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)

The present study was performed to examine neuroprotective effects of 5-hydroxytryptamine (5-HT)(3) receptor antagonists against beta-amyloid protein (25--35)-, a synthetic 25--35 amyloid peptide, induced neurotoxicity using cultured rat cortical neurons. beta-Amyloid protein (25--35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca(2+) channel blocker, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. The 5-HT(3) receptor antagonists, tropanyl-3,5-dichlorobenzoate (MDL-72222, 0.1--10 microM) and N-(1-azabicyclo[2.2.2.]oct-3-yl)-6-chloro-4-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride (Y 25130, 0.05--5 microM), decreased the beta-amyloid protein (25--35) (10 microM)-induced neuronal cell death as assessed by a colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the number of apoptotic nuclei, evidenced by Hoechst 33342 staining. MDL 72222 and Y 25130 inhibited the beta-amyloid protein (25--35) (10 microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) and glutamate release, generation of reactive oxygen species, and caspase-3 activity. These neuroprotective effects of MDL 72222 (10 microM) and Y 25130 (5 microM) were completely blocked by the simultaneous treatment with 100 microM 1-phenylbiguanide, a 5-HT(3) receptor agonist, indicating that the protective effects of these compounds were due to 5-HT(3) receptor blockade. These results suggest that the activation of the 5-HT(3) receptor may be partially involved in beta-amyloid protein-induced neurotoxicity, by membrane depolarization for Ca(2+) influx. Therefore, the blockade of 5-HT(3) receptor with MDL 72222 and Y 25130, may ameliorate the beta-amyloid protein-induced neurotoxicity by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of reactive oxygen species and caspase-3 activity.
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PMID:Blockade of 5-HT(3) receptor with MDL 72222 and Y 25130 reduces beta-amyloid protein (25--35)-induced neurotoxicity in cultured rat cortical neurons. 1615 Apr 39

Although the indazole compound, YC-1, is reported to exert anticancer activities in several cancer cell types, its target and mechanism of action have not been well explored. The objectives of this study were to ascertain whether YC-1 directly induces apoptosis in prostate cancer cells and to explore the mechanism(s) whereby YC-1 causes cell death. Hormone-refractory metastatic human prostate cancer PC-3 cells were selected for this study. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay indicated that YC-1 suppresses growth of PC-3 cells in a concentration-dependent and time-dependent manner. Apoptosis was determined using 4',6-diamidino-2-phenylindole staining, and cell cycle progression was examined by FACScan flow cytometry. YC-1 treatment showed chromatin condensation and increased the percentage of PC-3 cells in the hypodiploid sub-G0-G1 phase, indicative of apoptosis. Additionally, exposure to YC-1 was found to induce activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Translocation and activation of nuclear factor-kappaB (NF-kappaB) were determined by immunofluorescent staining and ELISA, respectively. The results showed that YC-1 abolished constitutive nuclear translocation and activation of NF-kappaB/p65. Furthermore, inhibition of inhibitor of kappaBalpha (IkappaBalpha) phosphorylation and accumulation of IkappaBalpha were observed. The antitumor effects of YC-1 were evaluated by measuring the growth of tumor xenografts in YC-1-treated severe combined immunodeficient mice. The volumes of PC-3 tumors produced in severe combined immunodeficient mice were observed to decline significantly after treatment with YC-1 compared with vehicle controls. We concluded that the antitumor effects of YC-1 in PC-3 cells include the induction of apoptosis and the suppression of NF-kappaB activation. Given these unique actions, further investigations of the effects of YC-1 against hormone-refractory prostate cancer are warranted.
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PMID:YC-1 suppresses constitutive nuclear factor-kappaB activation and induces apoptosis in human prostate cancer cells. 1622 13

DNA topoisomerases (topo) I and II are molecular targets of several potent anticancer agents. Thus, inhibitors of these enzymes are potential candidates or model compounds for anticancer drugs. Leptosins (Leps) F and C, indole derivatives, were isolated from a marine fungus, Leptoshaeria sp. as cytotoxic substances. In vitro cytotoxic effects of Lep were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based viability assay. Lep F inhibited the activity of topos I and II, whereas Lep C inhibited topo I in vitro. Interestingly both of the compounds were found to be catalytic inhibitors of topo I, as evidenced by the lack of stabilization of reaction intermediate cleavable complex (CC), as camptothecin (CPT) does stabilize. Furthermore, Lep C inhibited the CC stabilization induced by CPT in vitro. In vivo band depletion analysis demonstrated that Lep C likewise appeared not to stabilize CC, and inhibited CC formation by CPT, indicating that Lep C is also a catalytic inhibitor of topo I in vivo. Cell cycle analysis of Lep C-treated cells showed that Lep C appeared to inhibit the progress of cells from G(1) to S phase. Lep C induced apoptosis in RPMI8402 cells, as revealed by the accumulation of cells in sub-G(1) phase, activation of caspase-3 and the nucleosomal degradation of chromosomal DNA. Furthermore, Leps F and C inhibited the Akt pathway, as demonstrated by dose-dependent and time-dependent dephosphorylation of Akt (Ser473). Our study shows that Leps are a group of anticancer chemotherapeutic agents with single or dual catalytic inhibitory activities against topos I and II.
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PMID:Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B. 1627 Oct 76

Estrogen-mediated neuroprotection is well established; however, no single mechanism of action for this effect has yet been established. As glial cells are integral for both the intact and injured nervous system, we hypothesized that estrogen-mediated neuroprotection may partly be attributed to attenuation of glial cell apoptosis, allowing them to protect neurons following injury. To assess the protective effects of estrogen on glia, C6 rat glioma cells were treated for 24 h with 500 microM glutamate. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was confirmed by cell morphology and DNA fragmentation. Pretreatment with 10 nM 17beta-estradiol (estrogen) increased cell viability and attenuated apoptosis. Treatment with the stereoisomer 17alpha-estradiol, or estrogen plus estrogen receptor antagonist ICI 182,780, was significantly less effective, indicating that cytoprotection was receptor-mediated. Estrogen treatment upregulated expression of estrogen receptor alpha. Cell impermeable bovine serum albumin-conjugated estrogen was also protective, indicating activation of estrogen receptors on the cell membrane. Intracellular free [Ca2+] was increased after glutamate treatment. This increase was attenuated in cells pretreated with estrogen. Glutamate increased the activity of pro-apoptotic proteases, such as calpain and caspase-3, and these protease activities were significantly attenuated by estrogen. The mechanism by which estrogen decreased intracellular Ca2+ was examined by assaying cell viability after using inhibitors that either blocked extracellular Ca2+ influx or prevented the release of intracellular Ca2+ stores. While several inhibitors increased cell viability in glutamate-treated cells, none were as protective as estrogen, and estrogen co-treatment significantly increased cell viability. These findings indicate that estrogen-mediated cytoprotection may be related to effects on Ca2+ entry but that these effects are not limited to any one of these Ca2+ entry points alone.
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PMID:Estrogen prevents glutamate-induced apoptosis in C6 glioma cells by a receptor-mediated mechanism. 1628 85

Curcumin, a major yellow pigment and active component of turmeric, has multiple anti-cancer properties. However, its molecular targets and mechanisms of action on human colon adenocarcinoma cells are unknown. In the present study, we examined the effects of curcumin on the proliferation of human colon adenocarcinoma HT-29 cells by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method and confirmed the curcumin-induced apoptosis by morphology and DNA ladder formation. At the same time, p53, phospho-p53 (Ser15), and other apoptosis-related proteins such as Bax, Bcl-2, Bcl-xL, pro-caspase-3, and pro-caspase-9 were determined by Western blot analysis. The colon adenocarcinoma cells were treated with curcumin (0-75 microM) for 0-24 h. We observed that p53 was highly expressed in HT-29 cells and curcumin could up-regulate the serine phosphorylation of p53 in a time- and concentration-dependent manner. An increase in expression of the pro-apoptotic factor Bax and a decrease in expression of the anti-apoptotic factor Bcl-2 were also observed in a time-dependent manner after exposure of 50 microM curcumin, while the expression of the anti-apoptotic factor Bcl-xL was unchanged. Curcumin could also down-regulate the expression of pro-caspase-3 and pro-caspase-9 in a time-dependent manner. These data suggest a possible underlying molecular mechanism whereby curcumin could induce the apoptosis signaling pathway in human HT-29 colon adenocarcinoma cells by p53 activation and by the regulation of apoptosis-related proteins. This property of curcumin suggests that it could have a possible therapeutic potential in colon adenocarcinoma patients.
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PMID:Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression. 1630 93

In an attempt to dissect the mechanism of Strychnos nux-vomica, a commonly used Chinese folk medicine in the therapy of liver cancer, the cytotoxic effects of four alkaloids in Strychnos nux-vomica, brucine, brucine N-oxide, strychnine, and isostrychnine, on human hepatoma cells (HepG2) were screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrasolium bromide (MTT) assay. Brucine, among the four alkaloids, exhibited the strongest toxic effect, the mechanism of which was found to cause HepG2 cell apoptosis, since brucine caused HepG2 cell shrinkage, the formation of apoptotic bodies, DNA fragmentation, cell cycle arrest, as well as phosphatidylserine externalization, all of which are typical characteristics of apoptotic programmed cell death. Brucine-induced HepG2 cell apoptosis was caspase dependent, with caspase-3 activated by caspase-9. Brucine also caused the proteolytic processing of caspase-9. In addition, brucine caused depolarization of the mitochondrial membrane of HepG2 cells, the inhibition of which by cyclosporine A completely abrogated the activation of casapses and release of cytochrome c in brucine-treated HepG2 cells. These findings suggested a pivotal role of mitochondrial membrane depolarization in HepG2 cell apoptosis elicited by brucine. Furthermore, brucine induced a rapid and sustained elevation of intracellular [Ca2+], which compromised the mitochondrial membrane potential and triggered the process of HepG2 cell apoptosis. Finally, Bcl-2 was found to predominately control the whole event of cell apoptosis induced by brucine. The elevation of [Ca2+]i caused by brucine was also suppressed by overexpression of Bcl-2 protein in HepG2 cells. From the facts given above, Ca2+ and Bcl-2 mediated mitochondrial pathway were found to be involved in brucine-induced HepG2 cell apoptosis.
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PMID:The apoptotic effect of brucine from the seed of Strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+ involved mitochondrial pathway. 1644 26

Smilax has various pharmacological effects including antiinflammatory, anticancer and antioxidant activity. The present study aims to investigate the effect of the methanol extract of Smilacis chinae rhizome (SCR) from Smilax china L. (Liliaceae) on amyloid beta protein (Abeta) (25-35), a synthetic 25-35 amyloid peptide, -induced neurotoxicity in cultured rat cerebral cortical neurons. Abeta (25-35) (10 microM) produced a reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca2+ channel blocker, and NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. SCR, over a concentration range of 10-50 microg/ml, inhibited 10 microM Abeta (25-35)-induced neuronal cell death, which was measured by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and Hoechst 33342 staining. SCR (50 microg/ml) inhibited 10 microM Abeta (25-35)-induced elevation of cytosolic calcium concentration ([Ca2+]c), which was measured by a fluorescent dye, Fluo-4 AM. Pretreatment of SCR (10 and 50 microg/ml) also inhibited glutamate release into medium induced by 10 microM Abeta (25-35), which was measured by HPLC, generation of reactive oxygen species and activation of caspase-3. These results suggest that SCR prevents Abeta (25-35)-induced neuronal cell damage in vitro.
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PMID:Protection of amyloid beta protein (25-35)-induced neurotoxicity by methanol extract of Smilacis chinae rhizome in cultured rat cortical neurons. 1649 58

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

The nephrotoxic metal cadmium at micromolar concentrations induces apoptosis of rat kidney proximal tubule (PT) cells within 3-6 h of exposure. The underlying cell death pathways remain poorly defined. Using Hoechst 33342/ethidium bromide nuclear staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell death assays, 10-50 microM cadmium induced apoptosis of immortalized rat kidney cells derived from the S1-segment of PT at 6 and 24 h, but necrosis at 24 h only. Cadmium (10-50 microM) also caused mitochondrial cytochrome c (cyt. c)- and apoptosis-inducing factor release at 24 h, but not at 6 h, as measured by immunofluorescence imaging and immunoblotting. Caspases-9 and -3 were activated only by 10 microM cadmium for 24 h, and accordingly apoptosis was significantly reduced by the respective inhibitors (z-LEHD-fmk, z-DEVD-fmk; 10 microg/ml) at 24 h, but not at 6 h, without affecting necrosis. At 6 h, 10 microM cadmium increased the activity of the calcium-activated protease calpain, but not at 24 h, and calpain inhibitors (ALLN, PD 150606; 10-30 microM) blocked apoptosis by 10 microM cadmium at 3-6 h. However, PD-150606 also attenuated caspase-3 activity and apoptosis at 24 h, suggesting calpain-dependent caspase activation. Thus cadmium-induced apoptosis of PT cells involves a complex and sensitive interplay of signaling cascades involving mitochondrial proapoptotic factors, calpains and caspases, whose activation is also determined by cadmium concentration and the duration of cadmium exposure.
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PMID:Caspase-dependent and -independent pathways for cadmium-induced apoptosis in cultured kidney proximal tubule cells. 1659 13

The new imidazole-coordinated chemotherapeutics with low epithelial toxicity (NICE) presented in this article feature innovative drugs that combine epithelial toxicity comparable with that of carboplatin with novel carrier ligands optimized for DNA interaction. Recent identification of the pivotal role of basolateral organic cation transporters (OCTs) in cisplatin nephrotoxicity by a new model system (electrical resistance breakdown assay) facilitated the search for substances with a favorable organotoxic profile. The assay uses the high transepithelial electrical resistance (TEER) of the C7-clone of Madin-Darby canine kidney (MDCK) cells and the exclusive basolateral expression of OCT2 in these cells. TEER and caspase-3 activity of MDCK-C7-cells grown on microfilter membranes were monitored in response to exposure of either the apical or basolateral plasma membrane to platinum complexes. The impact of complexes on cancer cell lines was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide tests. Effects of substituents on pharmacological properties of NICE were systematically investigated by introducing sterically demanding groups as well as electron-donating and electron-withdrawing groups. Derivatives of NICE showed different renal epithelial toxic profiles and effects on cancer cells. NICE were significantly less toxic than cis- or oxaliplatin. The chlorine substituted NICE had no effect on epithelial integrity but markedly cytotoxic activity against amelanotic melanoma cells. Together, side effect targeted screening for new anticancer drugs with the electrical resistance breakdown assay offers an interesting approach for identifying and investigating new compounds. NICE feature the first group of platinum-based cytostatics discovered by using this system for systematic screening of new chemotherapeutics with low renal epithelial toxicity.
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PMID:New imidazole-coordinated chemotherapeutics with low epithelial toxicity. 1667 62


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