Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Follicular lymphoma (FL) is the most common form of low-grade non-Hodgkin's lymphoma. Transformation to diffuse large B cell lymphoma (DLBCL) is an important cause of mortality. Using cDNA microarray analysis we identified 113 transformation-associated genes whose expression differed consistently between serial clonally related samples of FL and DLBCL occurring within the same individual. Quantitative RT-PCR validated the microarray results and assigned blinded independent group of 20 FLs, 20 DLBCLs, and five transformed lymphoma-derived cell lines with 100%, 70%, and 100% accuracy, respectively. Notably, growth factor cytokine receptors and p38beta-mitogen-activated protein kinase (MAPK) were differentially expressed in the DLBCLs. Immunohistochemistry of another blinded set of samples demonstrated expression of phosphorylated p38MAPK in 6/6 DLBCLs and 1/5 FLs, but not in benign germinal centers. SB203580 an inhibitor of p38MAPK specifically induced caspase-3-mediated apoptosis in t(14;18)+/p38MAPK+-transformed FL-derived cell lines. Lymphoma growth was also inhibited in SB203580-treated NOD-SCID mice. Our results implicate p38MAPK dysregulation in FL transformation and suggest that molecular targeting of specific elements within this pathway should be explored for transformed FL therapy.
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PMID:Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. 1275 97

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

In this study, a novel approach to antitumor therapy was devised by generating a chimeric tumor-targeted killer protein, referred to as immunocasp-3, that comprises a single-chain anti-erbB2/HER2 antibody with a NH(2)-terminal signal sequence, a Pseudomonas exotoxin A translocation domain, and a constitutively active caspase-3 molecule. In principle, cells transfected with the immunocasp-3 gene would express and secrete the chimeric protein, which then binds to HER2-overexpressing tumor cells. Subsequent cleavage of the constitutively active capase-3 domain from the immunocasp-3 molecule and its release from internalized vesicles would lead to apoptotic tumor cell death. To test this strategy, we transduced human lymphoma Jurkat cells with a chimeric immunocasp-3 gene expression vector and showed that they not only expressed and secreted the fusion protein but also selectively killed tumor cells overexpressing HER2 in vitro. i.v. injection of the transduced Jurkat cells led to tumor regression in a mouse xenograft model because of continuous secretion of immunocasp-3 by the transduced cells. The growth of HER2-positive tumor cells in this model was inhibited by i.m. as well as intratumor injection of immunocasp-3 expression plasmid DNA, indicating that the immunocasp-3 molecules secreted by transfected cells have systematic antitumor activity. We conclude that the immunocasp-3 molecule, combining the properties of a tumor-specific antibody with the proapoptotic activity of a caspase, has potent and selective antitumor activity, either as cell-based therapy or as a DNA vaccine. These findings provide a compelling rationale for therapeutic protocols designed for erbB2/HER2-positive tumors.
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PMID:Specific tumoricidal activity of a secreted proapoptotic protein consisting of HER2 antibody and constitutively active caspase-3. 1281 Jun 56

Rel/nuclear factor-kappaB (NF-kappaB) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-kappaB. Namely, JD inhibits tumor necrosis factor-alpha-induced activation of NF-kappaB in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-kappaB pathway by inhibiting the inhibitor of kappaB kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IkappaBalpha, inhibits the activity of a constitutively active form of the IKKbetacatalytic subunit, and converts IKKbetato stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-kappaB at 20 microM, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-kappaB at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-kappaB activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.
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PMID:Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase. 1281 68

Nitric oxide (NO) is an important modulator involved in immune regulation. Here, we describe conditions under which NO-donors induce apoptosis on Nb2 lymphoma cells, as evidenced by decreased cell viability and increased hypodiploid DNA content determined by flow cytometry. In addition, DNA fragmentation typical of apoptosis was shown by agarose gel electrophoresis. This apoptosis was accompanied by a significant increase of caspase-3-like enzymatic activity. Both ovine prolactin (oPRL) and ovine placental lactogen (oPL) exerted a protective effect on the NO-donor-induced apoptosis. Furthermore, dexamethasone (Dex)-induced cell death was also associated with caspase-3-like activity and oPL had the same potency as oPRL in its protective effect on Dex-induced apoptosis of Nb2 cells.
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PMID:Protective effect of prolactin and placental lactogen on NO-induced Nb2 lymphoma cell apoptosis. 1289 3

Magnolol, an active component extracted from Magnolia officinalis, has various pharmacological effects, including potent antioxidant activity. In the present study, we investigated the effect of magnolol on apoptosis in rat vascular smooth muscle cells (VSMCs), using terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and flow cytometric analysis. Magnolol (5-20 micro M) concentration-dependently induced significant VSMC apoptosis, this effect being blocked by the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk, 50 micro M). To study the molecular mechanism, the mitochondrial death pathway was examined. Magnolol increased caspase-3 and caspase-9 activities significantly and reduced the mitochondrial potential (Deltapsi(m)). The levels of B-cell leukaemia/lymphoma-2 (Bcl-2), but not those of Bcl-2-associated X protein (Bax) or Bcl-x(L), were down-regulated concentration dependently by magnolol. In an animal model, balloon angioplasty-induced neointima formation was inhibited significantly by magnolol and Bcl-2 protein levels were reduced. Taken together, these results show that magnolol induces apoptosis in VSMCs via the mitochondrial death pathway. This effect is mediated through down-regulation of Bcl-2 protein levels, both in vivo and in vitro. Magnolol thus shows potential as a novel therapeutic agent for the treatment of atherosclerosis and re-stenosis.
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PMID:Magnolol induces apoptosis in vascular smooth muscle. 1289 28

FL5.12 pro-B lymphoma cells utilize the mitochondrial pathway to apoptosis in response to tumor necrosis factor (TNF) receptor occupation, yet high levels of the Bcl-2 family antiapoptotic protein, Bcl-x(L), fail to protect these cells against TNF-receptor-activated death. Bcl-x(L) expression delays, but does not totally block, the release of mitochondrial cytochrome c (cyt c) in these cells in response to TNFalpha-induced apoptosis and caspase-9 is processed prior to mitochondrial cyt c release under these circumstances. Early processing of caspase-9 also occurred in Apaf-1 knockout murine fibroblasts in response to TNF-receptor occupation. A caspase-9-specific inhibitor was more effective in delaying the progression of apoptosis in the FL5.12 Bcl-x(L) cells than was an inhibitor specific to caspase-3. Furthermore, downregulation of caspase-9 levels by RNA interference resulted in partial protection of these cells against TNF-receptor-activated apoptosis, indicating that caspase-9 activation contributed to early amplification of the caspase cascade. Consistent with this, proteolytic processing of caspase-9 was observed prior to processing by caspase-3, suggesting that caspase-3 was not responsible for early caspase-9 activation. We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome. Our results suggest that, in addition to processing procaspase-3 and the BH3 protein Bid, active caspase-8 can cleave and activate procaspase-9 in response to TNF receptor crosslinking in murine cells.
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PMID:Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells. 1293 75

The myelodysplastic syndromes (MDS) are a group of disorders characterized by peripheral pancytopenia despite normo- or hyper-cellular bone marrow. This is thought to be due to apoptosis of hematopoietic bone marrow cells, resulting in ineffective hematopoiesis. The heterogeneous nuclear ribonucleoprotein (hnRNP) B1 is involved in pre-mRNA processing and binds to telomeric cDNA repeats. The hnRNP B1 is a marker for early cancer. The aim of our study was to clarify the relationships between prognosis and apoptosis, telomerase activity (TA) and hnRNP expression in the bone marrow. The subjects were 51 patients with MDS, including patients with refractory anemia (RA) (n = 32), refractory anemia with ringed sideroblasts (RARS) (n = 1), refractory anemia with excess blasts (RAEB) (n = 7), refractory anemia with excess blasts in transformation (RAEB-t) (n = 8) and chronic myelomonocytic leukemia (CMMoL) (n = 3). We also studied 6 cases with acute myelogenous leukemia (AML) arising from MDS (AML-MDS) and 10 control subjects. Bone marrow biopsies were stained immunohistochemically for caspase-3 (marker of apoptotic activity) and human telomerase reverse transcriptase (hTERT), and hnRNP B1. Fatal pancytopenia was the cause of death in 19 of the 51 patients. The caspase-3 positive cell rate was higher in MDS (16.3%) than in controls (4.4%) and AML-MDS (0.5%). The percentage of hnRNP B1-positive cells was higher in MDS (15.3%) and AML-MDS (56.3%) than in controls (5.6%). In MDS, hnRNP B1 levels were higher in RAEB and RAEB-t subtypes than in RA and RARS. The percentage of hTERT-positive cells was higher in AML-MDS (50.0%) than in controls (20.2%) and MDS (23.6%). Our findings suggest that activation of apoptosis occurs in MDS in the absence of hTERT expression, implicating high apoptosis in the absence of high TA with ineffective hematopoiesis. Poor prognosis correlated with higher caspase-3 and lower hTERT rates. In MDS, hnRNP B1 activity may be associated with leukemic transformation.
Leuk Lymphoma 2003 Aug
PMID:Imbalance between apoptosis and telomerase activity in myelodysplastic syndromes: possible role in ineffective hemopoiesis. 1295 27

The transcription factor NF-kappa B is elevated in murine T-cell lymphoma lines compared with normal thymic lymphocytes, and may play a role in the neoplastic transformation of these cells. When T lymphoma cells were treated with the soy isoflavone genistein, a marked reduction in nuclear NF-kappa B levels was detectable predominantly for the p50/p50 homodimer and p50/p65 heterodimer. To examine the mechanism by which NF-kappa B is reduced by genistein, we analyzed the NF-kappa B inhibitor, I kappa B alpha, and detected a 34 kDa cleavage product Delta I kappa B alpha, which was induced by genistein in a dose-dependent manner. Our observation that a pan-caspase inhibitor could inhibit the induction of Delta I kappa B alpha by genistein suggested that caspase activity was responsible for this cleavage product. In support of this idea, we detected an increase in caspase-3 activity in response to increasing time of genistein exposure. When the induction of Delta I kappa B alpha was prevented, we detected no reduction of NF-kappa B levels by genistein. These results support a direct role for Delta I kappa B alpha in the reduction of NF-kappa B by genistein. To determine the effect of genistein on some NF-kappa B target gene products, we examined the antiapoptotic proteins Bcl-2, Bcl-X(L), A1, and cIAP-1. Only changes in A1 and cIAP-1 levels were affected with significant reductions in response to genistein. Generation of the repressive activity of Delta I kappa B alpha on NF-kappa B is a novel mechanism for the reduction of this transcription factor by genistein and the possible effect this may have on the ability of genistein to induce apoptosis in tumor cells.
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PMID:Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha. 1296 87

The effects of the constituents isolated from ginger species including curcumin, 6-gingerol and labdane-type diterpene compounds on cell proliferation and the induction of apoptosis in the cultured human T lymphoma Jurkat cells were studied. Among the tested compounds, galanals A and B, isolated from the flower buds of a Japanese ginger, myoga (Zingiber mioga Roscoe), showed the most potent cytotoxic effect. Exposure of Jurkat human T-cell leukemia cells to galanals resulted in the induction of apoptotic cell death characterized by DNA fragmentation and caspase-3 activation. The mitochondrial damage pathway was suggested to be involved in galanal-induced apoptosis because the treatment of cells with galanals induced mitochondrial transmembrane potential (DeltaPsim) alteration and cytochrome c release. The anti-apoptotic Bcl-2 protein was downregulated by the galanal treatment together with enhancement of the Bax expression. In conclusion, the results from this study provide biological evidence that ginger-specific constituents other than curcuminoids are potential anticancer agents.
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PMID:Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in Human T lymphoma Jurkat cells. 1296 83


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