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: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) Cadmium is an extremely toxic metal commonly found in industrial workplaces, a food contaminant and a major component of cigarette smoke. Cadmium can severely damage several organs, including the brain. In this work, we have studied both the cadmium toxicity on rat cortical neurons in culture and the possible protective effect of serum. (2) Our results indicate that: (1) cadmium is taken up by the neurons in a dose and serum dependent way; (2) cadmium, at concentrations from 1 micro M or 10 micro M (depending on the absence or the presence of serum) up to 100 micro M, decreases the metabolic capacity, which was evaluated by the XTT (tetrazolium salt) test; (3) cadmium induces apoptosis and LDH (lactate dehydrogenase) release in a dose dependent way; (4) in a serum-free medium, the cadmium-induced apoptosis is accompanied by caspase-3 activation; (5) both the caspase-3 activation and the cadmium-induced apoptosis are reversed by N-acethyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), a selective caspase-3 inhibitor, indicating that the caspase-3 pathway is involved in cadmium-induced apoptosis in cortical neurons; and (6) the cadmium concentrations which produce caspase-3 activation do not modify the intracellular ATP levels; however, higher cadmium concentrations lead to both intracellular ATP depletion and ATP release, but do not increase the caspase-3 activity, indicating that cadmium also produces cellular death by necrosis. (3) These results suggest that cadmium induces either apoptosis or necrosis in rat cortical neurons, depending on the cadmium concentration.
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PMID:Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. 1264 92

A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.
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PMID:Novel benzylidene-9(10H)-anthracenones as highly active antimicrotubule agents. Synthesis, antiproliferative activity, and inhibition of tubulin polymerization. 1285 68

Luteolin is a common constituent of many kinds of fruits and vegetables. It possesses the anti-neoplastic activities against several human cancers, but its activity against hepatocellular carcinoma (HCC) is seldom mentioned. To evaluate the activity against HCC and to provide information about the mechanism, we tested luteolin against five human hepatoma cell lines, namely HepG2, SK-Hep-1, PLC/PRF/5, Hep3B, and HA22T/VGH, with XTT assay and flow cytometry. The results showed that luteolin inhibited PLC/PRF/5, Hep3B and HA22T/VGH at a concentration of 1 microg/ml, but it needed 5 microg/ml to inhibit HepG2 and 10 microg/ml for SK-Hep1 (P <0.05). The inhibitive concentrations of 50% (IC50) of luteolin were between 7.29 microg/ml and 32.59 microg/ml, which were comparable with those of 5-FU (15.35 microg/ml to 32.84 microg/ml). The least effective cell line as affected by luteolin (SK-Hep1) was the most effective one when treating with 5-FU. The least effective cell line as affected by 5-FU (HA22T/VGH) was effectively affected by luteolin. It seemed that luteolin had some complementary activity to 5-FU against these HCC cell lines. The luteolin-treated PLC/PRF/5 cells exhibited typical changes of apoptosis with a characteristic DNA laddering pattern on gel electrophoresis. Luteolin also activated casepase-3, increased Bax protein with a concomitant decrease in Bcl-XL level. Increase in Bax/ Bcl-XL ratio and activation of caspase-3 supported the apoptotic finding on gel electrophoresis. Luteolin also induced cell cycle arrest at G0/G1 phase. We suggested that luteolin might exhibit anti-HCC activity as efficient as 5-FU by the mechanism of not only cell cycle arrest but also apoptosis.
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PMID:Increase of Bax/ Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. 1569 65

BAG-1 is a multi-functional protein that exists in three major isoforms, BAG-1 p50, p46, and p36. A fourth isoform of 29 kDa also exists but its function remains mostly unknown. To further understand the role of this smaller isoform in ovarian cancer cells, the SKOV3 cell line was transfected with a doxycycline-inducible human BAG-1 p29 isoform or control plasmid. Ovexpression of BAG-1 p29 promotes protection from apoptosis in the presence of EGF as shown by decreased cell death measured by XTT assay and caspase-3 activity. Unexpectedly, however, BAG-1 p29 does not associate with the EGF receptor. When BAG-1 p29 transfectants were incubated in hydrogel-coated plates, BAG-1 p29-expressing SKOV3 cells were significantly more resistant to anoikis as compared to controls, and this correlated with decreased activation of caspase-3. The results of this study implicate BAG-1 p29 in the regulation of both the EGF signaling cascade and the apoptotic cascade induced by loss of anchorage.
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PMID:BAG-1 p29 protein prevents drug-induced cell death in the presence of EGF and enhances resistance to anoikis in SKOV3 human ovarian cancer cells. 1570 60

In this paper, we present data which demonstrate that, in cortical neurons, SNAP induces loss in cell viability as evaluated by the XTT test. This cell death started at 250 microM SNAP when the treatment was performed in a serum-free medium and at 10 microM when the treatment was given in the presence of serum. This death was mediated, at least in part, by an apoptotic mechanism detected by flow cytometry and DNA fractionation. The highest SNAP concentrations induced a dual behavior on caspase-3 activity. Concentrations of 250 microM in the absence of serum and 10 microM to 300 microM in the presence of serum produced caspase-3 activation. This indicates that NO induces neuronal death by an apoptotic mechanism in which the caspase pathway is implicated. Higher SNAP concentrations (500 microM to 1 mM) diminished the caspase-3 activity to levels similar or even lower than control values. This profile was observed in the absence as well as in the presence of serum in the medium. The caspase-3 inhibition mediated by the highest SNAP concentrations did not imply NO cellular protection since the caspase-3 inhibition mediated by these SNAP concentrations neither correlated with cellular viability nor with cellular apoptosis. The possible mechanism of caspase-3 inhibition at the highest SNAP concentrations used is discussed.
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PMID:SNAP, a NO donor, induces cortical neuron death by a mechanism in which the caspase pathway is implicated. 1592 31

Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), one of the simplest naturally occurring alkaloids, was isolated from the leaves of the evergreen tree Ochrosia elliptica Labill (Apocynaceae). Here, we reported that ellipticine inhibited the cell growth of human hepatocellular carcinoma cell line HepG2 and provided molecular understanding of this effect. The XTT assay results showed that ellipticine decreased the cell viability of HepG2 cells in a dose- and time-dependent manner, and the IC50 value was 4.1 microM. Furthermore, apoptosis induction by ellipticine in HepG2 cells was verified by the appearance of DNA fragmentation and annexin V-FITC/propidium iodide (PI) staining assay. Ellipticine treatment was found to result in the upregulation of p53, Fas/APO-1 receptor and Fas ligand. Besides, ellipticine also initiated mitochondrial apoptotic pathway through regulation of Bcl-2 family proteins expression, alteration of mitochondrial membrane potential (DeltaPsim), and activation of caspase-9 and caspase-3. Taken together, ellipticine decreased the cell growth and induced apoptosis in HepG2 cell.
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PMID:Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. 1633 42

Proinflammatory cytokine-mediated injury to oligodendrocyte progenitor cells (OPCs) has been proposed as a cause of periventricular leukomalacia (PVL), the most common brain injury found in preterm infants. Preventing death of OPCs is a potential strategy to prevent or treat PVL. In the current study, we utilized an in vitro cell culture system to investigate the effect of insulin-like growth factor-1 (IGF-1) on tumor necrosis factor-alpha (TNFalpha)-induced OPC injury and the possible mechanisms involved. OPCs were isolated from neonatal rat optic nerves and cultured in chemically defined medium (CDM) supplemented with platelet-derived growth factor and basic fibroblast growth factor. Exposure to TNFalpha resulted in death of OPCs. IGF-1 protected OPCs from TNFalpha cytotoxicity in a dose-dependent manner as measured by the XTT and TUNEL assays. IGF-1 activates both the PI3K/Akt and the extracellular signal-regulated kinase (ERK) pathway. However, IGF-1-enhanced cell survival signals were mediated by the PI3K/Akt, but not by the ERK pathway, as evidenced by the observation that IGF-1-enhanced cell survival was partially abrogated by Akti, the Akt inhibitor, or wortmannin, the PI3K inhibitor, but not by PD98,059, the MAPK kinase/ERK kinase inhibitor. The downstream events of IGF-1-triggered survival signals included phosphorylation of BAD, blockade of TNFalpha-induced translocation of Bax from the cytosol to the mitochondrial membrane, and suppression of caspase-9 and caspase-3 activation. These observations indicate that the protection of OPCs by IGF-1 is mediated, at least partially, by interruption of the mitochondrial apoptotic pathway via activation of PI3K/Akt.
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PMID:IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. 1757 43

Cinnamaldehyde (Cin) has been shown to be effective in inducing apoptotic cell death in a number of human cancer cells. The aim of this study was to investigate the effect of pifithrin-alpha (PFTalpha; a specific p53 inhibitor) and mitogen-activated protein kinases (MAPKs) inhibitors [namely SP600125 (a specific JNK inhibitor), SB203580 (a specific p38 inhibitor) and PD98059 (a specific ERK inhibitor)] on apoptotic signaling transduction mechanism induced by Cin in human hepatoma PLC/PRF/5 (CD95-negative) cells. Using XTT assay, Cin exhibited a powerful cytotoxic effect and apoptotic induction in PLC/PRF/5 cells. Apoptosis was elicited when cells were treated with 1 microM Cin as characterized by morphological changes and the appearance of phosphatidylserine on the outer surface of the plasma membrane. Cin down-regulated the expression of Bcl-(XL), up-regulated mutant p53 and Bax proteins and promoted caspase-3 to active forms, as well as cleaving poly (ADP-ribose) polymerase (PARP) in a time-dependent pattern. This could be supported by the activation and phosphorylation of MAPKs, including JNK, ERK and p38 kinases. Pre-incubation with PFTalpha and specific MAPK inhibitors significantly diminished the effect of Cin-induced apoptosis. The activities of anti-apoptotic (Bcl-(XL)) and pro-apoptotic (Bax) proteins were remarkably affected by PFTalpha and PD98059 pre-treatment. PFTalpha effectively blocked PARP cleavage in cells treated with Cin, and also markedly prevented the phosphorylation of JNK, p38 and ERK proteins. These results suggest that p53 induction and MAPK signaling pathways are required for Cin-mediated apoptosis in PLC/PRF/5 cells.
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PMID:MAPK inhibitors and pifithrin-alpha block cinnamaldehyde-induced apoptosis in human PLC/PRF/5 cells. 1767 46

Flavonoids are polyphenolic compounds and capable of inhibiting the growth of human cancer cells. Protoapigenone, a novel flavonoid, was isolated from the whole plant Thelypteris torresiana (Gaud), a native fern in Taiwan. In the present study, we explored the cytotoxic effects of protoapigenone on ovarian cancer cells and the immortalized ovarian epithelial cells by XTT assay. The effects of protoapigenone on cell cycle progression and apoptosis were also analyzed by FACS analysis, immunofluorescence study and immunoblotting analysis. The anti-ovarian cancer effect of protoapigenone was further examined using nude mice xenograft assay and immunohistochemistry. Our results showed that protoapigenone had a significant cytotoxicity on human ovarian cancer cells MDAH-2774 and SKOV3 but not on the immortalized non-cancer ovarian epithelial cells HOSE 6-3 and HOSE 11-12. Protoapigenone arrested MDAH-2774 and SKOV3 cells at S and G2/M phases via decreasing the expression of p-Cdk2, Cdk2, p-Cyclin B1 and Cyclin B1, as well as increasing the expression of inactive p-Cdc25C. Besides, protoapigenone had an enhanced cytotoxicity on SKOV3 cells enriched at S and G2/M phases, and ability to induce apoptosis through decreasing the protein levels of Bcl-xL and Bcl-2 and increasing the cleaved PARP by activating caspase-3. In nude mice study, protoapigenone treatment significantly suppressed the tumor growth, without major side effects. Taken together, protoapigenone showed a significant anti-ovarian cancer activity with low toxicity, suggesting its potential to be developed as a chemotherapeutic agent.
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PMID:Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo. 1843 May 9

A systematic study on the in vitro interactions of 7-20 nm spherical silver nanoparticles (SNP) with HT-1080 and A431 cells was undertaken as a part of an on-going program in our laboratory to develop a topical antimicrobial agent for the treatment of burn wound infections. Upon exposure to SNP (up to 6.25 microg/mL), morphology of both the cell types remained unaltered. However, at higher concentrations (6.25-50 microg/mL) cells became less polyhedral, more fusiform, shrunken and rounded. IC(50) values for HT-1080 and A431 as revealed by XTT assay were 10.6 and 11.6 microg/mL, respectively. When the cells were challenged with approximately 1/2 IC(50) concentration of SNP (6.25 microg/mL), clear signs of oxidative stress, i.e. decreased GSH ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) and SOD ( approximately 1.6-folds in HT-1080, 3-folds in A431) as well as increased lipid peroxidation ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) were seen. Changes in the levels of catalase and GPx in A431 cells were statistically insignificant in both cell types. DNA fragmentation in SNP-exposed cells suggested apoptosis. When the apoptotic thresholds of SNP were monitored with caspase-3 assay the concentrations required for the onset of apoptosis were found to be much lower (0.78 microg/mL in HT-1080, 1.56 microg/mL in A431) than the necrotic concentration (12.5 microg/mL in both cell types). These results can be used to define a safe range of SNP for the intended application as a topical antimicrobial agent after appropriate in vivo studies.
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PMID:Cellular responses induced by silver nanoparticles: In vitro studies. 1850 9


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