Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FTY720 has immunosuppressive activity in experimental organ transplantation and shows a prompt and protracted decrease of blood T lymphocytes upon oral administration. The blood lymphocyte decrease in vivo was mainly a result of FTY720-induced apoptosis. However, this apoptotic mechanism is not well understood. We examined the mechanism of FTY720-induced apoptosis in lymphoma. Western blotting and fluorescent caspase-specific substrate revealed that caspase-3 is involved in FTY720-induced apoptosis, whereas caspase-1 is not. Apoptotic cell death was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, suggesting that caspase activation is essential for FTY720-induced apoptosis. FTY720 reduced mitochondrial transmembrane potential and released cytochrome c from the mitochondria of intact cells as well as in a cell-free system even in the presence of Z-VAD-FMK. As these mitochondrial reactions occurred before caspase activation, we concluded that FTY720 directly influences mitochondrial functions. The inhibition of mitochondrial permeability transition by Bcl-2 overexpression or by chemical inhibitors prevented all apoptotic events occurring in intact cells and in a cell-free system. Moreover, using a cell-free system, FTY720 did not directly affect isolated nuclei or cytosol. These results indicate that FTY720 directly affects mitochondria and triggers permeability transition to induce further apoptotic events.
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PMID:Immunosuppressant FTY720 induces apoptosis by direct induction of permeability transition and release of cytochrome c from mitochondria. 1097 41

The representational difference analysis (RDA) and other subtraction techniques are used to enrich sample-specific sequences by elimination of ubiquitous sequences existing in both the sample of interest (tester) and the subtraction partner (driver). While applying the RDA to genomic DNA of cutaneous lymphoma cells in order to identify tumor relevant alterations, we predominantly isolated repetitive sequences and artificial repeat-mediated fusion products of otherwise independent PCR fragments (PCR hybrids). Since these products severely interfered with the isolation of tester-specific fragments, we developed a considerably more robust and efficient approach, termed ligation-mediated subtraction (Limes). In first applications of Limes, genomic sequences and/or transcripts of genes involved in the regulation of transcription, such as transforming growth factor beta stimulated clone 22 related gene (TSC-22R), cell death and cytokine production (caspase-1) or antigen presentation (HLA class II sequences), were found to be completely absent in a cutaneous lymphoma line. On the assumption that mutations in tumor-relevant genes can affect their transcription pattern, a protocol was developed and successfully applied that allows the identification of such sequences. Due to these results, Limes may substitute/supplement other subtraction/comparison techniques such as RDA or DNA microarray techniques in a variety of different research fields.
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PMID:Identification of sample-specific sequences in mammalian cDNA and genomic DNA by the novel ligation-mediated subtraction (Limes). 1116 Sep 40

This study examined the growth inhibitory effects of theasinensin A (from oolong tea) and black tea polyphenols, including theaflavin (TF-1), a mixture (TF-2) of theaflavin-3-gallate (TF-2a) and theaflavin-3'-gallate (TF-2b), and theaflavin-3,3'-digallate (TF-3) in human cancer cells. Theasinensin A, TF-1, and TF-2 displayed strong growth inhibitory effects against human histolytic lymphoma U937, with estimated IC50 values of 12 microM, but were less effective against human acute T cell leukemia Jurkat, whereas TF-3 and (-)-epigallocatechin-3-gallate (EGCG) had lower activities. The molecular mechanisms of tea polyphenol-induced apoptosis as determined by annexin V apoptosis assay, DNA fragmentation, and caspase activation were further investigated. Loss of membrane potential and reactive oxygen species (ROS) generation were also detected by flow cytometry. Treatment with tea polyphenols caused rapid induction of caspase-3, but not caspase-1, activity and stimulated proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Pretreatment with a potent caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethyl ketone, inhibited theasinensin A induced DNA fragmentation. Furthermore, it was found that theasinensin A induced loss of mitochondrial transmembrane potential, elevation of ROS production, release of mitochondrial cytochrome c into the cytosol, and subsequent induction of caspase-9 activity. These results indicate that theasinensin A allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. The results suggest that induction of apoptosis by theasinensin A may provide a pivotal mechanism for their cancer chemopreventive function.
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PMID:Induction of apoptosis by the oolong tea polyphenol theasinensin A through cytochrome c release and activation of caspase-9 and caspase-3 in human U937 cells. 1131 5

Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently discovered human tumour virus, is the causative agent of Kaposi's sarcoma, primary effusion lymphoma and some forms of Castleman's disease. KSHV is a rhadinovirus, and like other rhadinoviruses, it has an extensive array of regulatory genes obtained from the host cell genome. These pirated KSHV proteins include homologues to cellular CD21, three different beta-chemokines, IL-6, BCL-2, several different interferon regulatory factor homologues, Fas-ligand ICE inhibitory protein (FLIP), cyclin D and a G-protein-coupled receptor, as well as DNA synthetic enzymes including thymidylate synthase, dihydrofolate reductase, DNA polymerase, thymidine kinase and ribonucleotide reductases. Despite marked differences between KSHV and Epstein-Barr virus, both viruses target many of the same cellular pathways, but use different strategies to achieve the same effects. KSHV proteins have been identified which inhibit cell-cycle regulation checkpoints, apoptosis control mechanisms and the immune response regulatory machinery. Inhibition of these cellular regulatory networks app ears to be a defensive means of allowing the virus to escape from innate antiviral immune responses. However, due to the overlapping nature of innate immune and tumour-suppressor pathways, inhibition of these regulatory networks can lead to unregulated cell proliferation and may contribute to virus-induced tumorigenesis.
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PMID:Molecular virology of Kaposi's sarcoma-associated herpesvirus. 1131 14

Between 1989 and 1999 we studied the ICE regimen in sequential trials in 290 patients with malignant lymphoma and germ-cell tumours. For patients with relapsed or refractory lymphoma we could demonstrate a comparable efficacy of ICE to other high-dose chemotherapy (HDCT) regimens but with a toxicity profile in favour of ICE. From a retrospective comparative analysis of ICE as HDCT regimen in patients with malignant lymphoma and germ-cell tumours we conclude that the characteristic toxicity profile of ICE varies depending on prior drug exposure of individual patients. Further dose intensification of ICE may be achieved with acceptable toxicity by adding further drugs (e.g. anthracyclines) or by treatment with sequential cycles of ICE (Tandem-HDCT). More convenient drug formulations (e.g. etoposide phosphate) might further improve the therapeutic index of ICE.
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PMID:ICE--an efficient drug combination for stem cell mobilization and high-dose treatment of malignant lymphoma. 1148 2

The value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/m2 x 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 x 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m2 daily x 5, idarubicin x 2, etoposide x 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P = .66), survival following randomization (61% vs 62%; P = .91), or the cumulative incidence of relapse (43% vs 51%; P = .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit.
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PMID:A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. 1521 95

Hepatitis C virus (HCV) core protein features many intriguing properties and plays a pivotal role in cellular immunity, cell growth, apoptosis, cell transformation, and eventually in tumor development. However, the role of B cells, the primary players in the humoral immune response, during HCV infection is largely unknown. To explore the molecular effects of HCV core on human B cells, we conducted gene expression profiling of serial RNA samples from B cells that were infected with adenovirus harboring full-length HCV core protein and beta-galactosidase as a reference using a microarray platform containing 22,149 human oligo probes. The entire experiment was performed in duplicate in B lymphocytes that were isolated from two individual donors and incubated for up to 3 days after infection with adenovirus expressing HCV core protein to identify dynamic gene expression patterns. Differential expression of representative genes was validated by quantitative RT-PCR. We found that HCV core significantly inhibited B-lymphocyte apoptosis. We showed a dramatic downregulation of MHC class II molecules in B cells expressing HCV core, whereas the expression of immunoglobulin genes was not significantly altered. Moreover, genes associated with leukemia and B-lymphoma were consistently upregulated by HCV core. In contrast, downregulation of caspase-1 and caspase-4 was found to be associated with core's ability to prevent B-lymphocyte apoptosis. In summary, we have identified several clusters of genes that are differentially expressed in human B lymphocytes expressing HCV core, suggesting a potential impairment of antigen processing and presentation, which may provide more insights into HCV infection in B lymphocytes.
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PMID:Effect of hepatitis C virus core protein on the molecular profiling of human B lymphocytes. 1683 65

Chemotherapy-susceptive multiple myeloma (MM) has an indication for high-dose melphalan (HDM) followed by autologous stem cell transplantation (auto-SCT). HDM was a most simple and convenient regimen among various preparatory regimens, because of rapid infusion divided over 2 days. In order to assess the potential of auto-SCT by HDM in a outpatient setting, we evaluated the toxicities of HDM compared with the ICE regimen generally applied to patients with refractory or relapsed lymphoma. We reviewed 27 cases of auto-SCT from April 2003 to December 2004. The preparatory regimen was HDM (melphalan 200 mg/m(2)) for 18 cases of multiple myeloma and ICE therapy (ifosfamide 12 g/m (2), carboplatin 1,200 mg/m(2), etoposide 800 mg/m2) for 9 malignant lymphomas. Gastrointestinal (GI) adverse events for a patient per hospital day were 0.93 for myeloma and 0.95 for lymphoma (no significant differences), with GI toxicity of more than grade 3, 0.08 and 0.12, respectively (p=0.07). Hematological toxicity was not significantly different between the 2 therapies. The clinical toxicity of HDM was milder compared to ICE, especially regarding the speculated GI-associated nutritional disorders. We thus concluded that outpatient auto-SCT could be validated first in myeloma patients treated by HDM with careful supportive treatments, thereby avoiding regimen-related severe adverse events.
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PMID:[Comparison of regimen-related toxicity between high-dose melphalan and ICE as a preparatory regimen for autologous stem cell transplantation]. 1794 Mar 79

Two commonly used chemotherapy regimens for lymphoma salvage therapy were compared: ICE (ifosphamide, carboplatin and etoposide) +/- rituximab and IVE (ifosfamide, epirubicin and etoposide) +/- rituximab, for their efficacy in mobilising peripheral blood stem cells for autologous transplantation. Significant differences were observed between the cohorts in terms of number of patients mobilising the stipulated minimum >2 x 10(6) CD34+/kg (99.2% in IVE group versus 83% in ICE group: P = 0.0002) and also in terms of the number of patients achieving the predetermined target of >5 x 10(6) CD34+/kg, both in total and during the first apheresis procedure (72% in IVE versus 51% in ICE group and 49% in IVE versus 7% in ICE group: P = 0.02 and P < 0.0001 respectively). This analysis of two similar groups of patients treated within a single-centre appears to demonstrate that the IVE regimen is a more effective stem cell mobilisation regimen than ICE in the context of salvage therapy for Hodgkin and non-Hodgkin lymphoma, allowing more patients to achieve the target CD34+ cell collection and proceed to high-dose therapy and autologous stem cell transplantation.
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PMID:IVE (ifosfamide, epirubicin and etoposide) is a more effective stem cell mobilisation regimen than ICE (ifosphamide, carboplatin and etoposide) in the context of salvage therapy for lymphoma. 1835 64

The ALP (alkyl-lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) induces apoptosis in S49 mouse lymphoma cells. A variant cell line, S49AR, made resistant to ALP, was found previously to be impaired in ALP uptake via lipid-raft-mediated endocytosis. In the present paper, we report that these cells display cross-resistance to Fas/CD95 ligation [FasL (Fas ligand)], and can be gradually resensitized by prolonged culturing in the absence of ALP. Fas and ALP activate distinct apoptotic pathways, since ALP-induced apoptosis was not abrogated by dominant-negative FADD (Fas-associated protein with death domain), cFLIP(L) [cellular FLICE (FADD-like interleukin 1beta-converting enzyme)-inhibitory protein long form] or the caspase 8 inhibitor Z-IETD-FMK (benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone). ALP-resistant cells showed decreased Fas expression, at both the mRNA and protein levels, in a proteasome-dependent fashion. The proteasome inhibitor MG132 partially restored Fas expression and resensitized the cells to FasL, but not to ALP. Resistant cells completely lacked SM (sphingomyelin) synthesis, which seems to be a unique feature of the S49 cell system, having very low SM levels in parental cells. Lack of SM synthesis did not affect cell growth in serum-containing medium, but retarded growth under serum-free (SM-free) conditions. SM deficiency determined in part the resistance to ALP and FasL. Exogenous short-chain (C12-) SM partially restored cell-surface expression of Fas in lipid rafts and FasL sensitivity, but did not affect Fas mRNA levels or ALP sensitivity. We conclude that the acquired resistance of S49 cells to ALP is associated with down-regulated SM synthesis and Fas gene transcription and that SM in lipid rafts stabilizes Fas expression at the cell surface.
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PMID:Fas/CD95 down-regulation in lymphoma cells through acquired alkyllysophospholipid resistance: partial role of associated sphingomyelin deficiency. 1982 85


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