UNIPROT:P42574 - FACTA Search

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

The current study was undertaken to investigate the role of apoptosis in hydrazine induced hepatotoxicity. Hepatocytes were exposed to hydrazinium nitrate (HzN) at two doses (50 and 75 mM) for 2 h then placed in fresh HzN-free media and cultured for an additional 24 h. Post-exposure, cell viability was evaluated at several time points by lactate dehydrogenase (LDH) leakage and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Markers of apoptosis (mitochondrial membrane potential, annexin binding, DNA fragmentation, caspase activation, and cytochrome c release) were measured 24 h post-exposure. The viability data showed time dependent increase in LDH leakage at 75 mM of HzN, with only a slight increase at 50 mM. MTT reduction showed a decrease in mitochondrial activity at both doses immediately after the 2 h continuous exposure. However, MTT reduction returned to normal at 50 mM while at 75 mM, MTT reduction initially recovered but then deteriorated to approximately 50% of controls at 24 h post-exposure. Based on viability data, exposure to 50 mM HzN for 2 h is a marginally toxic dose while 75 mM is a significantly toxic dose. The results for apoptosis biomarkers showed a reduction in mitochondrial membrane potential, an increase in annexin binding, an increase in total caspase activity, moderate activation of caspase-3, and release of cytochrome c. However, the appearance of DNA fragmentation in HzN exposed cells was very low compared to positive controls (cadmium and cyclosporine). The possibility that HzN induces apoptosis without the involvement of DNA fragmentation can not be ruled out. The present results, overall, suggest that apoptosis may be a contributing factor in acute HzN toxicity.
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PMID:Involvement of apoptosis in hydrazine induced toxicity in rat primary hepatocytes. 1278 Dec 13

Parathyroid hormone-related protein (PTHrP) promotes or suppresses apoptosis in various settings depending on cell type and context. PTHrP 1-34 and PTHrP 67-86 are type II cell growth factors with effects on pneumocyte growth and surfactant secretion. This study investigated the effects of 24 h pretreatment with these two peptides on rat type II cell apoptosis after 0.3 J/cm2 ultraviolet-B irradiation. Adherent cells decreased in number by 15 +/- 5% and nonadherent cells increased > 5-fold 24 h after ultraviolet irradiation. Cell loss was due predominantly to apoptosis, based on ethidium bromide exclusion, nuclear condensation, and caspase 3 activity. Nuclear condensation increased from 15.6 +/- 2.2% of irradiated cells with no treatment to 25.6 +/- 4.9 and 22.9 +/- 1.8% of cells in ultraviolet/PTHrP 1-34 and ultraviolet/PTHrP 67-86 groups, respectively (P < 0.01), along with a 60% increase in caspase 3 activity. Effects on apoptosis were unaffected by the presence or absence of serum, but were ameliorated by growth to confluence or adherence to fibronectin. PTHrP 1-34 and PTHrP 67-86 augmented inositol phosphate levels, but had minimal effects on cAMP. Thus, PTHrP 1-34 and PTHrP 67-86 sensitize type II cells to apoptosis, possibly by a phospholipase C-dependent mechanism. The effects appear to be regulated by cell-matrix and cell-cell interactions.
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PMID:Proapoptotic effects of parathyroid hormone-related protein in type II pneumocytes. 1279 77

The epidermal growth factor receptor (EGFR) is an important novel target for anticancer therapy. In this study, we examined the molecular mechanisms that underlie the antitumor effects of the anti-EGFR monoclonal antibody C225 (Cetuximab) and the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca) in non-small cell lung cancer (NSCLC) cell lines. Cell growth, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was inhibited at low concentrations of ZD1839 and C225 in control A431 cells, whereas the NSCLC cell lines were comparatively more resistant. In A431 cells, but not in the NSCLC cells, ZD1839 treatment resulted in a modest increase in DNA fragmentation, the externalization of phosphatidyl serine, and the activation of caspase-3, known markers of apoptotic cell death. However, poly(ADP-ribose) polymerase cleavage was not detected, and caspase inhibition by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone partially reduced ZD1839-generated DNA fragmentation. Overexpression of the antiapoptotic protein Bcl-2 in A431 cells suppressed the cytotoxicity upon anti-EGFR treatment. These results thus demonstrate that the toxic effect of ZD1839 in A431 cells is caused by a form of cell death that involves a mitochondrial step and is, at least in part, dependent on caspase activation. EGFR expression levels showed no significant correlation with sensitivity to ZD1839 and C225. Evaluation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and phosphatidylinositol 3'-kinase/Akt pathways showed considerable inhibition of these pathways by ZD1839 and C225 in A431 cells, whereas one or both of these pathways remained active upon anti-EGFR treatment in NSCLC cells. In addition, treatment with specific inhibitors of mitogen-activated protein kinase kinase or phosphatidylinositol 3'-kinase resulted in a smaller effect on proliferation than simultaneous treatment with both inhibitors, whereas induction of apoptosis was observed only when both pathways were blocked. Together, these data suggest that persistent activity of either of these signaling pathways is involved in the lack of sensitivity of NSCLC cell lines to EGFR inhibitors.
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PMID:Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. 1279 1

The mechanism by which beta-amyloid protein (A beta) causes degeneration in cultured neurons is not completely understood, but several lines of evidence suggest that A beta-mediated neuronal death is associated with an enhanced production of reactive oxygen species (ROS) and oxidative damage. In the present study, we address whether supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protects rat primary neurons from A beta-induced degeneration and death. We found that P/M addition attenuated cell death evoked by beta-amyloid peptides (A beta(25-35) and A beta(1-40)) after 24 hr treatment and that this effect was blocked by alpha-ciano-3-hydroxycinnamate (CIN), suggesting that it requires mitochondrial pyruvate uptake. P/M supply to control and A beta-treated neuronal cultures increases cellular reducing power, as indicated by the ability to reduce the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The early increases in ROS levels, measured by dichlorofluorescein (DCF) fluorescence, and caspase-3 activity that follow exposure to A beta were notably reduced in the presence of P/M. These results place activation of caspase-3 most likely downstream of oxidative damage to the mitochondria and indicate that mitochondrial NAD(P) redox status plays a central role in the neuroprotective effect of pyruvate. Inhibition of respiratory chain complexes and mitochondrial uncoupling did not block the early increase in ROS levels, suggesting that A beta could initiate oxidative stress by activating a source of ROS that is not accesible to the antioxidant defenses fueled by mitochondrial substrates.
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PMID:Pyruvate protection against beta-amyloid-induced neuronal death: role of mitochondrial redox state. 1283 69

The purpose of this study was to investigate the potential neuroprotective effects of myricetin (flavonoid) and fraxetin (coumarin) on rotenone-induced apoptosis in SH-SY5Y cells, and the possible signal pathway involved in a neuronal cell model of Parkinson's disease. These two compounds were compared to N-acetylcysteine. The viability of cells was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and cytotoxicity was assayed by lactate dehydrogenase (LDH) released into the culture medium. Parameters related to apoptosis, such as caspase-3 activity, the cleavage of poly(ADP-ribose) polymerase and the levels of reactive oxygen species were also determined. Rotenone caused a time- and dose-dependent decrease in cell viability and the degree of LDH release was proportionally to the effects on cell viability. Cells were pretreated with fraxetin, myricetin and N-acetylcysteine at different concentrations for 30 min before exposure to rotenone. Cytotoxicity of rotenone (5 microM) for 16 h was significantly diminished as well as the release of LDH into the medium, by the effect of fraxetin, myricetin and N-acetylcysteine, with fraxetin (100 microM) and N-acetylcysteine (100 microM) being more effective than myricetin (50 microM). Rotenone-induced apoptosis in SH-SY5Y cells was detected by an increase in caspase-3 activity and in the cleavage of poly(ADP-ribose) polymerase. After exposing these cells to rotenone, a significant increase in reactive oxygen species preceded apoptotic events. Fraxetin (100 microM) and N-acetylcysteine (100 microM) not only reduced rotenone-induced reactive oxygen species formation, but also attenuated caspase-3 activity and poly(ADP-ribose) polymerase cleavage at 16 h against rotenone-induced apoptosis. The effect of fraxetin in both experiments was similar to that of N-acetylcysteine. These results demonstrated the protective action of fraxetin and suggest that it can reduce apoptosis, possibly by decreasing free radical generation in SH-SY5Y cells. Myricetin at 100 microM was without any preventive effect.
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PMID:Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine. 1286 Apr 76

The loss of retinal pigment epithelium (RPE) with aging is related to age-related macular degeneration (AMD). This study was conducted to investigate the mechanism of hydrogen peroxide (H2O2) induced cell death in a human retinal pigment epithelial cell line, ARPE-19. Hydrogen peroxide was added at different concentrations to ARPE-19 cells and cultured. The cytotoxicity was assayed by mitochondrial function using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) testing. The patterns of cell damage were assessed using an acridine orange-ethidium bromide differential staining method, in situ end labeling (ISEL) assay and transmission electron microscopy (TEM). Catalase, a major antioxidant, was used to prevent cell death. The cleavage of procaspase 3 and poly (ADP-ribose) polymerase (PARP) was determined by western blot analysis. Hydrogen peroxide significantly induced cell death in ARPE-19 cells, whereas pretreatment of the cells with catalase prevented cell death. Application of the ISEL assay and acridine orange/ethidium bromide staining demonstrated that the H2O2-induced cell death occurred by an apoptotic mechanism at lower concentrations of H2O2 (400, 500, 600 microM), whereas higher concentrations of H2O2 induced necrosis rather than apoptosis. Caspase 3 was associated with the apoptotic pathway in human RPE cell death. Western blot analysis confirmed caspase 3 activation and cleavage of substrate proteins in ARPE-19 cells treated with an H2O2 concentration of 600 microM. These results indicate that treatment with H2O2 induces apoptotic and necrotic cell death in ARPE-19, and that caspase 3 is associated with apoptotic cell death. Therefore, H2O2 may induce the destruction of RPE cells in AMD by the combined effects of apoptosis and necrosis.
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PMID:Hydrogen peroxide-induced cell death in a human retinal pigment epithelial cell line, ARPE-19. 1288 4

Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy fumaria species, possesses strong antimicrobial, anti-inflammatory, and antioxidant properties. We earlier showed that sanguinarine kills human epidermoid carcinoma A431 cells via an induction of apoptosis [N. Ahmad et al., Clin. Cancer Res., 6: 1524-1528, 2000]. In this study, using immortalized human keratinocytes (HaCaT cells), we provide information about mechanism of the antiproliferative effect of sanguinarine. Sanguinarine [0.1 (M-2 (M)] treatment to HaCaT cells was found to inhibit in a dose-dependent manner the cell proliferation and induce apoptosis, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA, respectively. Sanguinarine treatment also resulted in a significant cleavage of poly(ADP-ribose) polymerase in HaCaT cells. Because mitochondrial pathway is critical for the regulation of apoptosis, we studied the involvement and regulation of mitochondrial events in sanguinarine-mediated apoptosis of HaCaT cells. As shown by the immunoblot analysis, our data clearly demonstrated that sanguinarine treatment to HaCaT cells resulted in a dose-dependent (a) increase in the level of Bax with a concomitant decrease in Bcl-2 levels and (b) increase in Bax/Bcl-2 ratio. Sanguinarine also resulted in significant increases in the proapoptotic members of Bcl-2 family proteins, i.e., Bak and Bid. This was accompanied by increase in (a) protein expression of cytochrome c and apoptotic protease-activating factor-1 and (b) activity and protein expression of caspase-3, caspase-7, caspase-8, and caspase-9. Taken together, our data showed the involvement of mitochondrial pathway and Bcl-2 family proteins during sanguinarine-mediated apoptosis of immortalized keratinocytes. We suggest that sanguinarine could be developed as a drug for the management of hyperproliferative skin disorders, including skin cancer.
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PMID:Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratinocytes. 1291 70

The protective effect of Acanthopanax senticosus (AS) against ethanol (EtOH)-induced apoptosis of the human neuroblastoma cell line SK-N-MC was investigated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), and caspase-3 assay. It was shown that cells treated with EtOH exhibit classical apoptotic features, while cells pre-treated with Acanthopanax senticosus prior to EtOH exposure showed decreased occurrence of apoptotic features. In addition, Acanthopanax senticosus pre-treatment was shown to inhibit EtOH-induced increase in caspase-3 mRNA expression and activity. These results suggest that Acanthopanax senticosus may exert a protective effect against EtOH-induced apoptosis of human neuroblastoma cells.
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PMID:Protective effect of Acanthopanax senticosus against ethanol-induced apoptosis of human neuroblastoma cell line SK-N-MC. 1294 69

The differential effects of arsenic compounds and the effect of selenium on arsenic-induced changes in cytotoxicity, viability, and cell cycle of porcine aorta endothelial cells (PAECs) were investigated. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay indicated that arsenic trioxide (As(2)O(3)) and sodium arsenite (NaAsO(2)) showed similar cytotoxicity, whereas sodium arsenate (Na(2)HAsO(4)) did not show cytotoxicity in PAECs. As(2)O(3) and NaAsO(2) at 20 microM decreased PAEC viability, decreased G0/G1 phase, and increased apoptosis. An increased G2/M phase was observed in NaAsO(2)-treated PAECs, whereas an increase in secondary necrosis (late apoptosis) was observed in As(2)O(3)-treated PAECs. As(2)O(3)-induced apoptosis was associated with upregulation of p53 and caspase 3, whereas NaAsO(2)-induced apoptosis was associated with p53 upregulation. Sodium selenite (Na(2)SeO(3)) at 1 nM reduced 20 microM As(2)O(3)-induced cytotoxicity, but not apoptosis, at 24 h. Increased glutathione peroxidase (GPX) activity by Na(2)SeO(3) pretreatment in 20 microM As(2)O(3)-treated PAECs suggests that Na(2)SeO(3) modulates As(2)O(3)-induced cytoxicity by GPX modulation.
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PMID:Modulation of the arsenic effects on cytotoxicity, viability, and cell cycle in porcine endothelial cells by selenium. 1312 16

Current treatments for childhood brain tumor medulloblastoma (MB), radiation and chemotherapy, lead to undesirable side effects. Identification of antitumor agents that reduce the toxicity will thus have significant therapeutic value. In this study, we investigated all-trans-retinoic acid (ATRA) as an antitumor agent. Although high concentrations (1-10 microM) of retinoic acid derivatives are generally needed for significant antitumor effects in many cancer cells, we observed that pharmacologically relevant concentrations of ATRA were effective in inducing cell death in human MB cells. Using 10-fold lower concentrations (100-500 nM), we found that ATRA inhibits MB (DAOY, D283, D425, and D458) cell proliferation as determined by cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and bromodeoxyuridine incorporation assays. Furthermore, 100 nM ATRA was potent in inhibiting the anchorage-independent growth of the sensitive cell lines (D283, D425, and D458) in soft agar assays. We also demonstrate that the ATRA-induced decrease in cell viability was due to increased cell death by apoptosis, which was accompanied by a 20-fold induction of caspase-3 activity in the most sensitive cell line, D458. By contrast, induction of caspase-3 was only 2-fold in the relatively insensitive DAOY cells. Furthermore, ATRA-induced cell death in D283, D425, and D458 cells was accompanied by activation of caspase-3, a key executioner of apoptosis. We also demonstrate that activated caspase-3 resulted in cleavage of 116-kDa poly(ADP-ribose) polymerase 1 to its signature fragments (85 and 29 kDa). Pretreatment with a specific caspase-3 inhibitor, DEVD-CHO, significantly reduced ATRA-induced apoptotic cell death. Thus, we demonstrate for the first time that low concentrations of ATRA inhibit MB cell proliferation and induce apoptotic cell death in part by activating caspase-3/poly(ADP-ribose) polymerase 1 effector pathway, and we show that retinoic acids and novel retinoids are potential antitumor agents in MB therapy.
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PMID:All-trans-retinoic acid-induced apoptosis in human medulloblastoma: activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. 1451 26

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