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)

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G0/G1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.
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PMID:Resveratrol-induced apoptotic death in human U251 glioma cells. 1582 28

The cholesterol-lowering medications, statins, inhibit cellular proliferation and induce apoptosis in an array of cancer cell lines, including melanoma. We investigated the apoptotic mechanism of lovastatin on human melanoma cell lines in vitro. The cytotoxicity of statins on multiple cell lines was examined by Cell Titer 96 Aqueous One solution cell proliferation assay (MTS assay). Apoptosis was assayed by ethidium bromide and acridine orange morphologic assays, an Annexin V apoptosis detection kit and active caspase 3 assays. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate add-back experiments were performed to better define the molecular mechanisms mediating lovastatin cytotoxicity. Lovastatin caused cytotoxicity in human and murine melanoma cells, but did not induce toxicity in an epidermoid carcinoma cell line A431. For human melanoma cells, lovastatin precipitated cell rounding, increased the percentage of apoptotic cells detected by ethidium bromide and acridine orange staining and by the Annexin V apoptosis detection kit, and resulted in a 50-fold increase in active caspase 3, corroborating that lovastatin induced apoptosis. Adding back geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the effects of lovastatin in A375 cells. Of the five statins tested, pravastatin was least effective in killing melanoma cells. Lovastatin induced caspase-dependent apoptosis in multiple melanoma cell lines via a geranylation-specific mechanism. This study supports a possible role of lovastatin as a therapeutic, adjuvant or chemopreventive agent for melanoma.
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PMID:Lovastatin-induced apoptosis in human melanoma cell lines. 1584 40

Human glutamylcysteine ligase catalytic subunit (GCLC) is the rate-limiting enzyme for glutathione synthesis. The heavy subunit possesses all the catalytic activities. UV irradiation (UV-C, 30 J/m(2)) induced apoptosis in HEK293 cells, but the morphological changes were inhibited significantly by expression of GCLC. MTS assay and flow cytometry results also indicated that GCLC and JNK1(APF) expression enhanced cellular resistance to UV irradiation. Western blotting showed that irradiation strongly activated the c-Jun NH(2)-terminal kinases (JNKs) and caspase-3 as well as p38 in HEK293 cells. Interestingly, existing data show that GCLC blocks JNK1 phosphorylation but does not affect p38 phosphorylation. Therefore, overexpression of GCLC protected HEK293 cells against UV irradiation-induced cell death by inhibiting the phosphorylation and activation of JNK1, concomitantly with the inhibition of caspase-3 activation and p21(WAF1)-luciferase activity downstream of JNK.
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PMID:Human glutamylcysteine synthetase protects HEK293 cells against UV-induced cell death through inhibition of c-Jun NH2-terminal kinase. 1593 21

The anti-cancer effects of cytosine arabinoside (ARA-C) are well known. However, effects on nonmalignant cells have not been elucidated and may be important to understanding treatment-related toxicity. The purpose of this study was to examine the effect of ARA-C on nondividing vascular endothelial cells. The objectives were to determine the effects of ARA-C on cell viability and to ascertain whether ARA-C caused apoptosis in cultured vascular endothelial cells and hydrocortisone blunted caspase-3-induced apoptosis. Endothelial cells were cultured until confluent and mitotically quiescent then exposed to ARA-C (10(-7)to 10(-3) M) for 1 to 4 days. Some experiments involved cotreatment with hydrocortisone (10(-11),10(-10),10(-4), and 10(-3) M). Light microscopy and the colorimetric MTS assay were used to measure viability. Fluorescent annexin-V and DNA fragmentation assays were used to measure apoptosis, and a fluorescence-based enzymatic assay was used to measure caspase-3 activity, which is one pathway involved in the apoptosis cascade. Two-way ANOVA or the appropriate nonparametric test was used to determine statistical significance in studies of viability and apoptosis. Oneway ANOVA was used to determine statistical significance for caspase-3 activity. Viability was decreased with higher concentrations of ARA-C and increased days of treatment. The percentage of apoptotic cells increased with higher concentrations of ARA-C and increased days of treatment. ARA-C-treated samples showed DNA fragmentation, indicative of apoptosis. Caspase-3 activity increased after ARA-C addition; hydrocortisone blunted this increase. ARA-C caused apoptosis in nondividing endothelial cells in culture. Hydrocortisone may protect against ARA-C-induced apoptosis by reducing caspase-3 activity.
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PMID:Cytosine arabinoside induces programmed endothelial cell death through the caspase-3 pathway. 1658 99

Free radical production and, consequently, oxidative stress play an important role in the pathogenesis of AIDS and cause damage to lipids, proteins, and DNA. In our previous study, the HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 have been found to induce oxidative stress in an immortalized endothelial cell line from rat brain capillaries, RBE4 (in vitro model of the blood-brain barrier). Here, we have determined the effects of a novel antioxidant, N-acetylcysteine amide (NACA), on gp120- and Tat-induced oxidative stress. Various oxidative stress parameters, including reduced glutathione (GSH), oxidized glutathione (GSSG), catalase (CAT) activity, and glutathione reductase (GR) activity, as well as malondialdehyde (MDA) levels, were used as measures of oxidative stress. NACA significantly increased the levels of intracellular GSH, CAT, and GR and decreased the levels of MDA in RBE4 cells, showing that oxidatively challenged cells were protected. Gp120- and Tat-induced increases in intracellular reactive oxygen species (ROS) were observed by using the 2',7'-DCF assay; the ROS scavenger, NACA, blocked ROS generation. A well-known apoptosis indicator, caspase-3 activity, was measured and was also found to have been returned to its control levels by NACA. Treatment of RBE4 cells with gp120 and Tat caused an increase in toxicity, as measured by lactate dehydrogenase (LDH) and tetrazolium reduction (MTS) assays. HIV-1 protein-induced toxicity in these cells was blocked by treatment with NACA. These studies show that NACA reverses gp120- and Tat-induced oxidative stress in immortalized endothelial cells.
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PMID:A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. 1675 May 28

Oxidative stress has been implicated as an important factor in many neurological diseases. Oxidative toxicity in a number of these conditions is induced by excessive glutamate release and subsequent glutamatergic neuronal stimulation. This, in turn, causes increased generation of reactive oxygen species (ROS), oxidative stress, excitotoxicity, and neuronal damage. Recent studies indicate that the glutamatergic neurotransmitter system is involved in lead-induced neurotoxicity. Therefore, this study aimed to (1) investigate the potential effects of glutamate on lead-induced PC12 cell death and (2) elucidate whether the novel thiol antioxidant N-acetylcysteine amide (NACA) had any protective abilities against such cytotoxicity. Our results suggest that glutamate (1 mM) potentiates lead-induced cytotoxicity by increased generation of ROS, decreased proliferation (MTS), decreased glutathione (GSH) levels, and depletion of cellular adenosine-triphosphate (ATP). Consistent with its ability to decrease ATP levels and induce cell death, lead also increased caspase-3 activity, an effect potentiated by glutamate. Exposure to glutamate and lead elevated the cellular malondialdehyde (MDA) levels and phospholipase-A(2) (PLA(2)) activity and diminished the glutamine synthetase (GS) activity. NACA protected PC12 cells from the cytotoxic effects of glutamate plus lead, as evaluated by MTS assay. NACA reduced the decrease in the cellular ATP levels and restored the intracellular GSH levels. The increased levels of ROS and MDA in glutamate-lead treated cells were significantly decreased by NACA. In conclusion, our data showed that glutamate potentiated the effects of lead-induced PC12 cell death by a mechanism involving mitochondrial dysfunction (ATP depletion) and oxidative stress. NACA had a protective role against the combined toxic effects of glutamate and lead by inhibiting lipid peroxidation and scavenging ROS, thus preserving intracellular GSH.
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PMID:Potentiation of lead-induced cell death in PC12 cells by glutamate: protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant. 1678 45

AF5 neural cells derived from fetal rat mesencephalic tissue were immortalized with a truncated SV40 LT vector lacking the p53-inactivating domain to maintain long-term cultures with a p53-responsive phenotype. This study examined p53 function in producing programmed cell death in propagating AF5 neural cells after exposure to hydrogen peroxide (H2O2) and the kinase inhibitor staurosporine (STSP). Concentration-dependent exposure of AF5 cells to 0-800 mM H2O2 and STSP at 0-1000 nM revealed increasing cytotoxicity from MTS cell viability assays. Apoptosis occurred at 400 mM H2O2 as evidenced by subG1 DNA and Annexin V flow cytometry analyses and cellular immunofluorescence staining with propidium iodide, anti-Annexin V and DAPI. DNA fragmentation, caspase-3/7 activity and cytochrome c release into cytosol also confirmed H2O2-mediated apoptotic events. p53 protein levels were increased over 24 h by H2O2 in a coordinated fashion with mdm2 expression. p53 activation by H2O2 was evidenced by elevated Ser15 phosphorylation, increased luciferase p53 reporter activity and upregulation of the downstream p53 targets p21(waf1) and apoptotic proteins, bax, Noxa and PUMA. STSP exposure produced apoptosis demonstrated by DNA fragmentation, caspase-3/7 activity, cytochrome c release and over 24 h was accompanied by sustained increase in p53 and Ser15 phosphorylation, rise in p21(waf1) and bax and a transient increase in p53 reporter activity but without Annexin V binding. These findings demonstrate that AF5 cells undergo apoptosis in response to H2O2-mediated oxidative stress and signal pathway disruption by STSP that therefore would be useful in studies related to p53-dependent neuronal cell death and neurodegeneration.
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PMID:Apoptosis mediated by p53 in rat neural AF5 cells following treatment with hydrogen peroxide and staurosporine. 1690 71

Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. A synthetic analogue of cantharidin (CAN 037) has been shown to have cytotoxic effect on the SK-Hep 1 hepatoma cell line but its underlying working principle remains undefined. Here we further report the action of CAN 037 on an acute myelogenous leukaemia (AML) cell line, KG1a. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay was used to demonstrate the cytotoxicity of CAN 037 on KG1a cells. Morphological changes of CAN 037-treated leukaemia cells were recorded under an inverted microscope. Possible activation of caspase 3, 8 and 9 from KG1a cells was also investigated. KG1a AML cells were sensitive to CAN 037. Morphological changes including cell shrinkage and loss of colony formation ability were observed. Caspase 3, 8 and 9 activity was elevated, whereas pre-incubating the KG1a cells with the generic caspase inhibitor z-VAD-fmk could only partially reverse the CAN 037-induced cell death. In addition to the SK-Hep-1 hepatoma cell line, CAN 037 is also effective in inducing the death of KG1a AML cells in vitro. Apoptosis is involved in the action of CAN 037 including the activation of the caspase family. Caspase-dependent cell death pathway may be necessary but not essential in CAN 037-induced apoptosis of KG1a cells. Further consideration of the structural activity relationship of CAN 037 may provide opportunities to improve its therapeutic value.
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PMID:Apoptogenic activity of a synthetic cantharimide in leukaemia: implication on its structural activity relationship. 1708 29

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells.
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PMID:Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation. 1716 76

Because seaweed extracts have recently been found to have antioxidant and anti-tumor activities, we analyzed a hot-water-soluble polysaccharide (PS) of the marine alga Capsosiphon fulvescens for its potential as a functional foodstuff by determining its effects on cell growth and DNA synthesis. MTS assays showed that the C. fulvescens PS (Cf-PS) significantly inhibited the proliferation of cultured human cancer cells in a dose-dependent manner. Cf-PS-treated AGS cells exhibited a marked increase in caspase-3 activation and a decrease in Bcl-2 expression. In addition, phosphorylation of insulin-like growth factor-I receptor (IGF-IR) was decreased in Cf-PS-treated AGS cells as compared to non-treated control cells, which is consistent with PI3-kinase (PI3K)/Akt activation. Cf-PS also decreased IGF-I-stimulated recruitment of p85 to IGF-IR and IRS-1. These results indicate that Cf-PS inhibits cell proliferation and induces apoptosis by inhibiting IGF-IR signaling and the PI3K/Akt pathway.
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PMID:A polysaccharide of the marine alga Capsosiphon fulvescens induces apoptosis in AGS gastric cancer cells via an IGF-IR-mediated PI3K/Akt pathway. 1734 71


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