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)

Glucocorticoids are highly effective in inducing the cytolysis of cells of lymphocytic origin. This property has resulted in their incorporation into chemotherapy regimens used in the treatment of hematologic malignancies. Studies at the molecular and cellular levels have demonstrated that the hormone-induced cytolytic response is mediated through a highly specific cytoplasmic glucocorticoid receptor (GR). The GR has been cloned and sequenced and found to be organized into a discrete series of domains which mediate the receptor functions of hormone binding, nuclear translocation, DNA binding and transcriptional modulation. Thus, the binding of glucocorticoids by the GR induces a series of cellular events which result in the activation or repression of a network of glucocorticoid responsive genes and produces a specific cellular response. Prolonged exposure to glucocorticoids ultimately causes resistance to develop; thereby limiting the usefulness of this class of drugs. Studies addressing the mechanism of resistance have shown that the GR is the primary target of genetic alterations that lead to resistance to cytolysis. Using mouse and human cell lines as model systems, it has been shown that the vast majority of glucocorticoid resistant mutants express low levels or altered forms of the GR. Similarly, in vivo studies on patients have suggested that low GR levels are associated with a poor response to glucocorticoid based therapies. Recently, aberrant GR isolated from a patient with multiple myeloma resistant to glucocorticoids were found to harbor deletions in their hormone binding domains. Sequencing of the receptors suggested that each arose as a result of alternate splicing events. In both cases, the latter event produces a receptor unable to bind hormone leading to the speculation that alternate splicing may serve as a mechanism by which a cell evades the effects of glucocorticoids. The therapeutic implications for patients expressing aberrant receptors is discussed.
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PMID:Glucocorticoid receptors and resistance to glucocorticoids in hematologic malignancies. 787 93

The effects of dexamethasone on the growth of four human multiple myeloma cell lines were studied. In addition, the effects on the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes were investigated by the use of reverse-transcriptase polymerase chain reaction. Dexamethasone (Dex) concentrations of 10(-7) to 10(-6) mol/L inhibited IL-6 gene expression in three of four cell lines studied, whereas the higher concentration of the hormone inhibited also IL-6R gene expression. Dex effects were modulated through the glucocorticoid receptor (GR). Dex treatment resulted in killing of sensitive cells associated with DNA fragmentation, which could be reversed by concomitant treatment with IL-6. The reversal of Dex-mediated effects by IL-6 did not result from an inhibition of GR function as measured by receptor nuclear translocation or Dex-regulated reporter gene function. These results indicate that blockage of the IL-6 signaling pathway is essential for effective myeloma cell kill by Dex.
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PMID:Interleukin-6 prevents dexamethasone-induced myeloma cell death. 794 78

Glucocorticoids are highly effective chemotherapeutic agents used in the treatment of hematological malignancies including multiple myeloma. However, the clinical usefulness of this class of drugs is limited by the problem of resistance. In the following study, we have isolated two alternatively spliced transcripts of the glucocorticoid receptor from a complementary DNA library generated from the glucocorticoid-resistant myeloma cell line MM.1Re. In each of the clones, specific exons of the hormone binding domain are precisely deleted. Our data implicate alternate splicing as a mechanism by which a cell generates different receptor isoforms and as a consequence evades the effects of hormone.
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PMID:Alternatively spliced glucocorticoid receptor messenger RNAs in glucocorticoid-resistant human multiple myeloma cells. 835 12

We have carried out molecular scanning of the glucocorticoid receptor (GR) of the glucocorticoid resistant multiple myeloma cell line U266. An amplified fragment from the 3' untranslated region displayed an aberrant migration by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis. The mutant allele had a deletion of an 8 base pair sequence containing a half-site of an oestrogen response element. This motif was found conserved in rat GR. This same allele lacked four As in an upstream region with 18 consecutive As in the normal allele. These mutations may affect mRNA stability or alter interactions with regulatory factors.
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PMID:Deletion of a consensus oestrogen response element half-site in the glucocorticoid receptor of human multiple myeloma. 937 57

Multiple myeloma (MM) is characterized by bone marrow infiltration with abnormal plasma cells which synthesize monoclonal immunoglobulins (Ig) or Ig fragments. Regularly, MM cells exhibit a high intrinsic resistance to available chemotherapeutic strategies. A number of cellular alterations including the cellular membrane, such as mutations of the glucocorticoid receptor or expression of membrane transport proteins, detoxification mechanisms and altered expression of topoisomerases, have been described. In addition to anti-apoptotic survival mechanisms, involving abnormalities of several oncogenes and suppressor genes (ras, c-myc, p53, Rb and bcl-2), the broad resistance spectrum might be explained but clinical studies which include the evaluation of resistance factors are missing. On the other hand, risk factor evaluation would be important as a number of therapeutical strategies with different intensities from corticosteroid monotherapy up to high-dose chemotherapy with tandem autologous bone marrow transplantation exist.
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PMID:Cellular resistance mechanisms with impact on the therapy of multiple myeloma. 943 30

Multiple myeloma (MM) is characterized by bone marrow infiltration with abnormal plasma cells which synthesize monoclonal immunoglobulins (Ig) or Ig fragments. Regularly, MM cells exhibit a high intrinsic resistance to available chemotherapeutic strategies. A number of cellular alterations including the cellular membrane, such as mutations of the glucocorticoid receptor or expression of membrane transport proteins, detoxification mechanisms and altered expression of topoisomerases, have been described. In addition to anti-apoptotic survival mechanisms, involving abnormalities of several oncogenes and suppressor genes (ras, c-myc, p53, Rh and bcl-2), the broad resistance spectrum might be explained but clinical studies which include the evaluation of resistance factors are missing. On the other hand, risk factor evaluation is important as a number of therapeutical strategies with different intensities from corticosteroid monotherapy up to high-dose chemotherapy with tandem autologous bone marrow transplantation exist.
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PMID:Cellular resistance mechanisms with impact on the therapy of multiple myeloma. 966 83

Multiple myeloma is a neoplastic proliferation of plasma cells. Glucocorticoids are among the most effective agents against multiple myeloma, acting through the glucocorticoid receptor to induce programmed cell death. However, some patients do not respond to glucocorticoids, and those that do respond eventually develop resistance to this therapy. Alternative strategies using drugs that mediate cytotoxicity through complementary pathways have theoretical appeal. Cyclic adenosine-3',5'-monophosphate (cAMP) derivatives are cytotoxic to a number of cell lines of lymphocytic origin. cAMP analogues activate protein kinase A, affecting cell growth and differentiation. The cascade of events initiated by cAMP derivatives and glucocorticoid, although distinct, may share some distal molecular targets. We have found that pharmacological concentrations of 8-chloro-cAMP, dibutyryl-cAMP, and 8-bromo-cAMP are cytotoxic to multiple myeloma cells, enhance glucocorticoid effects, and can kill glucocorticoid-resistant clones. cAMP analogues induce apoptosis as demonstrated by the fragmentation of myeloma DNA chromatin in a distinctive ladder pattern. In contrast to glucocorticoids, cAMP growth inhibition cannot be reversed by exogenous interleukin 6. cAMP derivatives have activity against multiple myeloma and are appropriate candidates for clinical trials.
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PMID:Cyclic adenosine-3',5'-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma. 981 64

Monoclonal antibodies (MoAbs) that selectively identify Muc-1 core protein (MoAbs DF3-P, VU-4H5) determinants were used to identify the Muc-1 glycoform present on 7 multiple myeloma (MM) cell lines, 5 MM patient plasma cells, 12 MM patient B cells, as well as 32 non-MM cell lines and normal hematopoietic cells. Flow cytometry studies demonstrated that all MM cell lines, MM patient plasma cells, and MM patient B cells expressed Muc-1 core protein epitopes. Circulating B cells from 4 normal donors also expressed Muc-1 core protein. In contrast, Muc-1 core protein was absent on 28 of 32 non-MM neoplastic cell lines, 17 of which expressed Muc-1. Splenic and tonsillar B cells, CD34(+) stem cells, resting T cells, and bone marrow plasma cells obtained from normal donors both lacked Muc-1 glycoforms. We next studied the effects of estrogen, progesterone, and glucocorticoid receptor agonists and antagonists on Muc-1 expression, because consensus sequences for the response elements of these steroids are present on the Muc-1 gene promoter. These studies showed that dexamethasone (Dex) induced Muc-1 expression on MM cell lines, as determined by both flow cytometry and Western blot analyses. Dex also induced upregulation of Muc-1 on prostate and ovarian cancer cell lines. Time and dose-response studies demonstrated that Dex induced maximal cell surface Muc-1 expression by 24 hours at concentrations of 10(-8) mol/L. Dex induced Muc-1 upregulation could be blocked with a 10-fold excess of the glucocorticoid receptor antagonist RU486, confirming that Dex was acting via the glucocorticoid receptor. No changes in Muc-1 expression were observed on MM cells treated with estrogen and progesterone receptor agonists and antagonists or with RU486. These studies provide the framework for targeting Muc-1 core protein in vaccination and serotherapy trials in MM. In addition, the finding that Muc-1 expression on MM cells can be augmented by Dex at pharmacologically achievable levels suggests their potential utility in enhancing treatments targeting Muc-1 in MM.
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PMID:Muc-1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone. 994 72

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.
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PMID:Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells. 1135 9

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modifications of the RAFTK kinase, Jun kinase, p38 mitogen-activated protein kinase, or BAD. Sensitization was also not associated with a rapamycin-mediated increase in glucocorticoid receptor reporter expression. However, when cap-dependent translation was prevented by transfection with a mutant 4E-BP1 construct, which is resistant to mTOR-induced phosphorylation, cells responded to dexamethasone with enhanced apoptosis, mirroring the effect of coexposure to rapamycin. Thus, sensitization is mediated by inhibition of cap-dependent translation. A high-throughput screening for translational efficiency identified several antiapoptotic proteins whose translation was inhibited by rapamycin. Immunoblot assay confirmed rapamycin-induced down-regulated expressions of XIAP, CIAP1, HSP-27, and BAG-3, which may play a role in the sensitization to apoptosis. Studies in a xenograft model showed synergistic in vivo antimyeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with an enhanced multiple myeloma cell apoptosis in vivo. This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved.
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PMID:Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. 1648 35


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