Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Chlorella powder was screened using 52 in vitro assay systems for enzyme activity, receptor binding, cellular cytokine release, and B and T cell proliferation. The screening revealed a very potent inhibition of human protein tyrosine phosphatase (PTP) activity of CD45 and PTP1C with 50% inhibitory concentration (IC(50)) values of 0.678 and 1.56 microg/mL, respectively. It also showed a moderate inhibition of other PTPs, including PTP1B (IC(50) = 65.3 microg/mL) and T-cell-PTP (114 microg/mL). Other inhibitory activities and their IC(50) values included inhibition of the human matrix metalloproteinases (MMPs) MMP-1 (127 microg/mL), MMP-3 (185 microg/mL), MMP-7 (18.1 microg/mL), and MMP-9 (237 microg/mL) and the human peptidase caspases caspase 1 (300 microg/mL), caspase 3 (203 microg/mL), caspase 6 (301 microg/mL), caspase 7 (291 microg/mL), and caspase 8 (261 microg/mL), as well as release of the cytokines interleukin (IL)-1 (44.9 microg/mL), IL-2 (14.8 microg/mL), IL-4 (49.2 microg/mL), IL-6 (34.7 microg/mL), interferon-gamma (31.6 microg/mL), and tumor necrosis factor-alpha (11 microg/mL) from human peripheral blood mononuclear cells. Chlorella also inhibited B cell proliferation (16.6 microg/mL) in mouse splenocytes and T cell proliferation (54.2 microg/mL) in mouse thymocytes. The binding of a phorbol ester, phorbol 12,13-dibutyrate, to its receptors was also inhibited by Chlorella with an IC(50) of 152 microg/mL. These results reveal potential pharmacological activities that, if confirmed by in vivo studies, might be exploited for the prevention or treatment of several serious pathologies, including inflammatory disease and cancer.
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PMID:Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding. 1529 60

Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with lung epithelial cells. Apoptosis of lung epithelium is involved in some bacterial lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H(2)O(2). Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin- and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.
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PMID:Streptococcus pneumoniae-induced caspase 6-dependent apoptosis in lung epithelium. 1532 85

During the physiological process of PCD, the cell initiates a sequence of events culminating in the disintegration of the cell into small, membrane-bound apoptotic bodies. The intrinsic part of the PCD program arises from the mitochondria when it releases cytochrome c from the mitochondrial intermembrane space into the cytosol, forming the caspase-activating complex or apoptosome. The family of caspases is involved in the execution of genetically controlled PCD. Caspase-3 is expressed in normal and neoplastically transformed human cells and, like other caspases, is synthesized as an inactive, 32kDa proenzyme. Caspase-6 cleaves nuclear mitotic apparatus protein (NuMA) and mediates the shrinkage and fragmentation of cell nuclei. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis, while caspase-9 is the initiator caspase in the caspase cascade in apoptotic normal and neoplastically transformed cells. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did in fact demonstrate the presence of high apoptotic activity within the cellular microenvironment of high-grade astrocytomas and glioblastomas. The observations identified cytoplasmic expression of caspase-3 and caspase-6 in more than 50 per cent of tumor cells, caspase-8 and caspase-9 in more than 10 per cent of tumor cells in high-grade anaplastic ASTR and glioblastoma. The immunocytochemical expression pattern in about 10 per cent of the tumor cells for caspase-3 and caspase-6 and about 1 to 5 per cent of the tumor cells for caspase-8 and caspase-9 demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that caspase-3, -6, -8 and -9 immunocytochemistry could have prognostic and immunotherapeutic significance in the treatment of these highly malignant glial tumors.
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PMID:Immunocytochemical detection of members of the caspase cascade of apoptosis in high-grade astrocytomas. 1552 99

The anti-proliferative effects of a novel bromomethoxylated arylphosphate derivative of zidovudine (compound DDE46, CAS 213982-96-8) were first examined in a zebra fish embryo model. DDE46 blocked the cell division at the 2-cell stage of the embryonic development followed by total cell fusion. DDE46 also inhibited the proliferation of the leukemic cell lines NALM-6 and MOLT-3. DDE46 enhanced the activity of the pro-apoptotic enzymes Caspase-3, Caspase-6, Caspase-8, and Caspase-9 leading to the apoptotic death of the leukemic cell line Jurkat. These results justify the further development of this agent as a new anti-leukemic drug candidate.
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PMID:Anti-proliferative and anti-leukemic activity of DDE46 (compound WHI-07), a novel bromomethoxylated arylphosphate derivative of zidovudine, and related compounds. Studies using human acute lymphoblastic leukemia cells and the zebrafish model. 1578 79

alphaB-crystallin has been demonstrated, in tissue culture experiments, to be a caspase 3 inhibitor; however, no animal model studies have yet been described. Here, we show that morphological abnormalities in lens secondary fiber cells of alphaA-/alphaB-crystallin gene double knockout (DKO) mice are consistent with, and probably result from, elevated DEVDase and VEIDase activities, corresponding to caspase 3 and caspase 6, respectively. Immunofluorescence microscopy revealed an increased amount of caspase 6, and the active form of caspase 3, in specific regions of the DKO lens, coincident with the site of cell disintegration. TUNEL labeling illustrated a higher level of DNA fragmentation in the secondary fiber lens cells of DKO mice, compared with wild-type mice. Using a pull-down assay, we show interaction between caspase 6 and alphaA- but not alphaB-crystallin. These studies suggest that alpha-crystallin plays a role in suppressing caspase activity, resulting in retention of lens fiber cell integrity following degradation of mitochondria and other organelles, which occurs during the apoptosis-like pathway of lens cell terminal differentiation.
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PMID:Caspase-dependent secondary lens fiber cell disintegration in alphaA-/alphaB-crystallin double-knockout mice. 1643 75

The possible anti-proliferation and cell death induction potential of a novel microbial fermentation extract named as oncogen XP-180 (or simply as XP-180) was tested on three human solid tumour carcinoma cell lines (non-small cell lung cancer A549, breast cancer MDA-MB231, liver adenocarcinoma SK-Hep1) and on the acute myelogenous leukaemia KG1a cell line. Anti-proliferative activity of XP-180 was observed on all of these cancer cell lines with comparable efficiency and in a dose-dependent manner. Morphological investigation further suggested that common features of apoptosis, including cell shrinkage and rounding, are present in XP-180 treated cells. Loss of adhesion properties of these solid tumour cell lines was observed upon XP-180 incubation. Anchorage-dependent clonogenicity assay on solid tumour cell lines and semi-solid methylcellulose colony formation assay on leukaemia cell line further revealed that XP-180 strongly inhibited the regeneration potential of these cancer cells. Using KG1a as an experimental model system, XP-180 was shown to stimulate the activity of caspase 3, 8 and 9 without significant change in caspase 6 activity. Furthermore, XP-180 readily induced collapse of mitochondrial membrane potential after 2 h of incubation. However, the use of the generic caspase specific inhibitor Z-VAD-FMK does not significantly reverse XP-180 mediated cell death. The results obtained suggest that XP-180-mediated cancer cell death could involve mitochondria and both caspase-dependent and -independent pathways. Therefore, XP-180 is an efficient anti-cancer regimen in vitro.
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PMID:In vitro anti-cancer activity of a novel microbial fermentation product on human carcinomas. 1652 27

The PTEN/Akt signal pathway plays an important role in tumorigenesis. Mutations or deletions of PTEN have been observed in up to 60% of melanoma cell lines, resulting in PI3K/Akt activation. The Forkhead family of transcription factors induce apoptosis in their unphosphorylated forms and were recently reported to be a substrate of Akt kinase. In the present study, an adenovirus expressing a triple mutant (TM) of FKHRL1, which cannot be phosphorylated by Akt, was assessed for its ability to induce apoptosis in melanoma cells. Marked overexpression of FKHRL1/TM was evident in the SK-MEL-2 cell line 24 hours after infection with Ad-FKHRL1/TM by Western blot analysis. The expression of FKHRL1/ TM was moderately delayed in SK-MEL-28 cells. Overexpression of FKHRL1/TM can efficiently inhibit melanoma cell growth and result in rapid loss of cell viability. Cell cycle analysis showed overexpression of FKHRL1/TM in both melanoma cell lines resulted in development of a Sub-G1 population, indicating apoptosis by Ad-FKHRL1/TM infection. Apoptosis was confirmed by morphologic inspection, poly-ADP-ribosepolymerase (PARP) cleavage assay, and annexin V-PE analysis. After Ad-FKHRL1/TM infection, the expression of Bax and Bak did not differ markedly, whereas Mcl-1 and Bcl-x(L) levels decreased markedly. Involvement of caspase 3 and 6 in FKHRL1/TM-mediated apoptosis was demonstrated by cleavage of caspase 3/CPP32 and PARP as well as fragmentation of the caspase 6 substrate lamin B in SK-MEL-2 cells as early as 24 hours after Ad-FKHRL1/ TM infection, but those events were delayed 72 hours in SK-MEL-28. In addition, we found that p27(kip1) was cleaved in SK-MEL-2 cells at 24 hours after treatment with Ad-FKHRL1/TM. This cleavage was observed in SK-MEL-28 cells until 72 hours after infection with Ad-FKHRL1/TM. Our data suggest that adenovirus expressing a FKHRL1 triple mutant could be a useful vector for gene therapy of cancers resistant to chemotherapy and radiotherapy induced by hyperactivity of PI3K/Akt.
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PMID:Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells. 1686 5

Caspases are the main point in the apoptotic process. We have collected some information from 210 cases of Ductal breast cancer (pT1 - pT2) such as tumour size, histological differentiation degree, lymph node status and tumor necrosis in the infiltrating component and we have evaluated the number of apoptotic cells or bodies by TUNEL technique as well as immunohistochemical studies to evaluate the expression of caspase 3 and caspase 6, and proliferation index. Our results show that lymph node status and cell atypism are independent prognostic factors for recurrence and mortality and only tumour size is an independent prognostic factor for recurrence. However, the apoptotic index and the immunohistochemical expression of caspases and cell proliferation index have not turned out to be independent prognostic factors neither for recurrence nor mortality. These results show that classic prognostic factors known until now are the most important factors to predict the evolution of the illness.
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PMID:Caspase-3 and caspase-6 in ductal breast carcinoma: a descriptive study. 1697 83

Ethacrynic acid (EA) significantly enhances the ototoxic effects of cisplatin. To gain insights into the mechanisms underlying Cis/EA ototoxicity, cochleas were labeled with several apoptotic markers. Cis/EA treatment caused extensive outer hair cell (OHC) and inner hair cell (IHC) damage; OHC lesions decreased from the base towards apex of the cochlea whereas the IHC lesion was relatively constant (25-60%) along the length of the cochlea. Propidium iodide labeled OHC nuclei appeared relatively normal at 6h post-treatment, were condensed and fragmented at 12h post-treatment and were frequently missing 48 h post-treatment. Initiator caspase 8, associated with membrane death receptors, and TRADD, a protein that recruits caspase 8, were present in OHC at 6h post-treatment. Caspase 8 labeling increased from 6 to 24h, but was largely absent at 48 h post-treatment. Executioner caspase 3 and caspase 6, which lie downstream of caspase 8, were expressed in OHC 12-24h post-treatment. Initiator caspase 9, associated with mitochondrial damage, was only expressed at low levels at 48 h post-treatment. These results suggest that the rapid onset of Cis/EA induced programmed cell death is initiated by membrane death receptors associated with TRADD and caspase 8.
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PMID:Cell death after co-administration of cisplatin and ethacrynic acid. 1697 14

Apoptosis is an important process involved in diverse developmental pathways, homeostasis, and response to therapy for a variety of diseases. Thus, noninvasive methods to study regulation and to monitor cell death in cells and whole animals are desired. To specifically detect apoptosis in vivo, a novel cell-permeable activatable caspase substrate, TcapQ647, was synthesized and Km, kcat, and Ki values were biochemically characterized. Specific cleavage of TcapQ647 by effector caspases was demonstrated using a panel of purified recombinant enzyme assays. Of note, caspase 3 was shown to cleave TcapQ647 with a kcat 7-fold greater than caspase 7 and 16-fold greater than caspase 6. No evidence of TcapQ647 cleavage by initiator caspases was observed. In KB 3-1 or Jurkat cells treated with cytotoxic agents or C6-ceramide, TcapQ647 detected apoptosis in individual- and population-based fluorescent cell assays in an effector caspase inhibitor-specific manner. Further, only background fluorescence was observed in cells incubated with dTcapQ647, a noncleavable all d-amino acid control peptide. Finally, in vivo experiments demonstrated the utility of TcapQ647 to detect parasite-induced apoptosis in human colon xenograft and liver abscess mouse models. Thus, TcapQ647 represents a sensitive, effector caspase-specific far-red "smart" probe to noninvasively monitor apoptosis in vivo.
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PMID:Biochemical and in vivo characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. 1734 87


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