UMLS:C0079731 - FACTA Search

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Query: UMLS:C0079731 (B-cell lymphoma)
16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a first step toward identifying putative regulators of apoptosis in the heart, the impact of the anti-apoptosis protein Bcl-2 (B-cell lymphoma gene) on the NFkappaB (nuclear factor kappa beta) signalling pathway in suppressing apoptosis in ventricular myocytes was studied. The data indicate that adenovirus-mediated delivery of Bcl-2 resulted in a significant increase in NFkappaB-dependent DNA binding and NFkappaB-directed gene transcription. No change in NFkappaB protein content was observed in myocytes expressing Bcl-2. Moreover, the Bcl-2-mediated NFkappaB activation was found to be related to changes in the activity of the NFkappaB regulatory protein IkappaBalpha (inhibitor of kappa beta). In this regard, a marked reduction in IkappaBalpha protein content was observed in ventricular myocytes expressing Bcl-2. The mode by which Bcl-2 regulates IkappaBalpha was related to the N-terminal phosphorylation and degradation of IkappaBalpha by the proteasome since an N-terminal deletion mutant of IkappaBalpha or the proteasome inhibitor lactacystin abrogated Bcl-2's inhibitory effects on IkappaBalpha and prevented NFkappaB activation. Furthermore, adenovirus-mediated delivery of a phosphorylation defective form of IkappaBalpha rendered ventricular myocytes incapable of NFkappaB activation and susceptible to tumour necrosis factor alpha-mediated apoptosis. Moreover, Bcl-2's anti-apoptotic function was lost in cells defective for NFkappaB activation. The data provide evidence for a link between Bcl-2 and the NFkappaB signalling pathway for the suppression of apoptosis in ventricular myocytes.
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PMID:Bcl-2 intersects the NFkappaB signalling pathway and suppresses apoptosis in ventricular myocytes. 1105 26

The proteasome, which plays a pivotal role in the control of many cell cycle-regulatory processes, has become the focus of new approaches to the treatment of cancer, including B-cell malignancies, and the first proteasome inhibitor, bortezomib (VELCADE; formerly PS-341), has entered clinical trials. The proteasome controls the stability of numerous proteins that regulate progression through the cell cycle and apoptosis, such as cyclins, cyclin-dependent kinases, tumor suppressors, and the nuclear factor-kB. By altering the stability or activity of these proteins, proteasome inhibitors sensitize malignant cells to apoptosis. Bortezomib is a dipeptidyl boronic acid proteasome inhibitor that effectively and specifically inhibits proteasome activity. In preclinical studies, bortezomib and other proteasome inhibitors have shown activity against a variety of B-cell malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and Hodgkin's lymphoma. These agents can induce apoptosis and sensitize tumor cells to radiation or chemotherapy. Based on these findings, phase I clinical trials were conducted with bortezomib in various solid and hematologic malignancies. In these studies, bortezomib was generally well tolerated with manageable toxicities. Phase II trials have been initiated for relapsed and refractory multiple myeloma, refractory chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Preliminary data from the multiple myeloma phase II study indicate that a significant number of patients responded to therapy or exhibited stable disease and that the drug had manageable toxicities. These findings, along with extensive preclinical data, suggest that bortezomib and other proteasome inhibitors may have far-reaching potential in the treatment of various cancers, including B-cell malignancies.
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PMID:Proteasome inhibitors in the treatment of B-cell malignancies. 1214 56

Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.
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PMID:The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. 1616 92

The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant SUDHL-4 and bortezomib-sensitive SUDHL-6 diffuse large B-cell lymphoma lines in response to bortezomib. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in SUDHL-6 cells, but not in SUDHL-4 cells. We showed that overexpression of activating transcription factor 3 (ATF3), ATF4, ATF5, c-Jun, JunD and caspase-3 is associated with sensitivity to bortezomib-induced apoptosis, whereas overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance.
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PMID:Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. 1684 75

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies. The new small-molecule pan-Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from patients with MCL by releasing Bak from Mcl-1 and Bcl-X(L) at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage-sensor genes or cell-cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure, and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.
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PMID:The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. 1722 35

Bortezomib is a proteasome inhibitor with proven efficacy in multiple myeloma and non-Hodgkin's lymphoma. This study reports the effects of bortezomib in B-cell lymphoma cell lines with differing sensitivity to bortezomib to investigate factors that influence sensitivity. Bortezomib induced a time- and concentration-dependent reduction in cell viability in five lymphoma cell lines, with EC(50) values ranging from 6 nmol/L (DHL-7 cells) to 25 nmol/L (DHL-4 cells) after 72 h. Bortezomib cytotoxicity was independent of p53 function, as all cell lines exhibited mutations by sequence analysis. The difference in sensitivity was not explained by proteasome or nuclear factor-kappaB (NF-kappaB) inhibition as these were similar in the most and least sensitive cells. NF-kappaB inhibition was less marked than that of a specific NF-kappaB inhibitor, Bay 11-7082. Cell cycle analysis showed a marked G(2)-arrested population in the least sensitive DHL-4 line only, an effect that was not present with Bay 11-7082 treatment. Conversely, in DHL-7 cells, bortezomib treatment resulted in cells moving into an aberrant mitosis, indicative of mitotic catastrophe that may contribute to increased sensitivity to bortezomib. These studies show that although bortezomib treatment had similar effects on apoptotic and NF-kappaB signaling pathways in these cell lines, different cell cycle effects were observed and induction of a further mechanism of cell death, mitotic catastrophe, was observed in the more sensitive cell line, which may provide some pointers to the difference in sensitivity between cell lines. An improved understanding of how DHL-7 cells abrogate the G(2)-M cell cycle checkpoint may help identify targets to increase the efficacy of bortezomib.
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PMID:The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. 1736

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although front therapy induces a high rate of complete remission (CR), relapse is inevitable and new regimens are much needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but CR rates are low, with a short duration of response and severe toxicity. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Increasing doses of BTZ with a fixed dose of RTX and CTX (BRC regimen) resulted in markedly synergistic growth inhibition of MCL cells. BRC significantly enhanced apoptosis in MCL cell lines and primary tumor cells compared with single-agent treatment. Furthermore, western blotting analysis indicated that BRC induces apoptosis earlier via activation and cleavage of caspases-8, -9 and -3, and poly (ADP-ribose) polymerase, than single-agent treatment. The pan-caspase inhibitor completely blocked apoptosis induced by BRC. In vivo studies showed that BRC eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival in 70% of the mice. Hence, our study demonstrates that cytoreductive chemotherapy with both BTZ and anti-CD20 antibody may offer a better therapeutic modality for relapsed MCL.
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PMID:Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. 1789 87

Overexpression of antiapoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the antiapoptotic influence of these proteins can potentially overcome this resistance, and may complement conventional chemotherapy. ABT-737 is a BH3-only mimetic and potent inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X(L), and Bcl-w. In vitro, ABT-737 exhibited concentration-dependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ABT-737 showed synergism when combined with the proteasome inhibitors bortezomib or carfilzomib in select lymphoma cell lines and induced potent mitochondrial membrane depolarization and apoptosis when combined with either. ABT-737 plus bortezomib also induced significant apoptosis in primary samples of MCL, DLBCL, and chronic lymphocytic leukemia (CLL) but no significant cytotoxic effect was observed in peripheral blood mononuclear cells from healthy donors. In severe combined immunodeficient beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared with either drug alone and with the control. Collectively, these data suggest that ABT-737 alone or in combination with a proteasome inhibitor represents a novel and potentially important platform for the treatment of B-cell malignancies.
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PMID:The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. 1859 85

Mechanisms underlying interactions between the proteasome inhibitor bortezomib and small molecule Bcl-2 antagonists were examined in GC- and ABC-type human DLBCL (diffuse lymphocytic B-cell lymphoma) cells. Concomitant or sequential exposure to non- or minimally toxic concentrations of bortezomib or other proteasome inhibitors and either HA14-1 or gossypol resulted in a striking increase in Bax/Bak conformational change/translocation, cytochrome c release, caspase activation and synergistic induction of apoptosis in both GC- and ABC-type cells. These events were associated with a sharp increase in activation of the stress kinase JNK and evidence of ER stress induction (e.g., eIF2alpha phosphorylation, activation of caspases-2 and -4, and Grp78 upregulation). Pharmacologic or genetic (e.g., shRNA knockdown) interruption of JNK signaling attenuated HA14-1/bortezomib lethality and ER stress induction. Genetic disruption of the ER stress pathway (e.g., in cells expressing caspase-4 shRNA or DN-eIF2alpha) significantly attenuated lethality. The toxicity of this regimen was independent of ROS generation. Finally, HA14-1 significantly increased bortezomib-mediated JNK activation, ER stress induction, and lethality in bortezomib-resistant cells. Collectively these findings indicate that small molecule Bcl-2 antagonists promote bortezomib-mediated mitochondrial injury and lethality in DLBCL cells in association with enhanced JNK activation and ER stress induction. They also raise the possibility that such a strategy may be effective in different DLBCL sub-types (e.g., GC- or ABC), and in bortezomib-resistant disease.
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PMID:Bcl-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress. 3111 86

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-kappaB through blocking IkappaBalpha degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.ClinicalTrials.gov under identifier NCT00057902.
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PMID:Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. 1938 Aug 66

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