UMLS:C0026764 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

The understanding and control of many pathophysiological conditions is based on knowledge of subtly regulated intracellular signaling networks. We have found that in pervanadate (PV)-treated J558L myeloma cells, amongst other signaling proteins, protein kinase C (PKC)-delta and src homology 2-containing inositol phosphatase (SHIP) are tyrosine phosphorylated on expression of the B cell receptor, suggesting a role for these proteins in the preformed B cell receptor transducer complex. Rottlerin, a widely used PKC-delta-specific inhibitor, efficiently blocks these PV-induced tyrosine phosphorylation events. Furthermore, PV treatment of bone marrow-derived mast cells (BMMC) also results in tyrosine phosphorylation of PKC-delta, SHIP, and additional proteins. Rottlerin also inhibits these responses, indicating that PKC-delta might play an important enhancing role in the propagation of phosphotyrosine signals in B cells and mast cells and hence in the regulation of function of both cell types. Therefore, BMMC from PKC-delta -/- mice were generated by in vitro differentiation and assayed for tyrosine phosphorylation events in response to PV. Intriguingly, and opposite to the Rottlerin data, PKC-delta -/- BMMC show a stronger response to PV than wild-type cells, suggesting an attenuating role for PKC-delta. This response can be inhibited equally well by Rottlerin, indicating clearly that Rottlerin is not specific for PKC-delta in vivo. A comparison between Rottlerin and the panspecific PKC inhibitor bisindolylmaleimide suggests that Rottlerin also targets kinases beyond the PKC family. Moreover, Ser473 phosphorylation of protein kinase B (PKB) after PV treatment is blocked by Rottlerin as efficiently as by the phosphatidylinositol 3-kinase inhibitor LY294002. In this report, we provide evidence that PKC-delta constitutes a crucial attenuating factor in B cell and mast cell signal transduction and suggest that PKC-delta is important for the regulation of physiological B and mast cell functions as well as for their pathophysiology. Furthermore, dominant PKC-delta-independent effects of Rottlerin are presented, indicating restrictions of this inhibitor for use in signal transduction research.
...
PMID:Rottlerin-independent attenuation of pervanadate-induced tyrosine phosphorylation events by protein kinase C-delta in hemopoietic cells. 1150 60

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.
...
PMID:Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. 1183 Apr 93

Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 alpha) is crucially involved in the development of osteolytic bone lesions in multiple myeloma (MM). The current study was designed to determine the direct effects of MIP-1 alpha on MM cells. Thus, we were able to demonstrate that MIP-1 alpha acts as a potent growth, survival, and chemotactic factor in MM cells. MIP-1 alpha-induced signaling involved activation of the AKT/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) pathway. In addition, inhibition of AKT activation by phosphatidylinositol 3- kinase (PI3-K) inhibitors did not influence MAPK activation, suggesting that there is no cross talk between MIP-1 alpha-dependent activation of the PI3-K/AKT and extracellular-regulated kinase (ERK) pathway. Our data suggest that besides its role in development of osteolytic bone destruction, MIP-1 alpha also directly affects cell signaling pathways mediating growth, survival, and migration in MM cells and provide evidence that MIP-1 alpha might play a pivotal role in the pathogenesis of MM.
...
PMID:Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. 1250 12

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.
...
PMID:The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. 1268 35

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.
...
PMID:A new bisphosphonate, YM529 induces apoptosis in HL60 cells by decreasing phosphorylation of single survival signal ERK. 1367 34

Olanzapine has previously been shown to stimulate the growth of neuronal cells in culture. A major goal of the present studies was to determine if olanzapine also provided neuroprotection to pheochromocytoma (PC12) cells, SH-SY5Y neuroblastoma cells, and primary cultures of rat cortical neurons. Olanzapine was mitogenic and enhanced the survival of PC12 cells, SH-SY5Y cells and 3T3 preadipocytes, but not L6 myoblasts or myeloma cells. It protected neuronal cells from death induced by serum and glutamine deprivation, amyloid beta peptide (25-35), and fluphenazine. Molecular mechanisms of the neuroprotection by olanzapine were explored, specifically the activation of various protein kinase signaling pathways including Akt/protein kinase B (PKB), extracellular-regulated kinase (ERK), ERK1/2, and mitogen-activated protein kinase (MAPK), p38. Olanzapine treatment led to rapid phosphorylation of kinases from all three pathways in PC12 cells. Phosphorylation of Akt was blocked with selective inhibitors (wortmannin and LY294002), which implicates phosphoinositide 3-kinase (PI3K) in the signaling cascade. Short-term mitogenic effects of olanzapine were abolished with a selective inhibitor of Akt, but not by inhibition of the ERK pathway. Other antipsychotic drugs stimulated phosphorylation of a subset of the kinase panel, but not all three kinases. The present findings demonstrate that olanzapine has both mitogenic and neuroprotective effects in neuronal cells.
...
PMID:Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. 1514 Jun 44

There are many advantages to the use of protein-free media for biologics production, including a reduced risk of viral contamination from animal-derived proteins and simplification of downstream purification. In the course of developing protein-free media for hybridoma and myeloma cells, zinc was found to be an effective replacement for insulin, with no negative impact on viable cell density and antibody production. Transcript profiling using DNA microarrays indicated no major change in the global expression profile between the insulin and zinc-supplemented cultures, which is consistent with their similar growth and metabolic characteristics. Both DNA microarray and quantitative RT-PCR analysis showed increase in insulin receptor substrate 1 (Irs1) expression in zinc-supplemented cultures, while several key genes downstream of Irs1 in the insulin-signaling pathway, such as protein kinase B (PKB/Akt) and 3-phosphoinositide dependent protein kinase 1 (Pdpk1) did not show significant differences at the transcript level. Comparison of transcript profiles from cultures with low versus optimal zinc supplementation implicated the involvement of the insulin-related genes Pax6 and Phas1. Subtle differences were also observed between insulin and zinc in the serine-473 phosphorylation of Akt. Zinc increased serine-473 phosphorylation of Akt, but to a lesser extent than insulin. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, totally blocked the effect of both zinc and insulin on Akt activation, indicating the involvement of PI3K in the activation of Akt by zinc, rather than zinc acting on Akt directly. Our results highlight the impact of trace metal supplementation as protein-free media formulations move towards greater chemical definition.
...
PMID:Zinc as an insulin replacement in hybridoma cultures. 1622 92

Atiprimod is a novel anticancer and antiangiogenic drug candidate which is currently being evaluated in patients with liver carcinoid and multiple myeloma. In this study, we report that atiprimod selectively inhibited proliferation and induced apoptosis in HCC cells that expressed either hepatitis B virus (HBV) or hepatitis C virus, through deactivation of protein kinase B (Akt) and signal transducers and activators of transcription 3 (STAT3) signaling. In HepG2 AD38 cells, which express HBV genome under the control of a tetracycline-off promoter, both Akt and STAT3 were constitutively activated in response to HBV expression. However, this constitutive activation was not sensitive to lamivudine, a drug that inhibits HBV replication without affecting its gene expression, suggesting that HBV replication per se might not be responsible for the activation. Interestingly, the electrophoretic mobility of p-STAT3 protein bands on immunoblot was slower when AD38 cells were cultured in the absence of tetracycline, suggesting a differential phosphorylation in response to HBV expression. In HCC cells, interleukin 6 stimulates the phosphorylation of STAT3 both at serine 727 and at tyrosine 705 positions. The interleukin 6-stimulated activation of STAT3 and Akt was inhibited not only by atiprimod but also by LY294002, a phosphoinositide-3-kinase-specific inhibitor, and by NS398, a cyclooxygenase-2-selective inhibitor. The combination of these compounds did not produce any additive effect, implying that the mechanisms by which HBV activates Akt and STAT3 might also involve phosphoinositide-3-kinase and cyclooxygenase-2. Collectively, these results suggest that atiprimod could be useful as a multifunctional drug candidate for the treatment of HCC in humans.
...
PMID:Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod. 1723 71

NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is currently being evaluated in a phase I/II clinical trial. Here we show that NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary myeloma cells at nanomolar concentrations in a time and dose dependent fashion. Further experiments revealed induction of apoptosis in three of four cell lines. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and additive activity of NVP-BEZ235 together with melphalan, doxorubicin and bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly effective and NVP-BEZ235 represents a potential new candidate for targeted therapy in multiple myeloma.
...
PMID:The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. 1907 Nov 9

Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2'-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G(1) cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma.
...
PMID:Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. 1917 58

1 2 3 4 Next >>