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)

YC-1, a benzyl indazole derivative, is an NO-independent direct activator of soluble guanylyl cyclase (sGC), which presents a synergistic action with NO in stimulating cGMP synthesis. These properties have served to suggest YC-1 as an attractive therapeutic agent by permitting the reduction of nitrovasodilator dosage and regulating endogenous cGMP metabolism. Here we studied the effect of prolonged exposure of adrenomedullary endothelial and chromaffin cells to YC-1. We found that YC-1 increased cGMP in the two types of cells and this action was blocked by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, cytoskeletal disorganization and changes in membrane permeability after prolonged incubation with YC-1. Caspase-3-like protease activity and DNA fragments in the cytoplasm were increased in a dose-dependent manner by 16 h YC-1 treatment. The specific and cell permeable caspase-3-like protease inhibitor DEVD-CHO effectively inhibited YC-1-mediated caspase-3-like activation and DNA fragmentation. Moreover, YC-1 also induced cell shape changes accompanied by actin filament disorganization and alterations in membrane permeability. Cells incubated for 24h with YC-1 showed damaged membranes by binding to nucleic acid of a dye excluded by the intact plasma membrane of live cells. YC-1 also induced a decrease in the intracellular non-specific esterase activity, another indication of cell toxicity. Apoptotic phenomena were not prevented by the presence of ODQ although it effectively inhibited the YC-1-elicited cGMP increases. These findings indicate that YC-1 induces apoptosis by activating caspase-3-like protease through a mechanism independent of sGC activation.
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PMID:Prolonged exposure to YC-1 induces apoptosis in adrenomedullary endothelial and chromaffin cells through a cGMP-independent mechanism. 1168 54

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.
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PMID:Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells. 1214 93

Despite numerous experimental and clinical investigations, there is no unifying concept on pathophysiology and pathogenesis of chronic pancreatitis. Defining the interplay between pancreatic microcirculation and parenchymal tissue, we will provide a basis for the better understanding of pancreatic fibrogenesis using in vivo high-resolution multifluorescence microscopy in dibutyltin chloride (DBTC)-exposed rats. Pancreatic microcirculation at days 3 and 7 after DBTC revealed leukocyte activation with a two-fold higher fraction of rolling cells and a nine- to 10-fold increase of cells firmly adherent to the endothelial lining, followed by subsequent transendothelial migration into tissue, as given by chloracetate esterase histology. In vivo staining of acinar tissue with bisbenzimide presented single cells exhibiting nuclear chromatin condensation and fragmentation. Apoptotic cell death was confirmed by immunohistochemical staining for active caspase-3 as well as by TUNEL analysis. Necrotic cells were found dispersed throughout the exocrine tissue under observation. Both modes of cell death were found highest in extent at days 3 and 7 with 15-20 cells/mm2, but progressively decreased below 10 cells/mm2 up to 28 days after DBTC. By means of in vivo microscopy yellow-green autofluorescent collagen deposits were found at day 7 and progressively increased up to approximately 12% at day 28 after DBTC. Concomitantly, density of capillaries progressively decreased and capillaries failing to conduct blood flow became apparent. Present on-line analysis indicates an early inflammatory response with acinar cell death, most probably triggering progression of disease with collagen deposition, capillary rarefication and manifestation of perfusion failure. These temporal and spatial multiparameter measurements of the in vivo microenvironment provide new insights into the pathological processes of pancreatic fibrogenesis.
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PMID:In vivo characterization of developing chronic pancreatitis in rats. 1554 2

alpha-Tocopherol and its synthetic derivative, a-tocopheryl succinate (alpha-TS), are known to inhibit proliferation of cancer cells. alpha-TS is considered a more desirable anticancer agent because of the ability to induce apoptosis. It has been established previously that the whole intact alpha-TS molecule is necessary for its pro-apoptotic activity. For this reason, alpha-TS is not suitable for oral use because the ester bond linking succinate to tocopherol is subject to hydrolysis by intestinal esterases. One approach to overcome this problem is to replace the ester bond with an ether bond, since the latter is resistant to esterase-mediated hydrolysis. alpha-Tocopheryloxybutyrate (alpha-TOB) is the ether analog of alpha-TS. In this study, we compared the potency of alpha-TS and alpha-TOB using a panel of bioassays: cell growth, TUNEL labelling for apoptosis, PARP cleavage, caspase-3 and caspase-9 activation, as well as Akt and JNK phosphorylation. The experiments were carried out in two human prostate cancer cell lines: LNCaP and PC-3. Our results showed that alpha-TOB was capable of inhibiting cell growth and inducing apoptosis, although alpha-TOB was less active than alpha-TS on an equimolar basis. In general, it took twice as much alpha-TOB as alpha-TS to achieve the same response. Nonetheless, these two compounds shared the same mechanism of targeting the Akt and JNK signaling pathways, and activating the intrinsic cell death mediators of caspase-9 and caspase-3. Cellular analysis of alpha-TS and alpha-TOB showed that alpha-TOB was taken up as efficiently as alpha-TS (if not more so), suggesting that the lower activity of alpha-TOB is an inherent property of the molecule and not due to impaired uptake. Additional evidence is provided to show that beta-TS may act at the membrane level to interfere with Akt phosphorylation, although the exact nature of this disruption remains unclear. The future design of new anticancer tocopherol analogs should incorporate the ether linkage of the side chain for esterase resistance as well as other structural modifications for enhanced blocking of membrane signaling.
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PMID:Cellular and molecular effects of alpha-tocopheryloxybutyrate: lessons for the design of vitamin E analog for cancer prevention. 1573 14

An enhanced linkage-specific 9-O-acetylated sialic acid (9-O-AcSA) on peripheral blood mononuclear cells (PBMC) of children with acute lymphoblastic leukaemia, ALL (PBMC(ALL), 9-O-AcSA+ cells) was demonstrated by using a lectin, Achatinin-H, whose lectinogenic epitope was 9-O-AcSAalpha2-6GalNAc. Our aim was to evaluate the in vitro contributory role of this glycotope (9-O-AcSAalpha2-6GalNAc) towards the survival of these 9-O-AcSA+ cells in ALL patients. For direct comparison, 9-O-AcSA- cells were generated by removing O-acetyl group of 9-O-AcSA present on PBMC(ALL) using O-acetyl esterase. An elevated level of serum interferon gamma (IFN-gamma) in affected children led us to think that PBMC(ALL) are continuously exposed specifically to this cytokine. Accordingly, 9-O-AcSA+ and 9-O-AcSA- cells were exposed in vitro to IFN-gamma. A twofold increased NO release along with inducible NO synthase (iNOS) mRNA expression by the 9-O-AcSA+ cells was observed as compared to the 9-O-AcSA- cells. The decreased viability of IFN-gamma exposed 9-O-AcSA- cells as compared to 9-O-AcSA+ cells were reflected from a 5.0-fold increased caspase-3-like activity and a 10.0-fold increased apoptosis in the 9-O-AcSA- cells when production of NO was lowered by adding competitive inhibitor of iNOS in reaction mixture. Therefore, it may be envisaged that a link exists between induction of this glycotope and their role in regulating viability of PBMC(ALL). Taken together, it is reasonable to hypothesise that O-acetylation of sialic acids on PBMC(ALL) may be an additional mechanism that promotes the survival of lymphoblasts by avoiding apoptosis via IFN-gamma-induced NO production.
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PMID:Interferon gamma promotes survival of lymphoblasts overexpressing 9-O-acetylated sialoglycoconjugates in childhood acute lymphoblastic leukaemia (ALL). 1577 Jun 63

Our aim was to prepare curcumin derivatives and study their apoptosis-inducing effects on bladder cancer cells in order to establish a basis for targeted chemotherapy of cancer. n-Maleoyl-L-valine-curcumin (NVC) and n-maleoyl-glycine-curcumin (NGC) were chemically synthesized. Intracellular esterase activity of the human bladder cancer EJ cell line and renal tubular epithelial (HKC) cells was examined by 6-carboxyfluorescein diacetate fluorometry. After incubation with NVC or NGC for 6-24 h, cell viability was detected by MTT colorimetry. Cell apoptosis and apoptotic rates were measured by acridine orange/ethidium bromide staining, TUNEL labeling and flow cytometry. Intracellular caspase-3 activities were determined by spectrophotometry. The esterase activity within EJ cells was 10.2-fold higher than that of HKC cells, which was abolished by bis-p-nitrophenylphosphate, an esterase inhibitor, resulting in decreases in NVC- and NGC-mediated cell viability arrest. For EJ cells, the IC50 values of NVC (20.1 micromol/l) and NGC (18.7 micromol/l) were close to curcumin (16.5 micromol/l). Meanwhile, their IC50 values on HKC cells were, respectively, 4.06- and 3.23-fold higher than curcumin. Moreover, NVC and NGC induced apoptosis of EJ cells by 10.13-23.36 and 12.42-28.56%, respectively. Administration of these two derivatives resulted in decreased apoptosis of HKC cells compared with curcumin. The caspase-3 activities of EJ cells, but not of HKC cells, were 5.21- and 5.63-fold enhanced by NVC and NGC, respectively. Thus, novel esterase-sensitive curcumin derivatives were synthesized, which induced extensive apoptosis of bladder cancer EJ cells, but not normal cells.
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PMID:Apoptosis-inducing effects of curcumin derivatives in human bladder cancer cells. 1652 Jun 56

Because the phosphatidylinositol-3-kinase-AKT pathway is emerging as an important regulator of tumor cell survival, inhibitors of this pathway have enormous potential in cancer treatment. A specific inhibitor of AKT, [d-3-deoxy-2-O-methyl-myo-inositol-1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate]] (SH-5) has been recently synthesized, but little is known about its effects on cytokine signaling. We found that SH-5 potentiated the apoptosis induced by tumor necrosis factor (TNF), as indicated by intracellular esterase staining, annexin V staining, and caspase-3 activation. This effect of SH-5 correlated with downregulation of various gene products that mediate cell survival, proliferation, metastasis, and invasion, all known to be regulated by NF-kappaB. SH-5 also blocked NF-kappaB activation induced by TNF-alpha, lipopolysaccharide, phorbol ester, and cigarette smoke but not that activated by hydrogen peroxide and RANK ligand, indicating differential requirement of AKT. Inhibition of NF-kappaB correlated with abrogation of phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase (IKK). This led to suppression of the phosphorylation and translocation of p65 and also of NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKKbeta but not that induced by p65 transfection. Thus, our results clearly demonstrate that inhibition of AKT leads to potentiation of apoptosis through modulation of NF-kappaB signaling.
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PMID:SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. 1860 97

Activation of the complement cascade represents an important event during ischemia/reperfusion injury (IRI). This work was designed to investigate the role of the membrane attack complex (MAC; C5b-9) in the pathogenesis of hepatic IRI. Livers from B&W/Stahl/rC6(+) and C6(-) rats were harvested, stored for 24 hours at 4 degrees C, and then transplanted [orthotopic liver transplantation (OLT)] to syngeneic recipients. There were 4 experimental groups: (1) C6(+)-->C6(+), (2) C6(+)-->C6(-), (3) C6(-)-->C6(+), and (4) C6(-)-->C6(-). At day +1, C6(-) OLTs showed decreased vascular congestion/necrosis, contrasting with extensive necrosis in C6(+) livers, that was independent of the recipient C6 status (Suzuki score: 7.2 +/- 0.9, 7.3 +/- 1.3, 4.5 +/- 0.6, and 4.8 +/- 0.4 for groups 1-4, respectively, P < 0.05). The liver function improved in recipients of C6(-) grafts (serum glutamic oxaloacetic transaminase: 2573 +/- 488, 1808 +/- 302, 1170 +/- 111, and 1188 +/- 184 in groups 1-4, respectively, P < 0.05). Intragraft macrophage infiltration (ED-1 immunostaining) and neutrophil infiltration (myeloperoxidase activity) were reduced in C6(-) grafts versus C6(+) grafts (P = 0.001); these data were confirmed by esterase staining (naphthol). The expression of proinflammatory interferon-gamma, interleukin-1beta, and tumor necrosis factor messenger RNA/protein was also reduced in C6(-) OLTs in comparison with C6(+) OLTs. Western blot-assisted expression of proapoptotic caspase-3 was decreased in C6(-) OLTs versus C6(+) OLTs (P = 0.006), whereas antiapoptotic Bcl-2/Bag-1 was enhanced in C6(-) OLTs compared with C6(+) OLTs (P = 0.001). Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining of apoptotic cells was enhanced (P < 0.05) in C6(+) OLTs compared with C6(-) OLTs. Thus, the terminal products of the complement system are essential in the mechanism of hepatic IRI. This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients.
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PMID:The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury. 1866 46

Glycoconjugates represent a recent trend in cancer chemotherapy that adopts the concept of selective prodrug/drug targeting of tumor cells by selectively binding to specific transmembrane glucose transporters. Following preferential uptake of sugar conjugates into cancer cells, they are presumably subject to enzymatic cleavage by specific beta-glycosidases to liberate the free active cytotoxic aglycones that act selectively on cancer cells and spare other noncancerous ones. In this sense, the cytotoxicity of an array of newly synthesized glycoconjugates, including curcumin beta-glucoside, perillyl alcohol beta-glucoside, perillyl alcohol beta-galactoside, diethylstilbesterol beta-glucoside and diethylstilbesterol beta-galactoside have been investigated over 24-96 h in a panel of human colon cancer cells namely, Caco-2, HT29 and T84 cells. The role of beta-glycosidases and caspases in the bioactivation and cytotoxicity of these compounds has been addressed in the current study. All the glycoconjugates have proven cytotoxic efficacy in a time-dependent manner. Curcumin beta-glucoside was the most potent amongst all glycoconjugates tested. The sensitivity rank order of tumor cells towards all beta-glucosides was Caco-2 > HT29 > T84. This sensitivity ranking was well correlated with beta-glucosidase activity assessed in these cell lines. Unlike perillyl alcohol galactoside, the cytotoxicity rank order for diethylstilbesterol beta-galactoside was not coping with the beta-galactosidase activity detected. Apoptosis was assessed by fluorometric assay of caspase-3 and caspase-9 activities. Initiation and activation of apoptosis were increased in all colon cancer cells following exposure to most of the glycoconjugates, and this was well correlated with the cytotoxicity rank order of these prodrugs. Enzymatic cleavage of glycoconjugates was accomplished using a host of hydrolytic enzymes and cleavage kinetics was determined using HPLC. The glycoconjugates were only cleaved by beta-glucosidases and beta-galactosidases, but not by pancreatic lipase or hepatic esterase. Taken together, one could conclude that beta-glucosidases and beta-galactosidases are crucial for the bioactivation and cytotoxicity of these glycoconjugates. Also, initiation and activation of apoptosis in tumor cells may contribute, at least partly, for the cytotoxicity of these sugar conjugates.
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PMID:Possible contribution of beta-glycosidases and caspases in the cytotoxicity of novel glycoconjugates in colon cancer cells. 1941 82

Glycoconjugates represent a recent trend in cancer chemotherapy that adopts the concept of selective prodrug/drug targeting of tumor cells by binding to specific transmembrane glucose transporters. Following preferential uptake of sugar conjugates into cancer cells, they are presumably subject to enzymatic cleavage by specific beta-glycosidases to liberate the free active cytotoxic aglycones that act selectively on cancer cells and spare other noncancerous ones. In this sense, the role of beta-glucosidase and caspases in the bioactivation and cytotoxicity of glufosfamide has been addressed in the current study. The cytotoxicity of glufosfamide has been investigated over 24-96 h in a panel of human colon cancer cells namely, Caco-2, HT29 and T84 using a tetrazole dye; 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT assay technique. Apoptosis was assessed by fluorometric assay of caspase-3 and caspase-9 activities. Enzymatic cleavage of glufosfamide was accomplished using a host of hydrolytic enzymes and cleavage kinetics was determined using HPLC. Glufosfamide has proven cytotoxic efficacy in a concentration- and time-dependent manner. The sensitivity rank order of tumor cells towards the glycoconjugate was Caco-2>HT29>T84. This sensitivity ranking was well correlated with the enzymatic activity of beta-glucosidase assessed in these cell lines. Initiation and activation of apoptosis were increased in all colon cancer cells following exposure to glufosfamide and were well correlated with the cytotoxicity rank order of the glycoconjugate. Glufosfamide was cleaved by cytosolic and lysosomal beta-glucosidases but not by other hydrolytic enzymes such as cytosolic beta-galactosidase, pancreatic lipase or hepatic esterase. In conclusion, the current data could possibly unravel the mechanistic role of beta-glucosidase and apoptotic caspases in the bioactivation and cytotoxicity of glufosfamide within colon cancer cells.
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PMID:Possible contribution of beta-glucosidase and caspases in the cytotoxicity of glufosfamide in colon cancer cells. 1954 61


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