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)

Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We recently showed that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma (MM) cells. In this study, we focused on MM as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. We found that MM cells are irreversibly committed to cell death within few hours of incubation with SAHA. The hallmark molecular profile of MM cells before their commitment to SAHA-induced cell death is a constellation of antiproliferative and/or proapoptotic molecular events, including down-regulation of transcripts for members of the insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) and IL-6 receptor (IL-6R) signaling cascades, antiapoptotic molecules (e.g., caspase inhibitors), oncogenic kinases, DNA synthesis/repair enzymes, and transcription factors (e.g., XBP-1, E2F-1) implicated in MM pathophysiology. Importantly, SAHA treatment suppresses the activity of the proteasome and expression of its subunits, and enhances MM cell sensitivity to proteasome inhibition by bortezomib (PS-341). SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs. These findings highlight the pleiotropic antitumor effects of HDAC inhibition, and provide the framework for future clinical applications of SAHA to improve patient outcome in MM.
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PMID:Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. 1469 87

Multiple Myeloma (MM) is a progressive malignancy with poor prognosis, commonly treated by the use of the glucocorticoid Dexamethasone. Myeloma cells resist Dexamethasone induced apoptosis when exposed to IL-6 or IGF-1, both of which are known to activate several signaling cascades. For the first time, we show the actual contribution of downstream mediators, i.e., activated STAT factors, independent of the contribution of their upstream signaling pathways, on the proliferation and Dexamethasone rescue effects of IL-6 and IGF-1 in Multiple Myeloma. Retroviral transduction of cytokine dependent myeloma cells with activated STAT transcription factor constructs overcomes the cells dependence on cytokines for growth, allowing proliferation even in very low serum levels. However, the rescue of these previously cytokine dependent cells with activated STATs does not result in an increase in resistance to Dexamethasone induced apoptosis. Despite the presence of activated STAT3 and STAT5a, apoptosis is induced upon exposure to micromolar levels of Dexamethasone, and IL-6 or IGF-1 is still required to rescue the cells. The ability of these factors to block apoptosis is abrogated by the addition of PI-3 Kinase specific inhibitors, but not inhibitors that target the MAP Kinase pathway. However, ectopic expression of activated STAT3 results in partial rescue from apoptosis of cells treated with FAS ligand. Our data suggests that mechanisms of resistance to induced apoptosis and cellular proliferation are separate and distinct in cytokine dependent myeloma cells.
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PMID:Activating mutations in STAT3 and STAT5 differentially affect cellular proliferation and apoptotic resistance in multiple myeloma cells. 1497 30

In a series of 700 consecutive patients with prostate cancer, four patients were noted to have a history of multiple myeloma. An association between prostate cancer and multiple myeloma had not been previously described. An exploratory investigation of the biological basis of these two malignancies was undertaken to determine a possible mechanism for this association. A review of the genetic, molecular and chemical basis of prostate cancer and multiple myeloma development and progression is presented. A model suggesting the possible impact of immunosuppression from multiple myeloma and chemokines released by circulating myeloma cells including IGF-1, IL6, SDF1 and VEGF on the progression of prostate cancer to detectable stages is presented.
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PMID:Is there an association between multiple myeloma and prostate cancer? 1523 79

Myeloma is a deadly B-cell neoplasm, characterized by the monoclonal proliferation of plasma cells, the development of osteolytic lesions, and the induction of angiogenesis. Myeloma cells are predominantly localized in the marrow where they receive the appropriate survival and proliferation signals. To reach or spread over the marrow, the myeloma cells need to migrate from the vascular to the extravascular compartment of the marrow. A process called "homing". In this review, the steps of the homing scheme, analyzed in the 5TMM model, will be described. These murine models originated from spontaneously developed myeloma in elderly mice and have since been propagated by intravenous injection of myeloma cells into young syngeneic mice. These models resemble the human condition closely. The different studies reported here demonstrate that adhesion of 5TMM cells to marrow endothelial cells is partially mediated by CD44v10 and to stromal cells by CD44v6. The 5TMM cells migrate to the marrow through the effects of MCP-1, laminin-1, and IGF-1. Once past the marrow endothelium, they invade the extravascular compartment of the marrow by secreting MMP-9 and uPA. When they have settled in the marrow, they become susceptible to the effects of IGF-1, which stimulates the cells to proliferate and produce VEGF. Furthermore, studies targeting the marrow with inhibitors will be highlighted. These studies show that the 5TMM models are useful for unraveling basic biological processes and for identifying new therapeutic targets.
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PMID:Myeloma cells (5TMM) and their interactions with the marrow microenvironment. 1531 88

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.
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PMID:ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. 1604 63

Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.
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PMID:IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells. 1616 96

The association of fibroblast growth factor receptor 3 (FGFR3) expression with t(4;14) multiple myeloma (MM) and the demonstration of the transforming potential of this receptor tyrosine kinase (RTK) make it a particularly attractive target for drug development. We report here a novel and highly specific anti-FGFR3-neutralizing antibody (PRO-001). PRO-001 binds to FGFR3 expressed on transformed cells and inhibits FGFR3 autophosphorylation and downstream signaling. The antibody inhibited the growth of FGFR3-expressing FDCP cells (IC(50) of 0.5 microg/mL) but not that of cells expressing FGFR1 or FGFR2, and potently inhibited FGFR3-dependent solid tumor growth in a mouse xenograft model. Furthermore, PRO-001 inhibited the growth of the FGFR3-expressing, human myeloma cell line, UTMC2. Inhibition of viability was still observed when cells were cocultured with stroma or in the presence of IL-6 or IGF-1. PRO-001 did not inhibit constitutive activation of K650E, G384D, and Y373C FGFR3 in myeloma cell lines and failed to inhibit the growth of these cells. Most importantly, however, PRO-001 induced cytotoxic responses in primary t(4;14)(+) MM samples with an increase in apoptotic index of 20% to 80% as determined by annexin V staining. The data demonstrate that PRO-001 is a potent and specific inhibitor of FGFR3 and deserves further study for the treatment of FGFR3-expressing myeloma.
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PMID:The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. 1646

The Insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in a variety of tumors including breast, prostate and myeloma. Thus, IGF-1R and its downstream signaling effectors are good candidates for molecular-based targeted antitumor therapies. Indeed, protein inhibitors of IGF-1R signaling and IGF-1R blocking antibodies are undergoing clinical trials. Herein, the molecular basis for antibody-mediated IGF-1R signal inhibition has been investigated in a hematopoietic cell line model, FDC-P1, that has been rendered interleukin-3 independent in a ligand-dependent manner through retroviral-mediated expression of IGF-1R (FD/IGF-1R). Furthermore, the ability of an anti-IGF-1R antibody to synergize with signal-transduction pathway inhibitors and induce apoptosis was determined. The alphaIGF-1R antibody, A12, was capable of arresting IGF-1 or insulin-induced FD/IGF-1R cell proliferation in the G1 phase of the cell cycle and resulted in apoptotic induction. A12 effectiveness could be potentiated through combination treatment with small molecule inhibitors of the Ras/Raf/MEK/ERK or PI3K/Akt/mTOR pathways. These results validate the use of the FD/IGF-1R cells to evaluate the effectiveness and mechanisms of targeted IGF-1R therapeutic strategies.
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PMID:Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. 1664 49

The role of Bim in synergistic interactions between UCN-01 and MEK1/2 inhibitors in human multiple myeloma cells was investigated. Exposure of U266 or RPMI8226 cells to UCN-01 resulted in ERK1/2 activation-associated Bim(EL) phosphorylation/down-regulation, events abrogated by MEK1/2 inhibitors. Enforced activation of ERK1/2 by transfection with constitutively active MEK1 diminished the capacity of PD98059 but not PD184352 to block UCN-01-mediated Bim(EL) phosphorylation and to potentiate apoptosis. Cotreatment with MEK1/2 inhibitors increased the association of Bim(EL) with both Bcl-2 and Bcl-x(L) in UCN-01-treated cells, leading to Bax/Bak conformational change and Bax mitochondrial translocation. Down-regulation of Bim(EL) by shRNA substantially diminished UCN-01/MEK inhibitor-mediated Bax/Bak activation and apoptosis. Furthermore, transfection of cells with S65A Bim, a mutant resistant to UCN-01-mediated phosphorylation, significantly sensitized cells to UCN-01 lethality. Conversely, ectopic expression of either Bcl-2 or Bcl-x(L) did not alter UCN-01/MEK1/2 inhibitor-mediated modifications in Bim(EL) phosphorylation but largely prevented cell death. Finally, IL-6 or IGF-1 failed to prevent MEK1/2 inhibitors from blocking UCN-01-induced Bim(EL) phosphorylation/degradation or cell death. Collectively, these findings argue that UCN-01-mediated ERK1/2 activation leads to Bim(EL) phosphorylation/inactivation, resulting in cytoprotection, and that interference with these events by MEK1/2 inhibitors plays a critical role in synergistic induction of apoptosis by these agents.
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PMID:MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. 1754 Aug 43

The role of adenosine monophosphate activated protein kinase (AMPK) in regulating multiple myeloma (MM) cell growth is not yet clear. In this study, we show that the AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAr) and D942 inhibit cell growth in MM cell lines. AICAr also induced an S-phase cell cycle arrest in all four tested cell lines and led to phosphorylation and thus activation of AMPK. Furthermore, the inhibition of a nucleoside transporter by nitrobenzyl-thio-9-beta-d-ribofuranosylpurine (NBTI), inhibition of the adenosine kinase by iodotubericidine and inhibition of AMPK by AMPKI Compound C reversed AICAr effects, indicating that the cellular effects of AICAr were mediated by AMPK. Activation of AMPK inhibited basal extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR) and P70S6 kinase (P70S6K) as well as AKT phosphorylation, and blocked IL-6, IGF-1, and HS-5 stromal cell conditioned medium-induced increase of cell growth. Troglitazone, which has previously been shown to activate AMPK, similarly inhibited MM cell growth, activated AMPK, and decreased ERK and P70S6K phosphorylation. Our results suggest that activation of AMPK inhibits MM cell growth despite stimulation with IL-6, IGF-1, or HS-5 stromal cell conditioned medium and represents a potential new target in the therapy of MM.
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PMID:Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells. 1766 98


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