EC:3.4.22.56 - FACTA Search

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)

Sulforaphane, an isothiocyanate found in cruciferous vegetables, has been shown to possess growth-inhibiting and apoptosis-inducing activities in cancer cell lines in vitro. In order to further explore the critical events leading to apoptosis in sulforaphane-treated U937 human leukemia cells, the following effects of sulforaphane on components of the mitochondrial apoptotic pathway were examined: generation of reactive oxygen species (ROS), alteration of the mitochondrial membrane potential (MMP), and the expression changes of Bcl-2 family proteins. The cytotoxic effect of sulforaphane was mediated by its induction of apoptosis as characterized by the occurrence of DNA ladders, apoptotic bodies and chromosome condensation in U937 cells. The sulforaphane-induced apoptosis in U937 cells correlated with the generation of intracellular ROS, collapse of MMP, activation of caspase-3, and down-regulation of anti-apoptotic Bcl-2 expression. The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-elicited ROS generation, disruption of the MMP, caspase-3 activation and apoptosis. In conclusion, the present study reveals that the cellular ROS generation plays a pivotal role in the initiation of sulforaphane-triggered apoptotic death in U937 cells.
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PMID:Sulforaphane generates reactive oxygen species leading to mitochondrial perturbation for apoptosis in human leukemia U937 cells. 1831 57

Studies from our laboratory demonstrated the involvement of intrinsic apoptotic signaling in hyperpermeability following hemorrhagic shock (HS). Angiopoietin 1 (Ang-1), a potent inhibitor of hyperpermeability, was recently shown to inhibit apoptosis. The purpose of our study was to determine the effectiveness of Ang-1 in attenuating HS-induced hyperpermeability and its relationship to apoptotic signaling. HS was induced in rats by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 h, followed by reperfusion. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. Mitochondrial release of second mitochondrial derived activator of caspases (smac) and cytochrome c were determined by Western blot and ELISA, respectively. Caspase-3 activity was determined by fluorometric assay. Parallel studies were performed in rat lung microvascular endothelial cell (RLMEC) monolayers, utilizing HS serum and the proapoptotic Bcl-2 homologous antagonist/killer [BAK (BH3)] peptide as inducers of hyperpermeability. In rats, Ang-1 (200 ng/ml) attenuated HS-induced hyperpermeability versus the HS group (P < 0.05). Ang-1 prevented HS-induced collapse of mitochondrial transmembrane potential (DeltaPsi(m)), smac and cytochrome c release, and caspase-3 activity (P < 0.05). In RLMEC monolayers, HS serum and BAK (BH3) peptide both induced hyperpermeability that was inhibited by Ang-1 (P < 0.05). Ang-1 attenuated HS and BAK (BH3) peptide-induced collapse of DeltaPsi(m), smac release, cytochrome c release, activation of caspase-3, and vascular hyperpermeability. In vivo, BAK (BH3) induced vascular hyperpermeability that was attenuated by Ang-1 (P < 0.05). These findings suggest that Ang-1's role in maintaining microvascular endothelial barrier integrity involves the intrinsic apoptotic signaling cascade.
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PMID:Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock. 1834 75

Chemoresistance to anticancer drugs is a major issue in the successful treatment of acute myeloid leukemia (AML). In this study, we developed an AML cell line (AML-2/IDAC) that is resistant to treatment with a combination of idarubicin and cytosine arabinoside (Id/AraC) by chronic exposure for more than 3 months. We then investigated the ability of indomethacin to alleviate the chemoresistance of AML-2/IDAC cells. Treatment with indomethacin alone induced growth arrest, but not the death of AML-2/IDAC cells. However, when AML-2/IDAC cells were treated with combinations of indomethacin and Id/AraC, the cell death and apoptosis rate of AML-2/IDAC cells were significantly increased in a dose- and time-dependent manner. The combined treatment with indomethacin and Id/AraC caused the collapse of the mitochondrial membrane potential and was also demonstrated to enhance the activities of caspase-3 and -8 in AML-2/IDAC cells. Furthermore, indomethacin down-regulated expression of the ABCA3 and MRP1 genes, which were over-expressed in AML-2/IDAC cells. Taken together, the results of this study suggest that indomethacin can be used to increase the therapeutic potential against drug-resistant AML when combined with anti-leukemic drugs.
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PMID:Alleviation of the drug-resistant phenotype in idarubicin and cytosine arabinoside double-resistant acute myeloid leukemia cells by indomethacin. 1836 Jul 21

Apoptosis is a genetically programmed and physiological mode of cell death that leads to the removal of unwanted or abnormal cells. Cysteine-proteases called caspases are responsible for the apoptotic execution phase which is characterized by specific biochemical events as well as morphological changes. These changes, which lead to the orderly dismantling of the apoptotic cell, include cell contraction, dynamic membrane blebbing, chromatin condensation, nuclear disintegration, cell fragmentation followed by phagocytosis of the dying cell. They involve major modifications of the cytoskeleton which are largely mediated by cleavage of several of its components by caspases. For example, dynamic membrane blebbing is due to the increased contractility of the acto-myosin system following myosin light chain (MLC) phosphorylation. MLC phosphorylation is a consequence of the cleavage of a Rho GTPase effector, the kinase ROCK I, by caspase-3. This cleavage induces a constitutive kinase activity by removal of an inhibitory domain. Chromatin condensation is facilitated by the processing of lamins by caspases. Collapse of the cytokeratin network is mediated by cleavage of keratin 18. On another hand, the actin cytoskeleton rearrangement needed in the phagocyte for engulfment of the dying cell is due to the activation of the small GTPase Rac, a GTPase of the Rho family that induces actin polymerisation and formation of lamellipodia. In addition to mediating the morphological modifications of the apoptotic cell, several proteins of the cytoskeleton such as actin and keratins are also involved in the regulation of apoptotic signaling.
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PMID:Cytoskeleton and apoptosis. 1846 7

Two anthraquinones which inhibit activity of the Src tyrosine kinase were isolated from a water extract of Hedyotis diffusa WILLD. and identified as 2-hydroxy-3-methylanthraquinone (compound 1) and 1-methoxy-2-hydroxyanthraquinone (compound 2). Both compounds showed inhibitory activity against protein tyrosine kinases v-src and pp60src and arrested the growth of SPC-1-A, Bcap37 and HepG2 cancer cells. Observation of mitochondrial membrane potential collapse and caspase-3 activation following treatment with the compounds indicates that their apoptotic induction activity may act via the mitochondrial apoptotic pathway. Compared with compound 2, compound 1 is more active as an antagonist of Src kinase, which might account for its higher potency to induce growth arrest and apoptosis. These results provide a deeper insight into the functions of these two simple anthraquinones and the anti-tumour pathway of Hedyotis diffusa WILLD.
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PMID:Apoptosis-inducing effects of two anthraquinones from Hedyotis diffusa WILLD. 1852 33

AMAD, an emodin azide methyl anthraquinone derivative, was extracted from the nature giant knotweed rhizome of traditional Chinese herbs. Here, we investigated the anticancer activities and signaling pathways implicated in AMAD-induced apoptosis in human breast cancer cell lines MDA-MB-453 and human lung adenocarcinoma Calu-3 cells. AMAD was found to have a potent cytotoxic effect on both cell lines. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. Moreover, this apoptotic induction was associated with a collapse of the mitochondrial membrane potential and activated caspases (cysteine aspartase) cascade involving in caspase-8, caspase-9, caspase-3, and poly(ADP-ribose) polymerase cleavage in a concentration-dependent manner. It was noteworthy that AMAD also effectively cleaved Bid, a BH3 domain-containing proapoptotic Bcl-2 family member, and induced the subsequent release of cytochrome c from mitochondria into the cytosol. Furthermore, suppression of caspase-8 activity with Z-IETD-FMK partially inhibited release of cytochrome c and Bid cleavage induced by AMAD, whereas exposure to Z-LETD-FMK, a caspase-9 inhibitor, had no effect. Additionally, there was significant change in other mitochondrial membrane proteins triggered by AMAD, such as Bcl-xl and Bad. It was intriguing that AMAD decreased the generation of reactive oxygen species in both cell lines. DNA-binding assay exhibited apoptosis induced by AMAD was not involved in intercalating to DNA. Taken together, these data suggested that AMAD induced apoptosis via a mitochondrial pathway involving caspase-8/Bid activation in both cell lines.
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PMID:Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage. 1856 40

Streptochlorin is a small molecule that produced by marine Streptomyces sp. that is known to have anti-angiogenic and anti-cancer properties. However, the mechanism by which streptochlorin functions is not well understood. In this study, we investigated the pro-apoptotic effect of streptochlorin in human leukemic U937 cells. Streptochlorin treatment resulted in concentration- and time-dependent growth inhibition by inducing apoptosis. The increase in apoptosis that was induced by streptochlorin was correlated with down-regulation of anti-apoptotic Bcl-2 expression, up-regulation of pro-apoptotic Bax and FasL, a decrease in the mitochondrial membrane potential (MMP), activation of caspases and degradation of poly-(ADP-ribose)polymerase and phospholipase C-gamma1 protein. In addition, the cytotoxic effects and apoptotic characteristics induced by streptochlorin were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 played in the process. Furthermore, Bcl-2 overexpression significantly reversed the streptochlorin-induced growth inhibitory effects via inhibition of the MMP collapse and caspases activation and effectively attenuated the apoptotic response to streptochlorin. However, the elevated levels of FasL expression induced by streptochlorin were not reduced by Bcl-2 overexpression. Taken together, these findings demonstrate that the pro-apoptotic effect of streptochlorin is mediated through activation of caspases and mitochondria in U937 cells.
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PMID:Induction of apoptosis by streptochlorin isolated from Streptomyces sp. in human leukemic U937 cells. 1863 25

We have synthesized novel heterocyclic organobismuth compounds that have potent antibacterial properties. In this study, we examined their anticancer activity and addressed the cellular mechanisms involved. Heterocyclic organobismuth compounds showed anticancer activities in various human cancer cell lines. These compounds have particularly potent anticancer activities against leukemia cell lines. One of them, bi-chlorodibenzo [c,f][1,5] thiabismocine (compound 3), inhibited the growth of the human promyelocytic leukemia cell line HL-60 at a concentration of 0.22 microM. Low concentrations of compound 3 (0.22-0.44 microM) induced apoptosis, whereas at a higher concentration (>1.1 microM) it causes acute necrosis. During the apoptosis, caspase-3, -8, and -9 were activated but caspase-12 was not. A broad caspase inhibitor (z-VAD-fmk), and caspase-3 (z-DEVD-fmk) and caspase-9 (z-LEHD-fmk) inhibitors suppressed the compound 3-induced apoptosis, but a caspase-8 inhibitor (z-IETD-fmk) was less effective, suggesting that the caspase-8 activity only partially participates in the apoptosis. In the apoptotic cells, cytochrome c was released from mitochondria to cytosol and a loss of mitochondrial transmembrane potential (DeltaPsi(m)) was detected. Compound 3-induced apoptosis was associated with enhanced generation of intracellular reactive oxygen species (ROS). Pretreatment of the cells with N-acetyl-L-cysteine or catalase suppressed the apoptosis. On the other hand, buthionine sulfoximine enhanced the compound 3-induced collapse of DeltaPsi(m) and apoptosis. Taken together, these results indicate that compound 3 is a potent inducer of apoptosis, triggering a caspase-3-mediated mechanism via the generation of ROS and release of cytochrome c from mitochondria, suggesting a potential mechanism for the anticancer activity of compound 3.
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PMID:Heterocyclic organobismuth(III) induces apoptosis of human promyelocytic leukemic cells through activation of caspases and mitochondrial perturbation. 1876 Feb 61

The cardiotoxic effects of doxorubicin, a potent chemotherapeutic agent, have been linked to DNA damage, oxidative mitochondrial damage, and nuclear translocation of p53, but the exact molecular mechanisms causing p53 transactivation and doxorubicin-induced cardiomyopathy are not clear. The present study was carried out to determine whether extracellular signal-regulated kinases (ERKs), which are known to be activated by DNA damaging agents, are responsible for doxorubicin-induced p53 activation and oxidative mitochondrial damage in H9c2 cells. Cell death was measured by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, annexin V-fluorescein isothiocyanate, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). We found that doxorubicin produced cell death in H9c2 cells in a time-dependent manner, beginning at 6 h, and these changes are associated decreased expression of Bcl-2, increases in Bax and p53 upregulated modulator of apoptosis-alpha expression, and collapse of mitochondria membrane potential. The changes in cell death and Bcl-2 family proteins, however, were preceded by earlier activation and nuclear translocation of ERKs, followed by increased phosphorylation at Ser15 and nuclear translocation of the phosphorylated p53. The functional importance of ERK1/2 and p53 in doxorubicin-induced toxicity was further demonstrated by the specific ERK inhibitor U-0126 and p53 inhibitor pifithrin (PFT)-alpha, which abrogated the changes in Bcl-2 family proteins and cell death produced by doxorubicin. U-0126 blocked the phosphorylation and nuclear translocation of both ERK1/2 and p53, whereas PFT-alpha blocked only the changes in p53. Doxorubicin and ERK inhibitors produced similar changes in ERK1/2-p53, PARP, and caspase-3 in neonatal rat cultured cardiomyocytes. Thus we conclude that ERK1/2 are functionally linked to p53 and that the ERK1/2-p53 cascade is the upstream signaling pathway responsible for doxorubicin-induced cardiac cell apoptosis. ERKs and p53 may be considered as novel therapeutic targets for the treatment of doxorubicin-induced cardiotoxicity.
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PMID:ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. 1877 51

Platycodon D is a major constituent of triterpene saponins found in the root of Platycodon grandiflorum, Platycodi Radix, which is widely used in traditional Oriental medicine for the treatment of many chronic inflammatory diseases. The results of previous studies have shown that this compound has in vitro growth-inhibitory activity in human cancer cells, however, the mechanism by which this action occurs is poorly understood. In this study, we examined the effects of platycodon D on the production of reactive oxygen species (ROS) and evaluated the association of these effects with apoptotic tumor cell death using a human leukemic U937 cell line. The results of this study demonstrate that platycodon D mediates ROS production, and that this mediation is followed by a decrease in mitochondrial membrane potential (MMP, DJm), activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Both the cytotoxic effects and apoptotic characteristics induced by platycodon D treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 plays in the observed cytotoxic effect. Additionally, the transcription factor early growth response-1 (Egr-1) gene was transcriptionally activated and the levels of non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) protein were elevated in platycodon D-treatedU937 cells. However, the quenching of ROS generation in response to treatment with a ROS scavenger, N-acetyl-L-cysteine, reversed the platycodon D-induced apoptosis effects via inhibition of Egr-1 activation, ROS production, MMP collapse, and the subsequent activation of caspase-3. Although further studies are needed to demonstrate that increased expression of Egr-1 by platycodon D leads directly to NAG-1 induction and subsequent apoptosis, our observations clearly indicate that ROS induced through Egr-1 activation are involved in the early molecular events involved in the platycodon D-induced apoptotic pathway.
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PMID:Implication of intracellular ROS formation, caspase-3 activation and Egr-1 induction in platycodon D-induced apoptosis of U937 human leukemia cells. 1880 40

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