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)

The vascularization is a very important part of a structure of each tissue both normal, including bone marrow stroma, and pathologically changed. Neoplastic tissues secure supplying in necessary substances for growth and expansion through regulated by its own cells neovasculation. Key role in multipotential cell's differentiation to endothelial cells plays regulatory system consisted of vascular-epithelial growth factor's family (VEGF B, C, D), receptors VEGFR-1, -2, -3, and system Tie2/angiopoetins. Stimulation and importance of angiogenesis for expansion of neoplastic diseases is a current problem in oncology. It is pointed to importance of neovascularization in pathogenesis of acute and chronic leukemias, lymphomas and multiple myeloma. The knowledge of the importance ofvascularization of neoplastic tissues is availing in therapy (researching of substances inhibiting angiogenesis--semaxinib, SU6668, ZD 6474, thalidomid, cetuximab, gefitinib, interferon-alpha, irradiation and others), in diagnostics as a monitoring of a success of the therapy, and in prognosis. Inhibitors ofangiogenesis are antineoplastic drugs with relatively lower toxicity, and lower risk of drug-resistance than conventional chemotherapy what has the importance especially during prolong administration, so they can be an alternative way of therapeutic process. During qualification for antiangiogenic therapy it is necessary to have a consciousness of its limited efficiency.
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PMID:[Clinical importance of angiogenesis and angiogenic factors in oncohematology]. 1760 67

VEGF (vascular endothelial growth factor), a potent angiogenic molecule specific for vascular endothelial cells, is overexpressed in most tumours including MM (multiple myeloma) and closely associated with tumour growth and prognosis. It has been shown that a soluble fragment of the VEGF receptor Flt-1 (Fms-like tyrosine kinase-1) [sFlt-1 (soluble Flt-1)] has antiangiogenic properties by way of its antagonist activity against VEGF. VEGF and its receptors have been shown to be targets for treating tumours. In the present study, sFlt-1 gene was expressed in Pichia pastoris and the product was applied for studying the effect on KM3 MM cells. sFlt-1 gene was inserted into the pPICZalphaA vector and the expressed product was analysed by SDS/PAGE, immunoblot and ELISA. The sFlt-1 protein was expressed by 0.5% (v/v) methanol induction and it accumulated up to 23% of total proteins in the supernatant. The product was further purified with metal-chelating resin [Ni-NTA (Ni(2+)-nitrilotriacetate)]. The functional analysis of the sFlt-1 protein was performed with HUVEC (human umbilical-vein endothelial cells) proliferation assay. We next showed that the sFlt-1 protein acted directly on MM cells and inhibited the VEGF-induced proliferation of MM cells with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] and (3)H uptake assay. The sFlt-1 protein blocked VEGF-induced ERK (extracellular-signal-regulated kinase) phosphorylation and inhibited the MAPK (mitogen-activated protein kinase) signalling cascades. The present study demonstrated that anti-MM activity of the sFlt-1 protein, coupled with its antiangiogenic effects, provides the basis for clinical trials of this agent to improve the outcome in MM.
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PMID:Expression of soluble Flt-1 gene in Pichia pastoris and the effect of the product on multiple-myeloma cells in vitro. 1761 89

Angiogenesis plays an important role in the progression of tumors. This relationship has been described in several hematologic malignancies. Vascular endothelial growth factor and basic fibroblast growth factor are predictors of poor prognosis in leukemia and non Hodgkin's lymphoma. Bone marrow microvessels were found increased in multiple myeloma, but also in lymphoma and in acute lymphoblastic leukemia. Microvessel density is correlated with decreased survival in myeloma patients and relapse or resistance to chemotherapy in lymphoma. New drugs with antiangiogenic activity such as bevacizumab (binding and inactivation of VEGF) or VEGF-tyrosine kinase inhibitors have shown promising results in phase 1 trials. It will therefore be a future challenge to integrate anti-angiogenesis agents in currently existing treatment protocols to improve the outcome of therapy.
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PMID:[Angiogenesis and hematologic malignancy]. 1784 10

In order to investigate the effects of phenylhexyl isothiocyanate (PHI) on proliferation and apoptosis of multiple myeloma cells RPMI8226 in vitro, the RMPI8226 cells were co-cultured with PHI at various concentrations; the apoptosis of PHI-treated cells was assayed by TUNEL; the cell cycle changes of PHI-treated cells were analyzed by FCM; the mitochondrial potential changes of PHI-treated cells were detected by using a potential sensitive dye JC-1 as probe; the VEGF levels secreted from PHI-treated cells were measured by quantitative sandwich ELISA. The results showed that PHI significantly inhibited RPMI8226 cell proliferation, induced their apoptosis at low concentration (0.5 micromol/L), the inhibitory effect was related to PHI concentration. PHI-treated cells were arrested in G(0)/G(1) phase. The RPMI8226 cells showed shift from red fluorescence to green fluorescence in some concentration-dependent manner, indicating increase of mitochondrial depolarization and potential loss by 3-4-fold as compared with control, after treated RMPI8226 cells with 10 micromol/L of PHI for 48 hours, the VEGF level secreted from RMPI8226 cells significantly decreased, it was 35% of control. It is concluded that the PHI can inhibit cell proliferation, induce cell apoptosis of RMPI8226, the cell apoptosis is associated with mitochondrial depolarization and potential loss, the inhibiting VEGF secretion from RMPI8226 cells by PHI may be one of the reasons causing apoptosis. PHI may be a potential therapeutic drug for multiple myeloma.
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PMID:[Effect of phenylhexyl isothiocyanate on inducing apoptosis of multiple myeloma cells in vitro]. 1831 7

Our previous studies have demonstrated the effects of brain derived neurotrophic factor (BDNF) on promoting proliferation of multiple myeloma (MM) cells and inducing angiogenesis in MM in vitro. To further investigate whether the PI3K/Akt and MEK1/ERK pathway play a role in the BDNF-induced angiogenesis in vitro and to explore the further molecular mechanisms, two ways to establish human myeloma xenograft animal model were developed, their advantages and disadvantages were elucidated. The phosphorylation of AKT and ERK1/2 were detected in human umbilical vein endothelial cells (HUVECs) by Western blot. The angiogenic activity in vitro was evaluated by transwell migration assay and tubule formation assay. Cell proliferation was determined by crystal violet staining. Cell apoptosis was detected by FITC-Annexin-V/PI double staining and flow cytometry. The results showed that the BDNF activated the PI3K/Akt and MEK1/ERK pathway in the time-dependent manner. Ly294002 and PD98059 blocked the activation of Akt and ERK1/2 respond to BDNF. 100 ng/ml BDNF significantly increased HUVEC tube formation, migration and proliferation in vitro at a similar degree of 25 ng/ml VEGF. Furthermore, tube formation of HUVECs toward BDNF was significantly inhibited by 57% and 40% with 20 micromol/L Ly294002 and 20 micromol/L PD98059 treatment, respectively. At the same time, Ly294002 and PD98059 reduced the BDNF-induced migration of HUVECs by 74% and 36%, respectively. While BDNF-induced survival was only blocked by Ly294002 and BDNF-induced proliferation was only inhibited by PD98059. It is concluded that BDNF promotes angiogenesis of HUVECs in vitro. ERK and Akt are two crucial events in BDNF-mediated signal transduction leading to HUVECs angiogenesis by different mechanisms. Moreover, the latter is more important.
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PMID:Brain derived neurotrophic factor induces endothelial cells angiogenesis through AKT and ERK1/2 signal pathway. 1831 25

During the last decade several novel agents have been used in the management of patients with multiple myeloma. Immunomodulatory drugs and proteasome inhibitors exert their efficacy both directly by inducing apoptosis of myeloma cells and indirectly through the interruption of the interactions between myeloma and stromal cells in the bone marrow (BM) microenvironment. These interactions are crucial for myeloma cell growth and survival. The adherence of myeloma cells to BM stromal cells leads to the overproduction of several cytokines with angiogenic properties that enhance the survival and growth of myeloma cells through paracrine and autocrine loops. The correlation of these molecules with clinical features and survival of myeloma patients supports the importance of angiogenesis in the pathogenesis of the disease and reveals these cytokines as suitable targets for the development of novel anti-myeloma therapies. This review summarises all available preclinical and clinical data for the effect of novel agents that are used in myeloma therapy, such as thalidomide, lenalidomide, bortezomib and VEGF inhibitors, on angiogenesis, which is at least partially responsible for their remarkable anti-myeloma efficacy.
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PMID:Novel anti-myeloma agents and angiogenesis. 1839 34

This study was aimed to investigate the effect of VEGF antisense RNA on proliferation and apoptosis in myeloma cell line U266 as well as on angiogenesis in endothelial cell ECV304, and to explore the feasibility of gene therapy for multiple myeloma using VEGF antisense RNA. The VEGF121 cDNA was inserted into multiple clone site of eukaryotic expression vector pIRES2-EGFP to construct the recombinant plasmid AS-VEGF. Restriction endonuclease analysis and DNA sequencing were used to confirm the reverse orientation of the VEGF cDNA. The recombinant plasmid was transfected into human myeloma cell line U266 and the positive clone was screened by G418. The VEGF mRNA and protein expressions of the positive clone were detected by RT-PCR and Western blot respectively. The viability and apoptosis of U266 cells were observed by MTT assay, flow cytometry. Angiogenesis was tested by network formation of endothelial cells on matrigel. The results indicated that the recombinant plasmid AS-VEGF expressing VEGF antisense RNA were constructed successfully. VEGF expression in U266 cells was blocked partially by VEGF antisense RNA. Expression of VEGF mRNA and protein decreased more significantly in U266 cells transfected by AS-VEGF than that in control group. Then increasing of apoptosis and inhibition of proliferation in U266 cells transfected by AS-VEGF were observed. Vasoformation on matrigel in the supernatants of U266 culture group transfected by AS-VEGF decreased more significantly than that in control group. It is concluded that VEGF antisense RNA can inhibit the expression of VEGF gene in U266 cells, thereby inhibits the proliferation of U266 cells; increases the apoptosis of U266 cells; and inhibits angiogenesis in vitro.
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PMID:[Effect of VEGF antisense RNA on inducing apoptosis of myeloma cells and inhibition of angiogenesis in endothelial cells in vitro]. 1842 55

The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three "hot spots" at 400x magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF-positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three "hot spots". There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (> or = 15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma.
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PMID:Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance. 1844 11

Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6-induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein and mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells.
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PMID:Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. 3018 8

Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the myeloma cells and induced apoptosis in a concentration as low as 0.5 muM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 muM. Cell cycle analysis revealed that PHI caused G1-phase arrest of RPMI8226 cells. PHI induced p16 hypomethylation in a concentration- dependent manner. PHI was further shown to induce histone H3 hyperacetylation in a concentration-dependent manner. It was also demonstrated that PHI inhibited IL-6 receptor expression and VEGF production in the RPMI8226 cells, and reactivated p21 expression. It was found that PHI induced apoptosis through disruption of mitochondrial membrane potential. For the first time we show that PHI can induce both p16 hypomethylation and histone H3 hyperacetylation. We conclude that PHI has dual epigenetic effects on p16 hypomethylation and histone hyperacetylation in myeloma cells and targets several critical processes of myeloma proliferation.
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PMID:Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways. 1857 63

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