Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microarray analyses and gene targeting have recently enhanced the understanding of factors involved in normal plasma cells and multiple myeloma. Plasma cells develop from marginal zone or germinal center B cells following stimulation by antigen, microbial products, TNF family signals and cytokines. Transcription factors, B-lymphocyte-induced maturation protein 1 (Blimp-1) and X-box binding protein 1 (XBP-1) are required for plasma cell development. They regulate sets of genes that induce immunoglobulin secretion, halt proliferation and block alternative B-cell fates. In multiple myeloma, transforming events lead to proliferation and survival, but programs for plasma cell differentiation and the inhibition of B-cell genes appear to be largely intact.
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PMID:Plasma cell differentiation and multiple myeloma. 1502 17

A multiple myeloma (MM) cell line, XG2, has high-level expression of CD40, a tumor necrosis factor receptor (TNFR) family member. CD40 is present on the surfaces of a large variety of cells, including B cells, endothelial cells, dendritic cells and some carcinoma cells, and delivers signals regulating diverse cellular responses, such as proliferation, differentiation, growth suppression, cell death. In this research, we study the effects of cross-linking of CD40 on myeloma cells using different concentrations of anti-CD40 monoclonal antibody (mAb), 5C11. We found that low concentrations of 5C11 induced proliferation of XG2, while high concentrations of 5C11 resulted in homotypic aggregation of XG2, and strongly suppression of its proliferation and apoptosis after 24 h of treatment. These dose-dependent effects of 5C11 were verified by flow cytometry, Western blotting and immunoprecipitation. Autocrine or paracrine induction of IL-6, and up-regulation of membrane TNF and phosphorylation of TNFR1 may partially explain the contradictory biological effects of CD40 cross-linking on XG2 by anti-CD40 mAb.
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PMID:Cross-linking of CD40 using anti-CD40 antibody, 5C11, has different effects on XG2 multiple myeloma cells. 1515 11

These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNF alpha related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNF alpha related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNF alpha /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-kappa B and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-kappa B, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
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PMID:RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells. 1531 84

Thalidomide (THAL) is currently used as a novel drug in patients with chemotherapy resistant or relapsed multiple myeloma. THAL antitumor activity seems to be very complex, however the precise mechanisms of its action are still not fully understood. The aim of this study was to assess some of possible mechanisms of THAL action both in in vivo analysis of immune cells phenotype and in in vitro cultures with THAL. The study involved 30 patients with relapsed or chemotherapy refractory multiple myeloma who were qualified to THAL treatment. We assessed immunophenotype of malignant plasma cells and T lymphocytes in both peripheral blood (PB) and bone marrow (BM) samples taken before and after 4 and 8 weeks of THAL treatment. Before therapy cytokine secretion (VEGF, HGF, bFGF, TNF, IL-6 an sIL-6R) and Bcl-2 expression in PB and BM cell cultures with THAL were analyzed. We used flow cytometry technique and ELISA method. The clinical response to therapy was assessed after 4 and 8 weeks of treatment. We also investigated microvessel density (MVD) in bone marrow samples before the THAL treatment and after 6 months of therapy in the group of responding patients. In cell cultures with THAL we detected statistically significant lowering of analyzed cytokines concentration and the decrease in Bcl-2 expression by malignant plasma cells in BM and CD8(+) T lymphocytes in BM and PB. In the group of patients responding to therapy we observed the decrease in the number of myeloma cells and significant increase of CD4(+) and CD8(+) cells in both PB and BM samples. There was statistically significant increase of CD3(+)/CD69(+) cells in the course of therapy, while the percentage of CD3+/HLA-DR(+) cells was significantly lower after 8 weeks of therapy. We also detected lowering of MVD after THAL therapy in responders group. The obtained results demonstrate that THAL efficacy in MM is multidirected and included such mechanisms like down-regulation of proangiogenic cytokines, that could lead to lowering of MVD, induction of apoptosis and influence on malignant cells and T lymphocytes immunophenotype.
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PMID:The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma. 1580 Jul 17

Multiple myeloma (MM) is an as-yet incurable B-cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing antiapoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL (tumor necrosis factor [TNF]-related apoptosis inducing ligand) and Fas were identified as IFN targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events downstream receptor activation. In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
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PMID:Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells. 1586 Jun 71

Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well.
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PMID:Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities--the role of bupropion. 1596 26

Much of the morbidity and mortality associated with the plasma cell (PC) malignancy, multiple myeloma (MM), is owing to the severe osteolytic bone disease seen in patients with this disease. Although the molecular mechanisms responsible for osteolysis remain to be fully elucidated, it is clear from numerous studies that it is owing, in part, to an increase in osteoclastic bone resorption. Several known osteoclast (OC)-activating factors (OAFs) are produced by myeloma PCs (MPCs), or by stromal cells in response to MPCs and include interleukin-1beta (IL-1beta); tumor necrosis factor-alpha (TNF-alpha); IL-6; parathyroid hormone-related protein; macrophage inflammatory protein-1alpha; and, most recently, the TNF-ligand family member receptor activator of nuclear factor-kappaB ligand (RANKL). The identification and significance of any one of these myeloma-derived OAFs is dependent on robust and reliable assays that measure the de novo formation and activation of OCs. A number of in vitro assay systems have been described that examine the requirements for normal OC formation and are easily adaptable for examining which MM-derived OAF and to what extent it is responsible for the bone loss observed in individuals with myeloma. This chapter describes one such in vitro model system.
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PMID:An in vitro osteoclast-forming assay to measure myeloma cell-derived osteoclast-activating factors. 1596 8

OPG (osteoprotegerin), a secreted member of the TNF (tumour necrosis factor) receptor superfamily, has a variety of biological functions which include the regulation of bone turnover. OPG is a potent inhibitor of osteoclastic bone resorption and has been investigated as a potential therapeutic for the treatment of both osteoporosis and tumour-induced bone disease. Indeed, in murine models of cancer-induced bone disease, inhibition of osteoclastic activity by OPG was also associated with a reduction in tumour burden. The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival. A number of reports from studies using in vitro models have shown that OPG protects tumour cells from the effects of TRAIL, thereby possibly providing tumour cells that produce OPG with a survival advantage. However, the ability of OPG to act as a tumour cell survival factor remains to be verified using appropriate in vivo systems. A third area of interest has been the use of OPG as a prognostic marker in various cancer types, including myeloma, breast and prostate cancer. This review provides an overview of the role of OPG in cancer, both in cancer-induced bone disease and in tumour growth and survival.
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PMID:Role of osteoprotegerin (OPG) in cancer. 1646 70

Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell-mediated antitumor activity and has potential utility for anticancer therapy.
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PMID:Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. 1703 22

Bortezomib is the first proteasome inhibitor to be used clinically for the treatment of multiple myeloma and has been suggested as a possible treatment for a wide variety of hematologic and solid malignancies. Recent data suggests that potent immunomodulatory effects can also occur with systemic proteasome inhibition. This has been recently shown to occur in a graft-versus host disease model following bone marrow transplantation in mice. The suggested direct immunological effects of bortezomib treatment to include a decrease in anti-apoptotic protein levels, an increase in expression of TNF-family receptors (specifically Apo2L/TRAIL), induction of apoptosis, and inhibition of the transcription factor NF-kappaB. The NF-kappaB pathway has been associated with the regulation of numerous immune and inflammatory response mediators. In this review, we will present recent information concerning the potential therapeutic implications of bortezomib for a range of immune disorders. These findings would suggest that bortezomib treatment may be of clinical significance to suppress solid organ transplant rejection, autoreactive T cell responses, pro-inflammatory cytokine production, and consequently disease progression and pathology in autoimmunity.
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PMID:Use of systemic proteasome inhibition as an immune-modulating agent in disease. 1734 2


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