Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-CD20 monoclonal antibody rituximab (Rituxan, IDEC-C2B8) has shown promising results in the clinical treatment of a subset of patients with low grade or follicular non-Hodgkin's lymphoma (NHL). However, chemotherapy- and rituximab-refractory NHL patients may benefit from a regimen in which rituximab acts as a sensitizing agent. This study examined the apoptotic signaling mediated by rituximab on rituximab- and paclitaxel-resistant CD20(+) NHL B cell lines (Ramos, Raji, Daudi, and 2F7). Treatment with either rituximab (20 micro g/ml) or paclitaxel (0.1-1000 nM) inhibited viable cell recovery of NHL lines. Neither rituximab nor paclitaxel induced significant apoptosis, although the combination treatment resulted in synergy in apoptosis. Rituximab selectively down-regulated Bcl-xL and induced apoptosis protease activating factor 1 (Apaf-1) expressions in Ramos cells. Paclitaxel down-regulated the expression of Bcl-xL and inhibitor of apoptosis proteins (c-IAP-1) and up-regulated the expression of Bad and Apaf-1. The combination treatment resulted in the formation of truncated Bid, cytosolic accumulation of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI, activation of caspase-9, caspase-7, caspase-3, and cleavage of poly(ADP-ribose) polymerase. The findings identify two potential novel intracellular targets of rituximab-mediated signaling in Ramos NHL cells (i.e., Bcl-xL and Apaf-1). Further, the findings show that both rituximab and paclitaxel selectively modify the expression pattern of proteins involved in the apoptosis signal transduction pathway and, through functional complementation, the combination results in synergy in apoptosis. The potential therapeutic significance of these findings is discussed.
 ...
PMID:Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis. 1461 92

Renal cell carcinoma (RCC) responds very poorly to chemo- or radiotherapy. Renal cell carcinoma cell lines have been described to be resistant to apoptosis-inducing stimuli and to lack caspase expression. Here, we provide a structural and functional assessment of the apoptosome, the central caspase-activating signalling complex and a candidate for apoptosis-inactivating mutations. Cells from RCC cell lines and clinical samples isolated from RCC patients were included. Apoptosome function was measured as quantitative activation of caspases in protein extracts. In all five cell lines and in 19 out of 20 primary clear cell RCC samples, the expression of apoptosome components and caspase activation appeared normal. Of the four nonclear cell RCC that could be included, both oncocytomas gave no response to cytochrome c (in one case, no Apaf-1 was detected), one chromophobe RCC lacked caspase-9 and failed to activate caspase-3 in response to cytochrome c, and one papillary RCC showed good caspase activation despite the lack of caspase-7. Experiments utilising a peptide derived from Smac/DIABLO gave no indication that inhibitor of apoptosis proteins might exert an inhibiting effect in primary clear cell RCC. Thus, the apoptosome signalling complex is intact in human (clear cell) RCC, and an apoptosis defect must be located at other, probably upstream, sites.
 ...
PMID:Functional evaluation of the apoptosome in renal cell carcinoma. 1464 51

Azurin, a copper-containing redox protein released by the pathogenic bacterium Pseudomonas aeruginosa, is highly cytotoxic to the human breast cancer cell line MCF-7, but is less cytotoxic toward p53-negative (MDA-MB-157) or nonfunctional p53 cell lines like MDD2 and MDA-MB-231. The purpose of this study was to investigate the underlying mechanism of the action of bacterial cupredoxin azurin in the regression of breast cancer and its potential chemotherapeutic efficacy. Azurin enters into the cytosol of MCF-7 cells and travels to the nucleus, enhancing the intracellular levels of p53 and Bax, thereby triggering the release of mitochondrial cytochrome c into the cytosol. This process activates the caspase cascade (including caspase-9 and caspase-7), thereby initiating the apoptotic process. Our results indicate that azurin-induced cell death stimuli are amplified in the presence of p53. In vivo injection of azurin in immunodeficient mice harboring xenografted human breast cancer cells in the mammary fat pad leads to statistically significant regression (85%, P = 0.0179, Kruskal-Wallis Test) of the tumor. In conclusion, azurin blocks breast cancer cell proliferation and induces apoptosis through the mitochondrial pathway both in vitro and in vivo, thereby suggesting a potential chemotherapeutic application of this bacterial cupredoxin for the treatment of breast cancer.
 ...
PMID:Bacterial cupredoxin azurin as an inducer of apoptosis and regression in human breast cancer. 1498 43

Apoptosis protease-activating factor-1 (Apaf-1), which plays a central role in the formation of the apoptosome, is absent or poorly expressed (because of a transcriptional silencing by methylation) in a substantial percentage of metastatic melanomas and melanoma cell lines, which are unable to activate caspase-9 and execute the mitochondrial pathway of apoptosis. We studied cisplatin-induced apoptosis of the Apaf-1-positive human metastatic Me665/2/21 melanoma cells. Our results indicate that caspase-7 is already processed in still-adhering cells and such activation, contrary to the common view, precedes caspase-3 processing. As expected by the cytochrome c release into the cytosol, caspase-9 is processed to active forms (p37 and p35), along with a yet-unidentified p28. Interestingly, we also demonstrate a remarkable loss of Apaf-1 protein, along with the appearance of a related immunoreactive fragment of approximate, equals 26 kDa; such proteolytic degradation proves to be a caspase-3/-7-mediated event. Our data also indicate that the inhibition afforded by ac-DEVD-CHO on several components (i.e., caspase-3/-7 and caspase-9 activities), and Apaf-1 proteolytic degradation, does not significantly abrogate either the apoptotic morphology or the cleavage of canonical targets, such as poly(ADP-ribose) polymerase (PARP) and lamin B. These results suggest that caspase-3 and caspase-7 are dispensable for the execution of apoptosis and, in our cellular model, the point of no return could be out of the mitochondrial cascade.
 ...
PMID:Cisplatin-induced apoptosis in melanoma cells: role of caspase-3 and caspase-7 in Apaf-1 proteolytic cleavage and in execution of the degradative phases. 1503 20

The analgesic buprenorphine hydrochloride (Bph) induced apoptosis-like cell death in the caspase-3-deficient human breast cancer cell line, MCF-7. This apoptosis-like cell death activated key molecules in the mitochondrial apoptotic pathway: cytochrome c, caspase-9, caspase-7, and caspase-6. Bph caused the release of fluorescent protein from the mitochondria of MCF-7 cells transfected with the pDsRed2-Mito-vector in a time-dependent manner, suggesting disruption of the mitochondrial membrane. Zn(2+) as high as 2 mM did not inhibit the DNase that took part in this apoptosis. Thus, this unidentified DNase might resemble other DNases involved in apoptosis-like cell death whose activity is not inhibited by zinc ion.
 ...
PMID:Apoptosis-like cell death of human breast cancer cell line MCF-7 induced by buprenorphine hydrochloride. 1513 50

Screening of 26 gut peptides for their ability to inhibit growth of human colon cancer HT29-D4 cells grown in 10% fetal calf serum identified orexin-A and orexin-B as anti-growth factors. Upon addition of either orexin (1 microM), suppression of cell growth was total after 24 h and >70% after 48 or 72 h, with an EC(50) of 5 nm peptide. Orexins did not alter proliferation but promoted apoptosis as demonstrated by morphological changes in cell shape, DNA fragmentation, chromatin condensation, cytochrome c release into cytosol, and activation of caspase-3 and caspase-7. The serpentine G protein-coupled orexin receptor OX(1)R but not OX(2)R was expressed in HT29-D4 cells and mediated orexin-induced Ca(2+) transients in HT29-D4 cells. The expression of OX(1)R and the pro-apoptotic effects of orexins were also indicated in other colon cancer cell lines including Caco-2, SW480, and LoVo but, most interestingly, not in normal colonic epithelial cells. The role of OX(1)R in mediating apoptosis was further demonstrated by transfecting Chinese hamster ovary cells with OX(1)R cDNA, which conferred the ability of orexins to promote apoptosis. A neuroblastoma cell line SK-N-MC, which expresses OX(1)R, also underwent growth suppression and apoptosis upon treatment with orexins. Promotion of apoptosis appears to be an intrinsic property of OX(1)R regardless of the cell type where it is expressed. In conclusion, orexins, acting at native or recombinant OX(1)R, are pro-apoptotic peptides. These findings add a new dimension to the biological activities of these neuropeptides, which may have important implications in health and disease, in particular colon cancer.
 ...
PMID:Orexins acting at native OX(1) receptor in colon cancer and neuroblastoma cells or at recombinant OX(1) receptor suppress cell growth by inducing apoptosis. 1531 Jul 63

Alkylphosphocholines (APC) are candidate anticancer agents. We here report that APC induce the formation of large vacuoles and typical features of apoptosis in human glioma cell lines, but not in immortalized astrocytes. APC promote caspase activation, poly(ADP-ribose)-polymerase (PARP) processing and cytochrome c release from mitochondria. Adenoviral X-linked inhibitor of apoptosis (XIAP) gene transfer, or exposure to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoro-methylketone zVAD-fmk, blocks caspase-7 and PARP processing, but not cell death, whereas BCL-X(L) blocks not only caspase-7 and PARP processing but also cell death. APC induce changes in Delta Psi m in sensitive glioma cells, but not in resistant astrocytes. The changes in Delta Psi m are unaffected by crm-A (cowpox serpin-cytokine response modifier protein A), XIAP or zVAD-fmk, but blocked by BCL-X(L), and are thus a strong predictor of cell death in response to APC. Free radicals are induced, but not responsible for cell death. APC thus induce a characteristic morphological, BCL-X(L)-sensitive, apparently caspase-independent cell death involving mitochondrial alterations selectively in neoplastic astrocytic cells.
 ...
PMID:Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation. 1538 88

Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.
 ...
PMID:Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. 1564 37

Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, which is a product of lipid peroxidation. It is an environmental pollutant that has been implicated in multiple respiratory diseases. Acrolein is produced by the enzymatic oxidative deamination of spermine by amine oxidase. Oxidation products of polyamines have been involved in the inhibition of cell proliferation, apoptosis, and the inhibition of DNA and protein synthesis. The present study investigates the mechanism of cell death induced by acrolein. Acrolein induced apoptosis through a decrease in mitochondrial membrane potential, the liberation of cytochrome c, the activation of initiator caspase-9, and the activation of the effector caspase-7. However, acrolein inhibited enzymatic activity of the effector caspase-3, although a cleavage of pro-caspase-3 occurred. The activation of caspases-9 and -7 was confirmed by the cleavage of their pro-enzyme form by acrolein. Apoptosis was inhibited by an inhibitor of caspase-9, but not by an inhibitor of caspase-3. The induction of apoptosis by acrolein was confirmed morphologically by the condensation of nuclear chromatin and by the cleavage of the inhibitor of caspase activated DNase (ICAD), which leads to the liberation of CAD that causes DNA fragmentation. These results demonstrate that acrolein causes apoptosis through the mitochondrial pathway.
 ...
PMID:The aldehyde acrolein induces apoptosis via activation of the mitochondrial pathway. 1584 39

Interferon (IFN)-alpha directly inhibits proliferation of liver cancer cells by inducing apoptosis, but the molecular mechanisms by which IFN-alpha induces apoptosis in these cells are not fully understood. We examined the effect of broad spectrum caspase inhibitor, Z-VAD-fmk, and the caspase activation in IFN-alpha-mediated apoptosis by using 4 liver cancer cell lines that were sensitive or resistant to IFN-alpha-mediated apoptosis. Involvement of apoptosis-related mitochondrial proteins and Bcl-2 family proteins in IFN-alpha-mediated apoptosis was further examined in 1 sensitive cell line (KIM-1). The Z-VAD-fmk completely or moderately inhibited IFN-alpha-mediated apoptosis in the sensitive cells. IFN-alpha induced time-dependent activation of caspase-3 in the sensitive cells, while the resistant cells showed mild or no activation. Activation of caspase-9, caspase-8, and caspase-7, and the cleavage of poly(ADP-ribose)polymerase were identified in either or both of the sensitive cell lines, but not in the resistant cells. In KIM-1 cells, the release of cytochrome c and Smac/DIABLO from mitochondria to cytosole was confirmed. Meanwhile, Bcl-xL was upregulated, and Bid activation or translocation, or conformational changes of Bax were not identified. In conclusion, our results suggest IFN-alpha-mediated apoptosis in liver cancer cells involves the mitochondrial apoptotic pathway and is induced by activating various caspases.
 ...
PMID:Expression and activation of apoptosis-related molecules involved in interferon-alpha-mediated apoptosis in human liver cancer cells. 1587 Aug 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>