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Multiple Myeloma Cell Lines (multiple + myeloma_cell_line)
Selected AbstractsGlucocorticoid resistance in a multiple myeloma cell line is regulated by a transcription elongation block in the glucocorticoid receptor gene (NR3C1)BRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Beatriz Sánchez-Vega Summary Glucocorticoid (GC) effects are mediated by the glucocorticoid receptor (GR). Several studies have demonstrated that a lower number of receptors per cell were associated with poor GC response. The regulation of GR expression is complex; the levels of GR can be autologously regulated by its ligand and also by transcriptional, post-transcriptional and post-translational mechanisms. Using three human myeloma cell lines that parallel the development of GC resistance, this work describes the mechanism involved in the downregulation of GR expression. The decreased expression was neither due to mutations in the gene encoding GR, NR3C1, nor due to methylation of the promoters. A gradual decrease in NR3C1 transcripts was seen during the development of resistance, the level of expression of exon 1 to 2 RNA fragments remained the same in sensitive and resistant cell lines but a chromatin immunoprecipitation assay demonstrated that RNA polymerase II, detectable throughout exon 2 to 3 in the sensitive cells, was undetectable on exon 3 in the resistant variant, suggesting lower or no transcription at this site. These studies demonstrated that downregulation of NR3C1 mRNA in a resistant cell line involves a block to transcriptional elongation within intron B of NR3C1. This block may represent an important element in the regulation of GR expression. [source] Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffoldsDRUG DEVELOPMENT RESEARCH, Issue 4 2007Stephen Gately Abstract The strategic replacement of carbon with silicon within biologically prevalidated drug scaffolds can generate focused libraries of pharmaceutically relevant agents with novel, durable and marketable intellectual property. This approach can be cost-effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods. The change in shape, charge, and lipophilicity that can result from the addition of silicon can favorably alter the biological activity and toxicology of the parent drug. Silicon-containing derivatives of indomethacin are COX-2 selective, suggesting they will not be associated with the classical toxicities associated with nonselective inhibition of the cyclooxygenases. The silicon-indomethacin derivatives also demonstrated superior anti-cancer activity at clinically achievable concentrations when tested in vitro against a human pancreatic cancer cell line, MiaPaCa-2, and a panel of 14 human multiple myeloma cell lines. Bioorganosilicon chemistry represents an attractive approach for emerging biopharmaceutical organizations seeking to rapidly develop a portfolio of novel pharmacological agents that have the potential for enhanced therapeutic and pharmacological benefit. Drug Dev Res 68:156,163, 2007. ©2007 Wiley-Liss, Inc. [source] Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myelomaHEMATOLOGICAL ONCOLOGY, Issue 1 2007Daniela Intini Abstract Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K- Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N- Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. Copyright © 2006 John Wiley & Sons, Ltd. [source] Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells,AMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2009Egarit Noulsri Iron chelators have been reported to induce apoptosis and cell cycle arrest in cancer cells. Recent studies suggest broad and selective antitumor activity of the new iron chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT; Whitnall et al., Proc Natl Acad Sci USA 2006;103:14901,14906). However, little is known concerning its effects on hematological malignancies. Using acute leukemia cells, the effect of Dp44mT on apoptosis, cell cycle, caspase-3 activation, and mitochondrial trans-membrane potential has been examined by flow cytometry. Dp44mT acted to induce a G1/S arrest in NB4 promyelocytic leukemia cells at low concentrations (0.5,2.5 ,M), being far more effective than the clinically used chelator, desferrioxamine (DFO). Moreover, Dp44mT induced apoptosis of NB4 cells in a dose- and time-dependent manner with markedly less effect on nonproliferating cells. The apoptosis-inducing activity of Dp44mT was significantly more effective than DFO. Furthermore, this study also showed that Dp44mT had broad activity, inducing apoptosis in several types of acute leukemia and also multiple myeloma cell lines. Additional studies examining the cytotoxic mechanisms of Dp44mT showed that a reduction in the mitochondrial trans-membrane potential and caspase-3 activation could be involved in the mechanism of apoptosis. Our results suggest that Dp44mT possesses potential as an effective cytotoxic agent for the chemotherapeutic treatment of acute leukemia. Am. J. Hematol. 2009. © 2008 Wiley-Liss, Inc. [source] The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cellsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2005Julian C. Desmond Summary 2-Methyl-naphtho[2,3- b]furan-4,9-dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin-C and adriamycin, the cytotoxicity of FNQ3 is often 10- to 14-fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose-dependent fashion (50% inhibitory concentration ,1·25 ,g/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL-60 myeloid cells in the presence of either 1,, 25(OH)2 dihydroxyvitamin D3 [1,,25(OH)2D3] or all- trans -retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies. [source] | ||||||||||