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)

In this study, we show that adenosine monophosphate-activated protein kinase (AMPK) is expressed and activated in multiple myeloma cells. The inhibition of AMPK induced growth arrest and reduction of cell viability in the cell viability assay using the water-soluble tetrazolium salt 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1 assay). Induction of apoptosis was determined by annexin-V and propidium iodide staining. The prevention of apoptosis using the pancaspase inhibitor ZVAD-fmk and caspase-3 cleavage upon incubation with the AMPK inhibitor (AMPKI) is shown. Furthermore, incubation of myeloma cells with AMPKI resulted in the downregulation of pAMPK, Mcl-1 and Bcl-xL. Coincubation of AMPKI and melphalan led to a strong additional increase of apoptosis in myeloma cells. We conclude that AMPKI has a strong antimyeloma activity in vitro and represents a new targeted strategy in the treatment of multiple myeloma.
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PMID:Inhibition of adenosine monophosphate-activated protein kinase induces apoptosis in multiple myeloma cells. 1735 92

Apoptosis plays a critical role in intestinal mucosal homeostasis. We previously showed that the bile salt taurodeoxycholate has a beneficial effect on the intestinal mucosa through an increase in resistance to apoptosis mediated by nuclear factor (NF)-kappaB. The current study further characterizes the effect of bile salts on intestinal epithelial cell susceptibility to apoptosis and determines if the X-linked inhibitor of apoptosis protein (XIAP) regulates bile salt-induced resistance to apoptosis. Exposure of normal intestinal epithelial cells (IEC-6) to the conjugated bile salts taurodeoxycholate (TDCA) and taurochenodeoxycholate (TCDCA) resulted in an increase in resistance to tumor necrosis factor (TNF)-alpha and cycloheximide (CHX)-induced apoptosis, and NF-kappaB activation. Treatment with TDCA and TCDCA resulted in an increase in XIAP expression. Specific inhibition of NF-kappaB by infection with an adenoviral vector that expresses the IkappaBalpha super-repressor (IkappaBSR) prevented the induction of XIAP expression and the bile salt-mediated resistance to apoptosis. Treatment with the specific XIAP inhibitor Smac also overcame this increase in enterocyte resistance to apoptosis. Bile salts inhibited formation of the active caspase-3 from its precursor procaspase-3. Smac prevented the inhibitory effect of bile salts on caspase-3 activation. These results indicate that bile salts increase intestinal epithelial cell resistance to apoptosis through NF-kappaB-mediated XIAP expression. Bile salt-induced XIAP mediates resistance to TNF-alpha/CHX-induced apoptosis, at least partially, through inhibition of caspase-3 activity. These data support an important beneficial role of bile salts in regulation of mucosal integrity. Decreased enterocyte exposure to luminal bile salts, as occurs during starvation and parenteral nutrition, may have a detrimental effect on mucosal integrity.
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PMID:Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression. 1743 49

The intracellular uptake of Angiotensin II has been described, although its physiological role is not yet understood. We aimed to study the role of Angiotensin II internalization in Angiotensin II-induced apoptosis. Vascular smooth muscle cells were cultured from male Wistar-Kyoto rats and treated with Angiotensin II (1 microM, 48 h). Apoptosis was assessed by DNA fragmentation, cell cytometry and caspase-3 activity. The Angiotensin AT(1) receptor antagonist irbesartan (0.1-10 microM) and the inhibitors of Angiotensin II internalization phenylarsine oxide (PAO, 20 microM), but not the AT(2) receptor antagonist PD123319 (S-(+)-1-[(4-(Dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid di(trifluoroacetate) salt), decreased Angiotensin II-mediated apoptosis. Pre-treatment with irbesartan, but not with PD123319, blocked Angiotensin II internalization. We found a strong correlation between intracellular Angiotensin II staining and Angiotensin II-induced apoptosis for all compared groups. We therefore conclude that internalization of Angiotensin II is involved in apoptosis of vascular smooth muscle cells induced by this peptide.
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PMID:Importance of intracellular angiotensin II in vascular smooth muscle cell apoptosis: inhibition by the angiotensin AT1 receptor antagonist irbesartan. 1750 62

The central objective of the current study was to investigate the potential in vitro anti-proliferative properties of the parent ligand, coumarin-dioxy-acetic acid (cdoaH(2)), and its copper complex, copper-coumarin-dioxyacetic acetate-phenathroline ([Cu(cdoa)(phen)(2)]) using four human-derived model cell lines, two neoplastic and two non-neoplastic. In addition, selected mechanistic studies were carried out using one of the neoplastic-derived model cell lines, Hep-G2. Results obtained show that the complex, rather than the ligand, could alter the proliferation of both human neoplastic renal (A-498) and hepatic (Hep-G2) cells. Furthermore, hepatic non-neoplastic cells (Chang) appeared to be less sensitive. However, this effect was not mirrored in non-neoplastic renal (HK-2) cells, a profile shared with cisplatin. The observed anti-proliferative effect appeared to be concentration- and time-dependant, and could be attributed to the complex, rather than any of the component parts, i.e. 1,10-phenanthroline, the coumarin ligand, or the simple metal salt. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Based on IC(50) values, [Cu(cdoa)(phen)(2)] was shown to be almost six times more potent than cisplatin. Moreover, there was no evidence to show that P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) was likely to play a role in decreasing the anti-proliferative activity of the complex. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein], suggested that cell death could switch between apoptosis and necrosis, and this effect appeared to be concentration-dependent. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Cu(cdoa)(phen)(2)] has been shown to be a more potent anti-proliferative agent than either the ligand or cisplatin, and is capable of altering key biochemical events leading to the execution of apoptotic and/or necrotic cell death, suggesting that it is worthy of further investigation.
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PMID:An in vitro investigation of the induction of apoptosis and modulation of cell cycle events in human cancer cells by bisphenanthroline-coumarin-6,7-dioxacetatocopper(II) complex. 1751 8

The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of the parent ligand, 4-methylcoumarin-6,7-dioxyacyeic acid (4-MecdoaH(2)), and its copper (II) complex, bis(phenanthroline4-methylcoumarin-6,7-dioxacetatocopper(II) ([Cu(4-Mecdoa)(phen)(2)]) using four human model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could alter proliferation of both human neoplastic renal (A-498) and hepatic (HepG2) cells. Furthermore, non-neoplastic hepatic (CHANG) cells appeared to be less sensitive. However, this effect was not duplicated with non-neoplastic renal (HK-2) cells, a profile shared by cisplatin. The observed anti-proliferative effect appeared to be dose-and time-dependent, and could be attributed to the complex, rather than any of the free components i.e. the 1,10-phenanthroline or coumarin ligand, or the simple metal salt. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Based on IC(50) values, [Cu(4-Mecdoa)(phen)(2)] was shown to be almost 12 times more potent than cisplatin. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease anti-proliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein], showed that cell death could switch between apoptosis and necrosis, and this effect appeared to be concentration-dependent. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Cu(4-Mecdoa)(phen)(2)] has been shown to be a more potent anti-proliferative agent than either the ligand or cisplatin, and is capable of altering key biochemical events leading to the execution of apoptotic and/or necrotic cell death, suggesting that it is worthy of further investigation.
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PMID:Apoptotic cell death: a possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa)(phen)(2)] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6,7-dioxactetate), in human malignant cancer cells. 1758 2

Mycobacterium avium subsp. paratuberculosis is the etiologic agent of Johne's disease, a chronic granulomatous enteritis in ruminants. ATP has been reported to induce cell death of macrophages and killing of Mycobacterium species in human and murine macrophages. In this study we investigated the short-term effect of ATP on the viability of M. avium subsp. paratuberculosis-infected bovine mononuclear phagocytes and the bacilli within them. Addition of 5 mM ATP to M. avium subsp. paratuberculosis-infected bovine monocytes resulted in 50% cytotoxicity of bovine monocytes at 24 h. Addition of 2'(3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt (Bz-ATP), which is a longer-lived ATP homologue and purinergic receptor agonist, significantly increased the uptake of YO-PRO, which is a marker for membrane pore activation by P2X receptors. Addition of Bz-ATP also stimulated lactate dehydrogenase release and caspase-3 activity in infected bovine monocytes. Neither ATP nor Bz-ATP reduced the survival of M. avium subsp. paratuberculosis in bovine mononuclear phagocytes. Likewise, addition of ATP or Bz-ATP was cytotoxic to murine macrophage cell lines (RAW 264.7 and J774A.1 cells) but did not affect the intracellular survival of M. avium subsp. paratuberculosis, nor were the numbers of viable Mycobacterium avium subsp. avium or Mycobacterium bovis BCG cells altered in bovine mononuclear phagocytes or J774A.1 cells following ATP or Bz-ATP treatment. These data suggest that extracellular ATP does not induce the killing of intracellular M. avium subsp. paratuberculosis in bovine mononuclear phagocytes.
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PMID:Extracellular ATP is cytotoxic to mononuclear phagocytes but does not induce killing of intracellular Mycobacterium avium subsp. paratuberculosis. 1763 11

Midkine (MK), a heparin-binding growth factor, is expressed highly in various malignant tumors, so it acts as attractive therapeutic target. In the present study, we used siRNA targeting MK to downregulate human MK expression in human gastric cancer cell line BGC823 and SGC7901 so as to determine the advantages of this anticancer therapeutic. The cell proliferation was evaluated by a WST-8 (4-[3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate sodium salt) assay and colony formation assay. Apoptosis was determined by flow cytometer analysis and colorimetric assay. Our results showed that the BGC823 and SGC7901 cell growth were significantly inhibited by knockdown of MK gene. The loss of mitochondrial membrane potential, release of cytochrome c from the mitochondria into cytosol and increased activity of caspase-3, 8 and 9 occurred concomitantly with inhibition of MK gene. These results indicated that siRNA targeting MK gene can inhibit gastric cancer cells growth and induce apoptosis via mitochondrial depolarization and caspase-3 activation. MK siRNA may be a promising novel and potential therapeutic strategy for the treatment of gastric cancers.
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PMID:siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization. 1766 17

Radiocontrast agents are thought to induce acute kidney injury in part through increased production of reactive oxygen species and increased cellular apoptosis. In this study we determined whether heme oxygenase-1 could prevent or reduce radiocontrast-induced acute kidney injury and, if so, what were the mechanisms by which this can occur. Sodium iothalamate was administered to uninephrectomized, salt-depleted male Sabra rats to initiate acute kidney injury. Heme oxygenase-1 was induced with cobalt protoporphyrin or inhibited with stannous mesoporphyrin. Inhibition of heme oxygenase exacerbated kidney injury as measured by an increase in plasma creatinine and in superoxide production. Heme oxygenase-1 induction prevented the increase in plasma creatinine and in superoxide in both the cortex and medulla compared to untreated rats with acute kidney injury. This protective effect of heme oxygenase-1 was associated with increased anti-apoptotic proteins Bcl-2 and Bcl-xl and a decrease of pro-apoptotic caspase-3 and caspase-9 along with increased expression of inactive BAX. Our study suggests that increased levels of heme oxygenase-1 are protective against acute kidney injury due to radiocontrast exposure.
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PMID:Heme oxygenase-1 protects against radiocontrast-induced acute kidney injury by regulating anti-apoptotic proteins. 1791 15

Unlike oleate and linoleate, palmitate induced mitochondrial apoptosis in GL15 glioblastoma cells. Decrease in membrane potential in a subpopulation of mitochondria of palmitate-treated cells was revealed using the 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide probe. The diminished ability to reduce a tetrazolium salt indicated an impairment of mitochondrial function. Up to 50% cytochrome c (cyt c) was detached from the inner mitochondrial membrane and released outside mitochondria in palmitate-treated cells, whereas no release was detected after oleate and linoleate treatments. Cyt c release into the cytosol was followed by caspase 3 activation. Released cyt c and caspase 3 activity were not affected by neutral and acid sphingomyelinase inhibitors and by the inhibitor of serine palmitoyltransferase cycloserine, indicating that apoptosis was independent of the ceramide pathway, nor the mitochondrial pro-apoptotic AIF or Bcl-2/Bax factors appeared to be involved in the effect. Utilization of palmitate by GL15 cells altered phospholipid composition. Cardiolipin (CL), the lipid involved in cyt c interaction with the inner mitochondrial membrane, was decreased and highly saturated. This produced an imbalance in hydrophilic/hydrophobic interactions underlying the anchorage of cyt c, by weakening the hydrophobic component and facilitating detachment of the protein and activation of downstream processes. The primary role of CL was explored by supplying GL15 with exogenous CL through a fusion process of CL liposomes with cell plasma membrane. Fused CL moved to mitochondria, as detected by nonylacridine orange probe. Enrichment of mitochondrial membranes with CL prior to palmitate treatment of cells caused decreased cyt c release and caspase 3 activity.
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PMID:Loss of cardiolipin in palmitate-treated GL15 glioblastoma cells favors cytochrome c release from mitochondria leading to apoptosis. 1818 42

Tetrazolium violet (TV), a tetrazolium salt, has been applied in several fields, including estimating respiration rate, as a redox indicator of microbial growth, and for estimating the number of viable animal cells. It has recently been found that TV is capable of inducing apoptosis in rat glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that TV also induced apoptosis in mouse breast tumor C127 cells as evidenced by nucleus condensation and nucleus fragmentation. Our data showed that TV caused activation of caspase-3 and caspase-8, but not caspase-9. An enhancement in Fas and its two ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), might be responsible for the apoptotic effect induced by TV. Also, the results first reported that TV not only inhibited C127 cells proliferation but also blocked cell cycle progression in the G1 and G2 phase, determined by MTT assay and flow cytometry analysis. Immunofluorescence assay demonstrated that TV significantly increased the expression of p53 protein, which caused cell cycle arrest. Taken together, p53, Fas/FasL, and the caspase apoptotic system may participate in the antiproliferative activity of TV in C127 cells.
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PMID:Tetrazolium violet inhibits cell growth and induces cell death in C127 mouse breast tumor cells. 1854 55


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