Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The changes of phospholipase D (PLD) activity were investigated during the courses of apoptotic process induced by tumor necrosis factor (TNF)-alpha or anti-Fas/Apo1 antibody in human premyelocyte HL-60 and murine B cell lymphoma A20 cells. The treatment of recombinant TNF-alpha to HL-60 cells resulted in the increased PLD activity as determined by the phosphatidylethanol formation in the presence of 1% ethanol. The enhancement of PLD activity was also observed in the anti-Fas/Apo1 monoclonal antibody-treated A20 cells. However, the activity of PLD was maximized when HL-60 and A20 cells were treated with either TNF-alpha or anti-Fas/Apo1 monoclonal antibody for 6 h. Both TNF-alpha and anti-Fas/Apo1 monoclonal antibody increased PLD activity in a dose-dependent manner up to 200 U/ml and 200 ng/ml, respectively. When the intracellular activity of protein kinase C (PKC) was interrupted by treatment of calphostin-C, both the PLD activation and the apoptosis induced by TNF-alpha and anti-Fas/Apo1 monoclonal antibody appeared to be inhibited. Since PKC is reported to activate PLD, the results indicate that the intracellular signaling cascade via PLD may play a role in the induction of apoptosis induced by TNF-alpha and anti-Fas/Apo1 monoclonal antibody.
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PMID:Changes of phospholipase D activity in TNF-alpha and anti-Fas/Apo1 monoclonal antibody induced apoptosis in HL-60 and A20 cells. 987 18

The activation of phospholipase D in murine B cell lymphoma A20 cells treated with anti-Fas monoclonal antibody has been investigated. Fas cross-linking resulted in a both dose- and time-dependent increases in phospholipase D activity. There was a nearly maximum saturated rise in phospholipase D activity at the dose of 200 ng/ml anti-Fas monoclonal antibody showing a fourfold increase within 3 h. Fas activation also caused an approximately twofold increase of phosphatidylcholine-specific phospholipase C activity and 1,2-diacylglycerol release, which could be blocked by 30 min pretreatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 (50 microgram/ml). Pretreatment of D609 also effectively inhibited the translocation of protein kinase C betaI and betaII from the cytosol to the membrane and the activation of phospholipase D induced by Fas cross-linking, suggesting that 1, 2-diacylglycerol released from the cellular phosphatidylcholine pool through phosphatidylcholine-specific phospholipase C plays a major role in protein kinase C/phospholipase D activation. Anti-Fas monoclonal antibody failed to elicit phosphoinositide-specific phospholipase C activation and any changes in the intracellular Ca2+ level in A20 cells, indicating that the phosphoinositide-mediated pathway is not involved in this Fas signaling. Therefore, these results suggest that Fas-mediated phospholipase D activation may be a consequence of primary stimulation of phosphatidylcholine-specific phospholipase C and that phospholipase D may play a role in Fas cross-linking signaling downstream from phosphatidylcholine-specific phospholipase C.
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PMID:Fas-mediated activation of phospholipase D is coupled to the stimulation of phosphatidylcholine-specific phospholipase C in A20 cells. 1039 39

Tumour necrosis factor receptor (TNFR) superfamily members play critical roles in the regulation of cell proliferation and death. One member of the TNFR superfamily, CD27, is unique because it is the only covalently linked homodimer in the family. CD27 and its cellular ligand, CD70, have been implicated in the regulation of T cell and B cell interactions that lead to cellular activation and regulation of immunoglobulin expression. Due to the unique nature of CD27, we chose to screen a number of B cell lymphoma cell lines for CD27 and CD70 expression and evaluate CD27 activation by antibody cross-linking. Two cell lines, HT and SU-4, showed greater cellular proliferation when CD27 was cross-lined and this correlated with increased PKC activation. Additionally, in the HT cell line cell surface expression of IgG was increased by CD27 cross-linking. Thus we have identified cellular systems for the study of CD27 signal transduction that will allow definition of the CD27 signal cascade of some B cell lymphomas.
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PMID:CD27 signals through PKC in human B cell lymphomas. 1041 48

Signaling through the B cell receptor (BCR) of normal splenic B cells, as well as B cell lymphoma lines, can abrogate Fas-mediated apoptosis. Using the B lymphoma line A20.2J, BCR signaling immediately inhibited Fas-induced apoptosis upstream of caspase-8 activation, as determined by Ile-Glu-Thr-Asp-(IETD)ase activity and cleavage of the caspase-8 substrate Bid. Furthermore, following overexpression of a human Fas:FLICE construct, which directly induces caspase activation in a death-inducing signaling complex-independent manner, cells could not be protected through BCR stimulation.Co-incubation with cycloheximide partially reversed protection from apoptosis and increased Fas-stimulated initiator and effector caspase activation, suggesting new protein synthesis is necessary to induce protection upstream of caspase activation. Furthermore, co-incubation with a broad-spectrum protein kinase C (PKC) inhibitor, such as bisindolylmaleimide (Bis), also partially reversed protection from apoptosis, and examination of a panel of PKC inhibitors suggested a role for atypical isozymes in protection. Bis also acted to increase initiator and effector caspase activation upon anti-IgG and anti-Fas treatment. These data suggest that BCR-induced protection is being mediated upstream of initiator caspase activation, and is partially dependent upon both PKC family members and new protein synthesis.
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PMID:B cell receptor signaling mediates immediate protection from Fas-induced apoptosis upstream of caspase activation through an atypical protein kinase C isozyme and de novo protein synthesis. 1293 25

We sought to determine whether identification of poor-risk subgroups of diffuse large B-cell lymphoma (DLBCL) using immunohistochemical stains would have practical utility with regard to prognosis and therapeutic decisions. Tissue microarray blocks were created using replicate samples of formalin-fixed, paraffin-embedded tissue from 200 cases of de novo DLBCL. The sections were stained with antibodies to proteins that are expressed by activated or proliferating B cells including MUM1, FOXP1, bcl-2, survivin, protein kinase C-beta (PKC-beta), cyclin D2, cyclin D3, and Ki-67. In univariate analysis, tumor expression of cyclin D2 (P = 0.025) or PKC-beta (P = 0.015) was associated with a worse overall survival, whereas none of the other markers was predictive of overall survival. Patients with DLBCL that expressed either cyclin D2 or PKC-beta had a 5-year overall survival of only 30% as compared to 52% for those who were negative for both markers (P = 0.0019). In multivariate analysis, the expression of cyclin D2 or PKC-beta was an independent predictor of poor overall survival (P = 0.035). Cyclin D2 and PKC-beta expression will be useful in designing a 'biological prognostic index' for patients with DLBCL.
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PMID:Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. 1592 May 48

This review highlights the discovery and development of chemotherapy at Eli Lilly & Company over the past 30 years from the Vinca alkaloids-vincristine, vinblastine, and vindesine-to targeted therapy. During the late 1970s, Lilly began an exploration of new synthetic compounds based on solid tumor screening models. Several novel antimetabolites with the potential to treat solid tumors were identified. Two such agents, gemcitabine and pemetrexed, underwent clinical development and are now among Lilly's portfolio of approved anticancer drugs. Gemcitabine, a pyrimidine nucleoside that has a profound effect on DNA synthesis, has been approved for the treatment of pancreatic, non-small cell lung, bladder, and most recently, breast, and ovarian cancer. Pemetrexed, a novel antifolate with potent cytotoxic effects, is distinguished from other antifolates by virtue of its ability to inhibit multiple folate-dependent enzymes. Pemetrexed, given in combination with cisplatin, has been recently approved for the treatment of malignant pleural mesothelioma and as second-line treatment for non-small cell lung cancer. Spurred by advances in the understanding of cancer as a disease process, Lilly's anticancer drug program began to transition to a more "targeted" approach during the 1990s. These efforts have recently culminated in the identification and development of enzastaurin, a PKCbeta inhibitor with potent anti-angiogenic properties. Enzastaurin has shown promising single-agent activity in patients with relapsed diffuse large B-cell lymphoma and recurrent glioblastoma multiforme, and is an excellent candidate for combination with cytotoxic agents.
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PMID:The evolution of cancer research and drug discovery at Lilly Research Laboratories. 1614 73

Human leukocyte antigens (HLA) class II antigen-mediated apoptosis has been documented in antigen-presenting cells and B lymphoproliferations. Characteristics of the apoptosis include rapidity and selectivity for mature cells. Follicular lymphomas are particularly refractory to apoptosis. The B-cell lymphoma Ramos shares characteristics of this subgroup and is insensitive to apoptosis via simple HLA-DR engagement. However, oligomerization of HLA-DR antigens induced caspase activation followed by phosphatidylserine externalization, activation of PKC-delta and cleavage of nuclear lamin B. Mitochondrial injury was also detected. However, inhibition of caspase activation simply delayed the apoptotic phenotype but neither protected against cell death nor prevented mitochondrial injury. The data in this report demonstrate that the requirements for the initiating signal (oligomerization versus engagement) as well as the molecular pathways varies between different B lymphoproliferations despite their common expression of HLA-DR. Finally, blockade of caspase activation in parallel with HLA-DR mAb stimulation could provide a potent autovaccination stimulus by leading to necrotic death of B-cell lymphomas.
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PMID:Dissociation of caspase-mediated events and programmed cell death induced via HLA-DR in follicular lymphoma. 1630 98

The protein kinase C (PKC) plays an important role in the activation and survival of B cells. The purpose of this study was to analyze the clinical significance of PKC-beta 2 protein expression in patients with diffuse large B-cell lymphoma (DLBCL). Tumors from 76 patients with DLBCL who received anthracycline-containing chemotherapy were examined for PKC-beta 2 protein expression by immunohistochemistry. Twenty-six cases (34%) were positive for PKC-beta 2 protein, and 50 (66%) were negative. Patients with PKC-beta-2-positive tumors showed a lower complete remission rate (31 vs 62%; P=0.015) and a lower 5-year disease-free survival (DFS) (30 vs 60%; P=0.03) than the PKC-beta-2-negative group. Overall survival (OS) was significantly lower in patients with the membranous staining pattern of PKC-beta 2 protein when compared to those with PKC-beta-2-negative tumors (14 vs 64%; P=0.005). In patients with low international prognostic index (IPI), those with tumors showing membrane expression of PKC-beta 2 had a significantly inferior DFS and OS (0 vs 79%, P=0.003; 25 vs 80%; P=0.01) compared to PKC-beta-2-negative tumors. In multivariate analysis for OS, the membrane staining of PKC-beta 2 is the strongest independent adverse prognostic factor (OR=3.4, P=0.011). Our results suggest that membrane expression of PKC-beta 2 protein on DLBCL predicts for poor survival, especially in patients with low IPI.
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PMID:Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma. 1683 Jan 42

Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKC-beta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in high-risk patients (14 vs 58%, P<0.001) and in those with PKC-beta II positivity (36 vs 49%, P=0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P=0.033) and a worse 5-year EFS (48 vs 66%, P=0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio=1.68, P=0.037) and the IPI (HR=3.07, P<0.001) were independent poor prognostic factors. PKC-beta II (HR=1.72, P=0.046) and the IPI (HR=5.16, P<0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.
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PMID:PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma. 1723 50

The protein kinase C (PKC) family, the most prominent target of tumor-promoting phorbol esters, is functionally linked to cell differentiation, growth, survival, migration and tumorigenesis and so mediates tumor cell proliferation, survival, multidrug resistance, invasion, metastasis and tumor angiogenesis. Therefore, targeting PKC isozymes may represent an attractive target for novel anticancer therapies. Recent preclinical and clinical studies using the macrocyclic bisindolylmaleimide enzastaurin or the N-benzylstaurosporine midostaurin demonstrate promising activity of PKC inhibitors in a variety of tumors, including diffuse large B-cell lymphoma, multiple myeloma and Waldenstroem's macroglobulinemia. However, our knowledge of PKCs in tumorigenesis is still only partial and each PKC isoform may contribute to tumorigenesis in a distinct way. Specifically, PKC isoforms have vastly different roles, which vary depending on expression levels of organ and tissue distribution, cell type, intracellular localization, protein-protein and lipid-protein interactions and the biologic environment. Although PKC activation generally positively affects tumor cell growth, motility, invasion and metastasis, recent reports show that many PKCs can also have negative effects. Therefore, it is necessary to further dissect the relative contribution of PKC isozymes in the development and progression of specific tumors in order to identify therapeutic opportunities, using either PKC inhibitors or PKC activators.
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PMID:The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. 1792 32


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