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)

To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H20O)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pre-treatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the anti-apoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.
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PMID:Molecular basis of anti-apoptotic effect of immunophilin ligands on hydrogen peroxide-induced apoptosis in human glioma cells. 1526 Jan 30

The effect of the depletion or oxidation of cellular GSH on cytotoxicity of MG132 was assessed. Viability loss and decrease in GSH contents in small cell lung cancer (SCLC) cells treated with MG132 was attenuated by caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk). Thiol compounds (N-acetylcysteine and N-(2-mercaptopropionyl)glycine) and free radical scavengers reduced MG132-induced cell death. Antioxidants, including N-acetylcysteine, inhibited the MG132-induced nuclear damage, loss in mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c and caspase-3 activation. Depletion of GSH due to buthionine sulfoxime did not affect the cell viability loss, ROS formation and GSH depletion due to MG132 in SCLC cells. A thiol oxidant monochloramine, p-chloromercuribenzoate and N-ethylmaleiamide also did not affect cytotoxicity of MG132. The results suggest that the toxicity of MG132 on SCLC cells is mediated by activation of caspase-8, -9 and -3. Removal of free radicals and recovery of GSH contents may attenuate MG132-induced apoptotic cell death. Nevertheless, depletion or oxidation of cellular GSH may not affect toxicity of MG132.
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PMID:Differential response of MG132 cytotoxicity against small cell lung cancer cells to changes in cellular GSH contents. 1527 73

Glutathione (GSH) is important in free radical scavenging, maintaining cellular redox status, and regulating cell survival in response to a wide variety of toxicants. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), which is composed of catalytic (GCLC) and modifier (GCLM) subunits. To determine whether increased GSH biosynthetic capacity enhances cellular resistance to tumor necrosis factor-alpha- (TNF-alpha-) induced apoptotic cell death, we have established several mouse liver hepatoma (Hepa-1) cell lines overexpressing GCLC and/or GCLM. Cells overexpressing GCLC alone exhibit modest increases in GCL activity, while cells overexpressing both subunits have large increases in GCL activity. Importantly, cells overexpressing both GCL subunits exhibit increased resistance to TNF-induced apoptosis as judged by a loss of redox potential; mitochondrial membrane potential; translocation of cytochrome c to the cytoplasm; and activation of caspase-3, caspase-8, and caspase-9. Analysis of the effects of TNF on these parameters indicates that maintaining mitochondrial integrity mediates this protective effect in GCL-overexpressing cells.
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PMID:Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis. 1528 21

The mycotoxin fumonisin B1 (FB1) is produced by Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species are also a frequent finding in moisture-damaged buildings, causing possible human exposure to FB1. FB1 is neurotoxic and carcinogenic in a number of animal species. In this study, we have investigated the effects of FB1 on human U-118MG glioblastoma cells. The production of reactive oxygen species (ROS), lipid peroxidation, intracellular reduced glutathione (GSH) levels, cell viability, caspase-3-like protease activity and DNA fragmentation were studied in cells exposed to 0.01-100 microM FB1 for 0.5-144 h. FB1 increased lipid peroxidation and the production of ROS in U-118MG cells, showing significant effects after culture times from 48 to 144 h at dose levels of 10 or 100 microM FB1. These effects were accompanied by changes in the GSH levels and cell viability, which decreased significantly after incubating the cells for 48-144 h with the toxin. Signs of apoptosis were indicated by increased caspase-3-like protease activity and internucleosomal DNA fragmentation. Thus, oxidative stress and apoptosis may be involved in the neurotoxicity induced by FB1.
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PMID:Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. 1533 81

In this study, we investigated the role of reduced glutathione (GSH) and nuclear factor-kappaB (NFkappaB) in hypoxia-induced apoptosis. Hypoxia caused p53-dependent apoptosis in murine embryonic fibroblasts transfected with Ras and E1A. N-Acetyl-l-cysteine (NAC) but not other antioxidants, such as the vitamin E analog trolox and epigallocatechin-3-gallate, enhanced hypoxia-induced caspase-3 activation and apoptosis. NAC also enhanced hypoxia-induced apoptosis in two human cancer cell lines, MIA PaCa-2 pancreatic cancer cells and A549 lung carcinoma cells. In murine embryonic fibroblasts, all three antioxidants blocked hypoxia-induced reactive oxygen species formation. NAC did not enhance hypoxia-induced cytochrome c release but did enhance poly-(ADP ribose) polymerase cleavage, indicating that NAC acted at a post-mitochondrial level. NAC-mediated enhancement of apoptosis was mimicked by incubating cells with GSH monoester, which increased intracellular GSH similarly to NAC. Hypoxia promoted degradation of an inhibitor of kappaB(IkappaBalpha), NFkappaB-p65 translocation into the nucleus, NFkappaB binding to DNA, and subsequent transactivation of NFkappaB, which increased X chromosome-linked inhibitor of apoptosis protein levels. NAC failed to block degradation by IkappaBalpha and sequestration of the p65 subunit of NFkappaB to the nucleus. However, NAC did abrogate hypoxia-induced NFkappaB binding to DNA, NFkappaB-dependent gene expression, and induction of X chromosome-linked inhibitor of apoptosis protein. In conclusion, NAC enhanced hypoxic apoptosis by a mechanism apparently involving GSH-dependent suppression of NFkappaB transactivation.
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PMID:N-Acetyl-L-cysteine enhances apoptosis through inhibition of nuclear factor-kappaB in hypoxic murine embryonic fibroblasts. 1537 56

Pycnogenol (PYC), a patented combination of bioflavonoids extracted from the bark of French maritime pine (Pinus maritima), inhibits apoptosis and necrosis of developing neurons exposed acutely to ethanol (EtOH). The present study shows that the protective mechanisms of PYC in EtOH-exposed postnatal day 9 cerebellar granule cells (P9 CGCs) include (1) reduction of reactive oxygen species (ROS) production; (2) counteraction of suppressed copper/zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase/reductase (GSH-Px/GSSG-R) system activities; (3) upregulation of Cu/Zn SOD protein expression; (4) mitigation of the EtOH-mediated exacerbation of catalase (CAT) activity; and, (5) specific binding and inhibition of active caspase-3. These results indicate that the mechanisms by which PYC antagonizes EtOH-induced oxidative stress include oxidant scavenging and modulation of endogenous, cellular proteins. Using findings from the present and previous studies, a model delineating the mechanisms of EtOH effects on the system of antioxidant enzymes in developing CGCs is presented.
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PMID:Protective mechanisms of pycnogenol in ethanol-insulted cerebellar granule cells. 1538 91

The role of intracellular free zinc and its chelation by TPEN (N,N,N',N'- tetrakis(2-pyridylmethyl)ethylene-diamine) was studied in Bowes human melanoma cells. The content of free Zn pools was determined by fluorescent probe Zinquin. Depletion of zinc triggered apoptosis confirmed by cell blebbing, changes in mitochondrial transmembrane potential and GSH levels, caspase-3 activation and nuclear fragmentation. Apoptosis was only partially prevented by cyclosporin A or N-acetylcystein, suggesting various independent but likely interrelated mechanisms participating in this process.
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PMID:Depletion of endogenous zinc stores induces oxidative stress and cell death in human melanoma cells. 1544 56

The effect of GSH depletion on mitochondrial damage and cell death due to mitomycin c (MMC) was assessed in small cell lung cancer (SCLC) cells. Cytotoxicity of MMC was attenuated by Tempol and dicumarol, inhibitors of the enzymatic reduction, and increased by xanthine oxidase. The MMC-induced cell death and decrease in the GSH contents in SCLC cells were inhibited by caspase inhibitors (z-DQMD.fmk, z-IETD.fmk and z-LEHD.fmk) and antioxidants (N-acetylcysteine, dithiothreitol and N-(2-mercaptopropionyl)glycine, melatonin, rutin and carboxy-PTIO). Thiol compounds, melatonin and rutin attenuated the MMC-induced nuclear damage, decrease in mitochondrial transmembrane potential, release of cytochrome c and activation of caspase-3. Treatment of MMC caused a significant decrease in GSH contents in SCLC cells, which was followed by increase in the formation of reactive oxygen species. Depletion of GSH due to L-buthionine sulfoximine enhanced the MMC-induced activation of caspase-3 and cell death in SCLC cells. Antioxidants, including N-acetylcysteine, depressed formations of nitric oxide, malondialdehyde and carbonyls due to MMC in SCLC cells. The results show that the reductive activation of MMC may cause cell death in SCLC cells by inducing mitochondrial dysfunction, leading to caspase-3 activation, and by activation of caspase-8. The MMC-induced change in the mitochondrial membrane permeability, followed by cell death, in SCLC cells may be significantly enhanced by decrease in the intracellular GSH contents due to oxidative attack of free radicals.
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PMID:Effect of change in cellular GSH levels on mitochondrial damage and cell viability loss due to mitomycin c in small cell lung cancer cells. 1545 Sep 51

Two relatively recent discoveries stand behind our current effort to investigate the effects of the chemopreventive agent, selenium, on the proliferation and survival of NB4 cells. The first is that certain selenium compounds such as sodium selenite have pro-oxidant ability to catalyze the oxidation of thiols and simultaneously generate superoxide. The second lies in the exquisite susceptibility of NB4 cells to arsenic trioxide-induced, reactive oxygen species (ROS)-mediated apoptosis due to less efficiency of the cellular defense system. In this study, we demonstrated that sodium selenite could induce apoptosis in NB4 cells via the classic mitochondrial pathway involving caspase-3 activation and Bcl-2 cleavage. An increase in the basal cellular glutathione (GSH) content rendered NB4 cells resistant to arsenic trioxide, but could sensitize NB4 cells to sodium selenite. Moreover, combined treatment of NB4 cells with all- trans retinoic acid (ATRA) at low concentration and sodium selenite exhibited a synergistic effect on apoptosis induction. Together, our results suggest that selenite is a promising candidate for treatment of acute promyelocytic leukemia (APL) and the mechanism underlying its anticancer effects warrants further investigation.
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PMID:Sodium selenite induces apoptosis in acute promyelocytic leukemia-derived NB4 cells by a caspase-3-dependent mechanism and a redox pathway different from that of arsenic trioxide. 1548 Jun 64

In 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT), ALA taken up by tumor cells is metabolized to protoporphyrin IX (PpIX), which sensitizes photodamage leading to apoptotic or necrotic cell death. Since lipophilic PpIX originates in mitochondria, we postulated that photoperoxidation of highly unsaturated cardiolipin (CL), which anchors cytochrome c (cyt c) to the inner membrane, is an early proapoptotic event. As initial evidence, PpIX-sensitized photooxidation of liposomal CL to hydroperoxide (CLOOH) species precluded cyt c binding, but this could be reinstated by GSH/selenoperoxidase (GPX4) treatment. Further support derived from site-specific effects observed using (i) a mitochondrial GPX4-overexpressing clone (7G4) of COH-BR1 tumor cells, and (ii) an ALA treatment protocol in which most cellular PpIX is either inside (Pr-1) or outside (Pr-2) mitochondria. Sensitized cells were exposed to a lethal light dose, and then analyzed for death mechanism and lipid hydroperoxide (LOOH) levels. Irradiated Pr-1 vector control (VC) cells died apoptotically following cyt c release and caspase-3 activation, whereas 7G4 cells were highly resistant. Irradiated Pr-2 VC and 7G4 cells showed negligible cyt c release or caspase-3 activation, and both types died via necrosis. CLOOH (detected long before cyt c release) accumulated approximately 70% slower in Pr-1 7G4 cells than in Pr-1 VC, and this slowdown exceeded that of all other LOOHs. These and related findings support the hypothesis that CL is a key upstream target in mitochondria-dependent ALA-PDT-induced apoptosis.
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PMID:Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells. 1558


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