Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chimeric anti-CD20 antibody rituximab (Rituxan, IDEC-C2B8) is widely used in the clinical treatment of patients with non-Hodgkin's lymphoma (NHL). Rituximab sensitizes NHL B-cell lines to drug-induced apoptosis via down-regulation of Bcl-x(L) expression. We hypothesized that the mechanism by which rituximab down-regulates Bcl-x(L) may be, in part, due to inhibition of constitutive nuclear factor-kappaB (NF-kappaB) activity that regulates Bcl-x(L) expression. This hypothesis was tested in CD20(+) drug-resistant Ramos (Bcl-2(-)/Bcl-x(L)(+)) and Daudi (Bcl-2(+)/Bcl-x(L)(+)) cell lines. Rituximab decreased the phosphorylation of NF-kappaB-inducing kinase, IkappaB kinase, and IkappaB-alpha, diminished IKK kinase activity, and decreased NF-kappaB DNA binding activity. These events occurred with similar kinetics and were observed 3 to 6 hours post-rituximab treatment. Rituximab significantly up-regulated Raf-1 kinase inhibitor protein expression, thus interrupting the NF-kappaB signaling pathway concomitant with Bcl-x(L) and Bfl-1/A1 down-regulation. The role of NF-kappaB in the regulation of Bcl-x(L) transcription was shown using promoter reporter assays in which deletion of the two-tandem NF-kappaB binding sites in the upstream promoter region significantly reduced the luciferase activity. This was further corroborated by using IkappaB superrepressor cells and by NF-kappaB-specific inhibitors. The direct role of Bcl-x(L) in drug resistance was assessed by using Bcl-x(L)-overexpressing cells, which exhibited higher drug resistance that was partially reversed by rituximab. Rituximab-mediated inhibition of the NF-kappaB signaling pathway and chemosensitization was corroborated by the use of specific inhibitors. These findings reveal a novel pathway mediated by rituximab through Raf-1 kinase inhibitor protein induction that negatively regulates the constitutive NF-kappaB pathway and chemosensitization of the NHL B-cells.
 ...
PMID:Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin's lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. 1566 3

Bcl-2 is an apoptosis regulating protein, overexpression of which is associated with chemotherapy resistant disease, aggressive clinical course, and poor survival in patients with B-cell lymphoproliferative disorders. Overexpression of Bcl-2 protein results in an aberrant intrinsic apoptotic pathway that confers a protective effect on malignant cells against a death signal (e.g., chemotherapy or radiotherapy). Downregulation of this oncoprotein, thus, represents a possible new way to target clinically aggressive disease. Preclinical studies have shown that this oncoprotein can be effectively decreased by Bcl-2 antisense in malignant lymphoid cells and can reverse chemotherapy resistance, as well as enhance the anti-apoptotic potential of both chemotherapeutic and biologic agents. Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. Early results from these studies are promising and support the proof of the principle. As these studies are completed and mature data emerges, the role of Bcl-2 antisense therapy in the treatment of B-cell malignancies will become clearer.
 ...
PMID:Bcl-2 antisense therapy in B-cell malignancies. 1578 99

The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon crosslinking. Monomeric rituximab chemosensitizes drug-resistant NHL cells via selective downregulation of antiapoptotic factors through the type II mitochondrial apoptotic pathway. Several signaling pathways are affected by rituximab which are implicated in the underlying molecular mechanisms of chemosensitization. ARL (acquired immunodeficiency syndrome (AIDS)-related lymphoma) and non-ARL cell lines have been examined as in vitro model systems. In ARL, rituximab diminishes the activity of the p38MAPK signaling pathway resulting in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop leading to the inhibition of constitutive STAT-3 activity and subsequent downregulation of Bcl-2 expression leading to chemosensitization. Rituximab upregulates Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cells. Through physical association with Raf-1 and nuclear factor kappaB (NF-kappa B)-inducing kinase (NIK), RKIP negatively regulates two major survival pathways, namely, the extracellular signal-regulated kinase1/2 (ERK1/2) and the NF-kappa B pathways, respectively. Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors, respectively, both of which lead to the downregulation of Bcl-(xL) (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug-induced apoptosis. Bcl-(xL)-overexpressing cells corroborated the pivotal role of Bcl-(xL) in chemosensitization. The specificity of rituximab-mediated signaling and functional effects were corroborated by the use of specific pharmacological inhibitors. Many patients do not respond and/or relapse and the mechanisms of unresponsiveness are unknown. Rituximab-resistant B-NHL clones were generated to investigate the acquired resistance to rituximab-mediated signaling, and chemosensitization. Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.
 ...
PMID:Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. 1578 36

This study found that oridonin, a natural diterpenoid purified from Rabdosia rubescens, inhibited growth of multiple myeloma (MM; U266, RPMI8226), acute lymphoblastic T-cell leukemia (Jurkat), and adult T-cell leukemia (MT-1) cells with an effective dose that inhibited 50% of target cells (ED50) ranging from 0.75 to 2.7 microg/mL. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining showed that oridonin caused apoptosis of MT-1 cells in a time-dependent manner. We explored effects of oridonin on antiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), but not Bcl-2 protein, in both MT-1 and RPMI8226 cells. Further studies found that oridonin inhibited nuclear factor-kappa B (NF-kappa B) DNA-binding activity in these cells as measured by luciferase reporter gene, ELISA-based, and electrophoretic mobility shift assays. Oridonin also blocked tumor necrosis factor-alpha- and lipopolysaccharide-stimulated NF-kappa B activity in Jurkat cells as well as RAW264.7 murine macrophages. Of note, oridonin decreased survival of freshly isolated adult T-cell leukemia (three samples), acute lymphoblastic leukemia (one sample), chronic lymphocytic leukemia (one sample), non-Hodgkin's lymphoma (three samples), and MM (four samples) cells from patients in association with inhibition of NF-kappa B DNA-binding activity. On the other hand, oridonin did not affect survival of normal lymphoid cells from healthy volunteers. Taken together, oridonin might be useful as adjunctive therapy for individuals with lymphoid malignancies, including the lethal disease adult T-cell leukemia.
 ...
PMID:Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathways. 1582 31

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), a proliferating peripheral B-cell neoplasm, is a morphologic variant of diffuse large B-cell lymphoma (DLBCL), which may be confused with Hodgkin's lymphoma, non-Hodgkin's lymphoma, and reactive lymphadenopathies. Though more recent studies suggested that it might be a distinct clinicopathologic entity and/or a heterogeneous entity with derivation from germinal center B cells, its histogenetic derivation remains controversial. The authors analyzed 30 cases of THRLBCL to further characterize the origin of the neoplastic cells using immunohistochemical and molecular studies for expression of Bcl-6, CD10, and CD138, as well as rearrangements of IgH/bcl-2 genes on paraffin-embedded tissue. Half of the cases (15/30) showed Bcl-6 expression and five cases (19%) showed CD10 expression, but none had CD138 expression (0/20). Only three cases showed coexpression of both Bcl-6 and CD10. Molecular studies performed in 21 cases detected rearrangement of immunoglobulin heavy gene in 18 cases, with none having detectable Bcl-2 gene rearrangement. These data indicate that similar to DLBCL, the cell origin of neoplastic cells in THRLBCL is composed of a heterogeneous group of proliferating peripheral B cells, with only some cases originating from germinal center B cells and others derived from heterogeneous origins. Lack of Bcl-2 gene rearrangements seems to argue against a possible progression from preexisting follicular lymphoma. Thus, the normal counterpart of the neoplastic cells cannot at this time be the sole basis for the subclassification of THRLBCL.
 ...
PMID:T-cell/histiocyte-rich large B-cell lymphoma displays a heterogeneity similar to diffuse large B-cell lymphoma: a clinicopathologic, immunohistochemical, and molecular study of 30 cases. 1589 21

Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL.
 ...
PMID:Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. 1602 83

Plasmablastic lymphoma is an HIV-associated non-Hodgkin's lymphoma that primarily affects the oral cavity and jaws. The purpose of this report is to describe the first case of plasmablastic lymphoma occurring in an HIV-negative, nonimmunocompromised individual, and to review the histopathologic and immunohistochemical phenotype of this lymphoma. Histopathologically, our case exhibited a dense, diffuse lymphocytic infiltrate of noncohesive large lymphocytes with plasmacytoid features. Immunohistochemical analysis revealed positivity for the B-cell marker CD79a, VS38c, Epstein-Barr virus latent membrane protein (LMP), immunoglobulin G (IgG), and lambda light chain restriction. Neoplastic cells were negative for leukocyte common antigen, CD20, CD3, CD10, CD138, Bcl-2, Bcl-6, desmin, actin, EMA, S-100, HMB45, Alk-1, HHV8, IgA, IgM, and cytokeratin. The features of this rare disease are summarized based on a comprehensive review of the epidemiologic, clinical and immunohistochemical findings of previously reported cases.
 ...
PMID:Oral plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature. 1603 78

Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma and generally is incurable. Reliable prognostic markers to differentiate patients who progress rapidly from those who survive for years with indolent disease have not been established. Most cases overexpress Bcl-2, but the pathogenesis of FL remains incompletely understood. To determine whether a proteomic approach could help overcome these obstacles, we procured lymphoid follicles from 20 cases of FL and 15 cases of benign follicular hyperplasia (FH) using laser capture microdissection. Lysates were spotted on reverse-phase protein microarrays and probed with 21 antibodies to proteins in the intrinsic apoptotic pathway, including those specific for posttranslational modifications such as phosphorylation. A panel of three antibodies [phospho-Akt(Ser473), Bcl-2, and cleaved poly(ADP-ribose) polymerase] segregated most cases of FL from FH. Phospho-Akt(Ser473) and Bcl-2 were significantly increased in FL (P = 0.001 and P < 0.0001, respectively). Additionally, the Bcl-2/Bak ratio completely segregated FL from FH. High ratios of Bcl-2/Bak and Bcl-2/Bax were associated with early death from disease with differences in median survival times of 7.3 years (P = 0.0085) and 3.8 years (P = 0.018), respectively. Using protein microarrays, we identified candidate proteins that may signify clinically relevant molecular events in FL. This approach showed significant changes at the posttranslational level, including Akt phosphorylation, and suggested new prognostic markers, including the Bcl-2/Bak and Bcl-2/Bax ratios. Proteomic end points should be incorporated in larger, multicenter trials to validate the clinical utility of these protein microarray findings.
 ...
PMID:Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. 1611 25

Aim-To investigate whether clinical features of non-Hodgkin's lymphomas, at the time of first biopsy, correlate with studies of cell proliferation and cell death as well as with the level of bcl-2 expression.Methods-Bcl-2 expression, determined by immunocytochemistry, was compared with cell proliferation, measured using in situ hybridisation for histone mRNA, and cell death by apoptosis, measured using in situ end labelling for DNA cleavage.Results-Histone mRNA staining gave a labelling index of 30% of cells for reactive germinal centres, 5.2-13.5% of cells for low grade non-Hodgkin's lymphoma and 12.1-50.5% of cells for high grade non-Hodgkin's lymphoma. In situ end labelling gave a labelling index of 5.0-10.0% of cells for reactive germinal centres, 1.0-3.7% of cells for low grade non-Hodgkin's lymphoma and 4.7-13.5% of cells for high grade non-Hodgkin's lymphoma. There was a positive correlation between apoptotic index and proliferation index. More cases of low grade than high grade non-Hodgkin's lymphoma expressed bcl-2. There was no correlation between apoptotic index and bcl-2 expression for high grade non-Hodgkin's lymphoma.Conclusions-The molecular mechanisms controlling cell proliferation and death in non-Hodgkin's lymphoma are complex, probably involving a range of genes, including bcl-2. A better understanding of resistance to cell death is needed if the clinical goal of tailoring cancer treatment to individual tumours is to be achieved.
 ...
PMID:Correlation between apoptosis, proliferation and bcl-2 expression in malignant non-Hodgkin's lymphoma. 1669 87

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a 5-year survival rate of 35%-60%. Various clinical factors included in the International Prognostic Index have failed to identify the patients with DLBCL who will not benefit from the standard R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) treatment regimen. Bcl-2 has been implicated in conferring resistance to chemotherapy in non-Hodgkin's lymphoma and is therefore a candidate prognostic marker in DLBCL. To identify the correlation between Bcl-2 expression and response to rituximab-containing treatment regimens, histologic materials were analyzed from 292 elderly patients with confirmed DLBCL. Of these, 155 patients had received R-CHOP (53%) and 137 had received CHOP (47%). One hundred ninety-three patients (66%) were found to express high levels of Bcl-2 protein in > 50% of the tumor cells. Of the 193 Bcl-2-positive patients, the patients who received R-CHOP had a better 5-year overall rate than patients treated with CHOP (56% vs. 42%; P = 0.01), whereas in the patients with Bcl-2-negative disease, there was no statistically significant difference in the 5-year overall survival rates between the R-CHOP and CHOP regimens (58% vs. 52%; P = 0.6). Therefore, the addition of rituximab to the standard chemotherapy regimen seems to have overcome the Bcl-2-associated resistance to chemotherapy.
 ...
PMID:Bcl-2 gene expression as a predictor of outcome in diffuse large B-cell lymphoma. 1679 75


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