant to Nef-induced apoptosis, became sensitive upon transfection with a CXCR4-expressing vector. This study suggests that extracellular Nef protein could contribute to the decline of CD4 counts prior to and during the onset of AIDS in patients with human immunodeficiency virus type 1 infections.
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PMID:Extracellular Nef protein targets CD4+ T cells for apoptosis by interacting with CXCR4 surface receptors. 1499 Jul 29

Non-small-cell lung carcinomas (NSCLCs) are resistant to the induction of apoptosis by conventional anticancer treatment. However, NSCLC cell lines are sensitive to the action of the broad protein kinase inhibitor, staurosporine (STS). In the NSCLC cell line U1810, STS induced the mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) followed by activation of caspases, nuclear condensation, DNA fragmentation and finally cell death. Although preincubation of U1810 cells with the broad-spectrum caspase inhibitor z-VAD.fmk delayed the occurrence of nuclear apoptosis induced by STS, it did not impede mitochondrial alterations (such as the release of Cyt c and AIF) and cell death to occur. Moreover, the microinjection of neither Cyt c nor recombinant active caspase-3 into the cytoplasm promoted nuclear apoptosis-related changes in U1810 cells. Evaluation of the role of the caspase-independent factor AIF in STS-mediated death revealed that, upon immunodepletion of AIF, cytosols from STS-treated U1810 lost their capacity to induce nuclear condensation when incubated with isolated nuclei. In addition, microinjection of an anti-AIF antibody prevented AIF from translocating to the nuclei of STS-treated U1810 cells and reduced STS-induced cell death. Finally, although the transfection-enforced overexpression of AIF was not sufficient to induce cell death, it did enhance STS-mediated cell killing. Altogether, these results indicate that activation of caspases is not sufficient to kill U1810 cells and rather suggests an important role for the AIF-mediated mitochondrial-mediated death pathway.
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PMID:Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas. 1528 13

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxi-dative stress and apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 microM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (100 microM), the p38 mito-gen-activated protein kinase inhibitor SB203580 (2.5 microM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 microM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 microM), and antioxidants alpha-tocopherol (5 microg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride staining, annexin-V phosphatidyl- serine/propidium iodide, and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored Hcy-induced apoptosis. JNK inhibitor II, alpha-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580 and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively, our results suggested that Hcy may induce oxidative stress and apopto-sis through an NADPH oxidase and/or JNK-dependent mechanism(s).
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PMID:Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells. 1573 81

Nitric oxide (NO) may block apoptosis by inhibiting caspases via S-nitrosylation of cysteines. Here, we investigated whether effector caspases might cleave and thereby inhibit endothelial nitric oxide synthase (eNOS). Exposure of eNOS-transfected COS-7 cells and bovine aortic endothelial cells to staurosporine resulted in significant loss of 135-kDa eNOS protein and activity, and appearance of a 60-kDa eNOS fragment; effects were inhibited by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp[OMe]-fluoromethyl ketone (zVAD-fmk). In eNOS-transfected COS-7 cells, staurosporine-induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage coincided with increased eNOS degradation and decreased activity. Loss of eNOS activity was greater than the degree of proteolysis. Incubation of immunoprecipitated eNOS with caspase-3, caspase-6 or caspase-7 resulted in eNOS cleavage. Staurosporine, a general protein kinase inhibitor, also reduced phosphorylation and decreased calmodulin binding, an effect that may explain the reduction in activity. eNOS, therefore, is both an inhibitor of apoptosis and a target of apoptosis-associated proteolysis.
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PMID:Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells. 1619 40

The general protein kinase inhibitor staurosporine (STS) has dual effects on human epidermoid cancer cells (A431) and normal rat kidney fibroblasts (NRK). It almost immediately stimulated increased lamellipodial activity of both cell lines and after 2 h induced typical signs of apoptosis, including cytoplasmic condensation, nuclear fragmentation, caspase-3 activation and DNA degradation. In the early phase we observed disruption of actin-containing stress fibres and accumulation of monomeric actin in the perinuclear region and cell nucleus. Increased lamellipodial-like extensions were observed particularly in A431 cells as demonstrated by co-localisation of actin and Arp2/3 complex, whereas NRK cells shrunk and exhibited numerous thin long extensions. These extensions exhibited uncoordinated centrifugal motile activity that appeared to tear the cells apart. Both cofilin and ADF were translocated from perinuclear regions to the cell cortex and, as expected in the presence of a kinase inhibitor, all the cofilin was dephosphorylated. Myosin II was absent from the extensions, and a reduction of phosphorylated myosin light chains was observed within the cytoplasm indicating myosin inactivation. Microtubules and intermediate filaments retained their characteristic filamentous organisation after STS exposure even when the cells became rounded and disorganised. Simultaneous treatment of NRK cells with STS and the caspase inhibitor zVAD did not inhibit the morphological and cytoskeletal changes. However, the cells underwent cell death as verified by positive annexin-V-staining. Thus it seems likely that cell death induced by STS may not only be a consequence of the activation of caspase, instead the disruption of the many motile processes involving the actin cytoskeleton may by itself suffice to induce caspase-independent cell death.
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PMID:Dual effects of staurosporine on A431 and NRK cells: microfilament disassembly and uncoordinated lamellipodial activity followed by cell death. 1669 76

The choroid plexus epithelium constitutes the structural basis of the blood-cerebrospinal fluid barrier. We previously demonstrated that Streptococcus suis (S. suis), a relevant cause of bacterial meningitis in pigs and humans, affects porcine choroid plexus epithelial cell (PCPEC) barrier function and integrity. We now characterized PCPEC cell death and investigated whether apoptosis or necrosis is responsible for the cytotoxicity after infection with different S. suis isolates. We found S. suis strain-dependent histone associated DNA-fragments quantified by ELISA. This response could partially be inhibited by cylcoheximide, cytochalasin D, dexamethasone, herbimycin A, but most effectively by the pan-caspase inhibitor zVAD-fmk. We further detected caspase-3 and -9 activation after infection with all tested S. suis isolates that could also be blocked by zVAD-fmk. However, we found a significantly stronger caspase activity with the protein kinase inhibitor staurosporine. All tested S. suis isolates induced loss of cell viability in PCPEC as shown with the Live/Dead assay, but strain dependent lactate dehydrogenase-release. Both parameters could not be influenced by zVAD-fmk. Immunostaining showed release of high-mobility group box 1 (HMGB1) protein from the nucleus, indicative of necrosis. Transmission electron microscopy showed cell swelling, cytoplasmic vacuolization, loss of membrane integrity, nuclear fermentation but no nuclear condensation, indices for a primarily necrotic cell morphology. Taken together, our findings indicate that S. suis causes cell death in PCPEC by different mechanisms. Although apoptosis may be involved in the process of PCPEC cell death, necrosis seems to be the predominant mechanism. Through inflammation in the choroid plexus during bacterial meningitis, the blood-cerebrospinal fluid barrier function will be compromised.
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PMID:Cell death, caspase activation, and HMGB1 release of porcine choroid plexus epithelial cells during Streptococcus suis infection in vitro. 1678 80


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