UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Farnesyl transferase inhibitors (FTIs) are anticancer agents designed to target ras processing and ras-dependent signal pathways. Because oncogenic ras mutations are found in up to 50% of multiple myeloma (MM) specimens, these agents may be effective in this disease. However, some preclinical studies suggest that FTI antitumor responses are unrelated to effects on ras. To address this issue in myeloma, we used the ANBL-6 myeloma cell line where interleukin (IL)-6-dependent cells are stably transfected with mutated N-ras or K-ras genes. Because expression of mutated ras allows for IL-6-independent growth, this is a good model to test whether FTIs specifically target growth-promoting ras-activated pathways in myeloma. Although they had little effect in 10% serum, two separate FTIs induced apoptosis of myeloma cells when cultured in low serum, and mutated ras-expressing cells were more sensitive than wild-type (WT) ras-expressing cells. However, induction of apoptosis did not correlate with inhibition of ras processing. Although they had no effect on AKT activity, under low serum conditions FTIs inhibited constitutive activation of the p70S6kinase and nuclear factor kappaB signal proteins in both mutated ras-expressing MM lines and extracellular signal-regulated kinase (ERK) activity in mutated N-ras-expressing cells. However, in studies where p70, nuclear factor kappaB, and ERK were comparably inhibited by other inhibitors or by gene transfer, we could not identify effects on these pathways as participating in the apoptotic response. FTIs were also able to abrogate the IL-6 proliferative response of WT ras-expressing MM cells, and this was associated with inhibition of IL-6-induced activation of ERK, AKT, and p70. The induction of apoptosis and prevention of the IL-6 response in MM cells containing mutated or WT ras provide support for the therapeutic potential of FTIs in this disease.
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PMID:Cytoreductive effects of farnesyl transferase inhibitors on multiple myeloma tumor cells. 1281 36

Cytokines exert multiple biological functions through binding to their specific receptors that triggers activation of intracellular signaling cascades. The cytokine-mediated signals may produce variable and even opposing effects on different cell types, depending on cellular context, which also are dictated by the differentiation stage of the cell. Multiple myeloma is a monoclonal proliferative disorder of human plasma cells. Despite their clonal origin, myeloma cells appear to include mixed subpopulations in accordance with expression of their surface antigens, such as CD45, CD49e, and MPC-1. Although interleukin-6 (IL-6) is widely accepted as the most relevant growth factor for myeloma cells in vitro and in vivo, only a few subpopulations of tumor cells, such as CD45(+)MPC-1(-)CD49e- immature cells, proliferate in response to IL-6. We recently showed that IL-6 efficiently activated both signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) in CD45- myeloma cell lines, although CD45- cells failed to proliferate in response to IL-6. In contrast, src family protein-tyrosine kinases (PTKs), the most important substrates for CD45 protein-tyrosine phosphatase (PTP) are found activated independently of STAT3 and ERK1/2 activation in CD45+ but not in CD45- myeloma cell lines. Therefore activation of both STAT3 and ERK1/2 is not sufficient for IL-6-induced proliferation of myeloma cells, which requires the src family kinase activation associated with CD45 expression. We propose a mechanism for IL-6-induced cell proliferation that is strictly dependent on the cellular context in myelomas.
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PMID:Interleukin-6-induced proliferation of human myeloma cells associated with CD45 molecules. 1295 2

Since the first identification of interleukin (IL)-6 as a myeloma cell growth factor by Dr. Kawano's and Dr. Klein's groups 14 years ago, numerous studies have emphasized its major roles in the emergence of malignant plasma cells in vivo and in the generation of normal plasma cells. Four transcription factors control B-cell differentiation into plasma cells. The B-cell transcription factor pax-5 is mainly responsible for a B-cell phenotype, and bcl-6 represses the plasma cell transcription factor blimp-1 and plasma cell differentiation. bcl-6 expression is triggered by CD40 and IL-4 activation. A lack of CD40 and IL-4 activation yields a down-regulation of bcl-6 expression, and IL-6 stimulation yields an up-regulation of blimp-1, mainly through STAT3 activation. Blimp-1 further down-regulates bcl-6 and pax-5 expression and makes plasma cell differentiation possible. IL-6 as well as IL-10 up-regulate XBP-1. XBP-1 is another transcription factor that is involved in plasma cell differentiation and whose gene expression is shut down by pax-5. The plasma cell transcription factors blimp-1 and XBP-1 are up-regulated, and the B-cell transcription factors bcl-6 and pax-5 are down-regulated, in malignant cells compared to B-cells. Apart from the recent identification of these 4 transcription factors, the factors involved in normal plasma cell generation are mostly unknown. Regarding malignant plasma cells, 3 categories of growth factors have been identified: (1) the IL-6 family cytokines, IL-10, and interferon alpha that activate the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase pathways; (2) growth factors activating the phosphatidylinositol (PI)-3 kinase/AKT and MAP kinase pathways, unlike the JAK/STAT pathway (insulin-like growth factor 1, hepatocyte growth factor, and members of the epidermal growth factor family able to bind syndecan-1 proteoglycan); and (3) B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL) that activate the nuclear factor KB and PI-3 kinase/AKT pathways. BAFF and APRIL bind to BAFF receptor and TACI and are major B-cell survival factors. Recent data indicate that these various growth factors may cooperate to provide optimum signaling because they are localized together and with cytoplasmic transduction elements in caveolinlinked membrane caveolae. The identification of these myeloma cell growth factors and of the associated transduction pathways should provide novel therapeutic targets in multiple myeloma.
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PMID:Survival and proliferation factors of normal and malignant plasma cells. 1295 3

It is believed that bisphosphonates (BPs) induce apoptosis in cells such as myeloma cells, as they inhibit prenylation of G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. In the present study, we attempted to clarify the mechanism by which YM529, a new bisphosphonate, induces apoptosis. YM529 induced cell deaths in HL60 cells in a concentration-dependent manner. At that time, we observed an increase in Caspase-3 activity and morphological fragmentation of the nuclei. We could confirm that these cell deaths were evidence of apoptosis. The apoptosis induced by YM529 was not inhibited by the addition of farnesyl pyrophosphate (FPP), but was by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of YM529 caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38) exhibited no change. In addition, no quantitative change was observed in Bcl-2, which is an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggest that YM529, the new bisphosphonate, induced apoptosis when inhibit GGPP synthase and consequently decreased the levels of phosphorylated ERK, which is a survival signal; moreover, during this process, there is no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggest that YM529 can be used as an anticancer agent, in addition to its use as a therapeutic agent to treat osteoporosis.
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PMID:A new bisphosphonate, YM529 induces apoptosis in HL60 cells by decreasing phosphorylation of single survival signal ERK. 1367 34

Multiple myeloma (MM) is an incurable form of cancer characterized by accumulation of malignant plasma cells in the bone marrow. During the course of this disease, tumor cells cross endothelial barriers and home to the bone marrow. In latter stages, myeloma cells extravasate through blood vessels and may seed a variety of organs. Insulin-like growth factor I (IGF-I) is one of several growth factors shown to promote the growth of MM cells. In the current study, we have assessed the ability of IGF-I to serve additionally as a chemotactic factor affecting the mobility and invasive properties of these cells. Results indicate that IGF-I promotes transmigration through vascular endothelial cells and bone marrow stromal cell lines. Analysis of endogenous signaling pathways revealed that protein kinase D/protein kinase Cmicro (PKD/PKCmicro) and RhoA were both activated in a phosphatidylinositol 3-kinase (PI-3K)-dependent manner. Inhibition of PI-3K, PKCs, or Rho-associated kinase by pharmacologic inhibitors abrogated migration, whereas mitogen-activated protein kinase (MAPK), Akt, and p70S6 kinase inhibitors had no effect. These results suggest that IGF-I promotes myeloma cell migration by activation of PI-3K/PKCmicro and PI-3K/RhoA pathways independent of Akt. The identification of IGF-I as both a proliferative and migratory factor provides a rational basis for the development of targeted therapeutic strategies directed at IGF-I in the treatment of MM.
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PMID:Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. 1450 85

Interactions between the small molecule Bcl-2 inhibitor HA14-1 and proteasome inhibitors, including bortezomib (Velcade; formerly known as PS-341) and MG-132, have been examined in human multiple myeloma cells. Sequential (but not simultaneous) exposure of MM.1S cells to bortezomib or MG-132 (10 h) followed by HA14-1 (8 h) resulted in a marked increase in mitochondrial injury (loss of DeltaPsim, cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), activation of procaspases-3, -8, and -9, and Bid, induction of apoptosis, and loss of clonogenicity. Similar interactions were observed in U266 and MM.1R dexamethasone-resistant myeloma cells. These events were associated with Bcl-2 cleavage, Bax, Bak, and Bad accumulation, mitochondrial translocation of Bax, abrogation of Mcl-1, Bcl-xL, and XIAP upregulation, and a marked induction of JNK and p53. Bortezomib/HA14-1 treatment triggered an increase in reactive oxygen species (ROS), which, along with apoptosis, was blocked by the free radical scavenger N-acetyl-L-cysteine (L-NAC). L-NAC also opposed bortezomib/HA14-1-mediated JNK activation, upregulation of p53 and Bax, and release of cytochrome c and Smac/DIABLO. Finally, bortezomib/HA14-1-mediated apoptosis was unaffected by exogenous IL-6. Together, these findings indicate that sequential exposure of myeloma cells to proteasome and small molecule Bcl-2 inhibitors such as HA14-1 may represent a novel therapeutic strategy in myeloma.
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PMID:The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. 1451 55

Insulin-like growth factor-1 (IGF-I) is a growth and survival factor in human multiple myeloma (MM) cells. Here we examine the effect of IGF-I on MM cell adhesion and migration, and define the role of beta1 integrin in these processes. IGF-I increases adhesion of MM.1S and OPM6 MM cells to fibronectin (FN) in a time- and dose-dependent manner, as a consequence of IGF-IR activation. Conversely, blocking anti-beta1 integrin monoclonal antibody, RGD peptide, and cytochalasin D inhibit IGF-I-induced cell adhesion to FN. IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85(PI3-K). IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and beta1 integrin colocalize to lipid rafts on the plasma membrane after IGF-I stimulation. In addition, IGF-I triggers polymerization of F-actin, induces phosphorylation of p125(FAK) and paxillin, and enhances beta1 integrin interaction with these focal adhesion proteins. Importantly, using pharmacological inhibitors of phosphatidylinositol 3'-kinase (PI3-K) (LY294002 and wortmannin) and extracellular signal-regulated kinase (PD98059), we demonstrate that IGF-I-induced MM cell adhesion to FN is achieved only when PI3-K/AKT is activated. IGF-I induces a 1.7-2.2 (MM.1S) and 2-2.5-fold (OPM6) increase in migration, whereas blocking anti-IGF-I and anti-beta1 integrin monoclonal antibodies, PI3-K inhibitors, as well as cytochalasin D abrogate IGF-I-induced MM cell transmigration. Finally, IGF-I induces adhesion of CD138+ patient MM cells. Therefore, these studies suggest a role for IGF-I in trafficking and localization of MM cells in the bone marrow microenvironment. Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.
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PMID:Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling. 1452 9

Multiple myeloma (MM) is a proliferative disorder of monoclonal plasma cells which accumulate in human bone marrow, and myeloma cells proliferate in response to a cytokine, interleukin-6 (IL-6). We recently found that MPC-1- CD49e- immature myeloma cells expressing CD45 form a proliferating population in MM. IL-6 activates at least two intracellular pathways including signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) following the activation of Janus kinases (JAKs) via its receptor complexes composed of the IL-6 receptor alpha chain and gp130. Although the roles of CD45 have been extensively studied for antigen receptors in B and T cells, its physiological consequences in other hematopoietic cells remain largely unknown. Myeloma cells expressing CD45 antigens which contain the activation of src family protein-tyrosine kinases (PTKs) independent of IL-6 stimulation proliferate in response to IL-6, whereas the proliferation of CD45- cells which lack a considerable activity of the src family PTKs is not promoted by IL-6. The STAT3 and ERK1/2 pathways are similarly activated by IL-6 in both cells either expressing or not expressing CD45. In this review, we argue a novel mechanism of proliferation of myeloma cells, in that the activation of both STAT3 and ERK1/2 is not sufficient for IL-6-induced proliferation which further requires IL-6-independent activation of the src family kinases associated with CD45 phosphatase. We propose that the cellular context, such as CD45 expression and src family kinase activation, is crucial for myeloma cells to proliferate in response to IL-6.
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PMID:Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation. 1456 47

Cytokines of the gp130 family, particularly interleukin 6 (IL-6), play a central role in the growth and survival of malignant plasma cells. Recently, novel neurotrophin-1 (NNT-1)/B cell-stimulating factor-3 (BSF-3), also reported as cardiotrophin-like cytokine (CLC), was identified as a cytokine belonging to the gp130 family. BSF-3, similar to IL-6, exerts regulatory effects on normal B cell functions, but its functional significance in haematological malignancies has not been defined. The purpose of this study was to evaluate the biological effects and signalling pathways that are induced by BSF-3 in malignant plasma cells. Recombinant human BSF-3 was found to have growth stimulatory activity on plasmacytoma cell lines and primary tumour cells. In addition, BSF-3 was able to protect from Dexamethasone (Dex)-induced apoptosis. BSF-3 stimulated cell growth could not be inhibited by neutralizing anti-IL-6 or anti-IL-6 receptor antibodies, but was abrogated by anti-gp130 antibodies. In INA-6.Tu11 cells, a subline of the IL-6-dependent human plasma cell line INA-6 expressing gp130 and the receptor for leukaemia inhibitory factor (LIF), stimulation with BSF-3 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). AG490, an inhibitor of Janus kinases, decreased BSF-3 induced cell growth in a dose-dependent manner. This correlated with a reduction of STAT3 phosphorylation levels, while p44/42 mitogen-activated protein kinase (MAPK) phosphorylation was not affected. In conclusion, BSF-3 is a novel myeloma growth and survival factor with a potential role in the pathophysiology of the disease.
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PMID:Functional significance of novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) for human myeloma cell growth and survival. 1463 78

Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.
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PMID:GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. 1464 94

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