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)

Multiple myeloma (MM) is an incurable plasma cell malignancy marked by eventual resistance to therapy. Although arsenic trioxide (ATO) can induce apoptosis in MM cell lines, the in vivo activity of ATO in MM has been disappointing. The existence of ATO resistance mechanisms in MM can be inferred. We sought to generate hypotheses for ATO resistance by studying the gene expression profiles of MM cells that survived in culture with 0.5 micromol/l ATO. Among the 31 genes whose quantitative levels of expression (QLE) significantly increased in ATO were haem oxygenase 1 (HO-1) and metallothionein-2A (MT-2A). Among the 56 genes whose QLE were significantly decreased were genes that modulate cell cycling [BTBD2 and IGFBP7 (mac25)] and sensitivity to reactive oxygen species (ROS) (BACH2). HO-1 exerts an anti-apoptotic effect in ischaemic cells, and MT-2A chelates ATO intracellularly. Inhibition of HO-1 with tin protoporphyrin enhances ROS in MM cells in ATO, and addition of N-acetylcysteine increases MT-2A. Protective antioxidant responses occur in MM cells exposed to ATO, and may occur in stromal cells as well, and act to quench ROS and provide diffusible anti-apoptotic factors. They may also involve cysteine-rich proteins that chelate ATO and modulate redox-sensitive residues on proteins, such as nuclear factor kappa B and p53. A better understanding of ATO resistance will enable ATO to be combined with other agents for MM.
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PMID:Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. 1572 85

The intravertebral vacuum cleft sign (VCS) is an uncommon radiological sign, characterized by a radiolucent zone in the vertebral body. It is composed of 95% nitrogen and small amounts of oxygen and carbon dioxide. Post-traumatic ischemic necrosis could be its physiopathological mechanism, along with other pathologies like osteoporosis, corticosteroid therapy, diabetes, arteriosclerosis, alcoholism, multiple myeloma, bone metastasis and osteomyelitis. The broad diagnosis is made by antero-posterior X-ray, but computed tomography scan (CT scan) and magnetic resonance imaging (MRI) may help with the differential diagnosis. The aims of this paper are, on one hand, to communicate the clinical case of a 73-year-old osteoporotic woman with traumatic vertebral fractures who developed this sign in her radiological survey. On the other hand, its secondary aims are to review the medical literature about this sign and to show the clinical and radiological evolution after a percutaneous vertebroplasty.
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PMID:The vacuum cleft sign: an uncommon radiological sign. 1573 85

The generation of reactive oxygen species (ROS) by mitochondrial electron transport chain (ETC) and oxidative phosphorylation activity, has been linked to modifications of multiple molecular processes, including lipid peroxidation, signaling pathway and transcription factor modulation, and oxidative damage to DNA. Oxidative damage by endogenous ROS has been associated with the etiology of various pathological states. There are numerous reports that levels of manganese superoxide dismutase enzyme (MnSOD), an antioxidant enzyme responsible for the attenuation of ROS, are lowered in cancer cells, but the reasons for this reduction are poorly defined. Epigenetic silencing of genes involved in tumor suppression and DNA repair is known to occur in a variety of malignant cell types. Here we report that in the human multiple myeloma cell line KAS 6/1, the SOD-2 gene, encoding manganese superoxide dismutase, is epigenetically silenced as a result of promoter hypermethylation. The DNA methyltransferase inhibitor Zebularine reverses SOD-2 promoter methylation, increasing gene expression and enzyme levels. Infection of KAS 6/1 cells with a recombinant adenovirus carrying the MnSOD cDNA reduced the cell proliferation rate by approximately one-half, confirming the detrimental effects of epigenetic silencing of SOD-2 expression.
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PMID:Epigenetic silencing of manganese superoxide dismutase (SOD-2) in KAS 6/1 human multiple myeloma cells increases cell proliferation. 1590 83

Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadolinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies. MGd induces apoptosis in B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and highly resistant myeloma cell lines. Furthermore, MGd is additive or synergistic with ionizing radiation, several chemotherapy agents, and rituximab in vitro and in vivo tumor models. Through gene expression profiling, various stress-related genes are upregulated in response to MGd, including genes encoding metallothioneins, heat shock proteins, and heme oxygenase. Preliminary results from clinical trials with MGd in hematopoietic malignancies have shown that it is well tolerated, with minimal hematologic side effects in both; it has single agent activity in very heavily pretreated chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and it has induced prompt complete remissions in combination with 90Yttrium-ibritumomab (Y-90 Zevalin; Biogen Idec Inc., Cambridge, MA) for relapsed non-Hodgkin's lymphoma in the first two cohorts of patients enrolled. Various clinical trials studying MGd as a single agent and in combination with radiation and/or chemotherapy for the treatment of hematologic malignancies are ongoing.
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PMID:Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies. 1596 82

The metabolism of myeloma cells was altered to reduce lactate production in consecutive fed-batch cultures. The glucose concentration was maintained at low levels (0.28-0.55 mM) by employing a dynamic nutrient feeding method based on on-line measurement of the oxygen uptake rate (OUR) to estimate the metabolic demand of the cells. This strategy has been previously reported to be applied to cultures of hybridoma cells, in which the production of lactate was significantly reduced by thus maintaining the glucose concentration at low levels. However, for this cell line, a single fed-batch culture was not sufficient to alter the cellular metabolism, even at a glucose concentration of 0.28 mM. Two consecutive fed-batch cultures were employed to ensure that the cells were cultivated under a low glucose concentration for a sufficiently prolonged period of time to allow a switch of the cellular metabolism from a glycolytic (high lactate production) to oxidative (low lactate production) state.
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PMID:Alteration of cellular metabolism by consecutive fed-batch cultures of mammalian cells. 1623 58

Recombinant human erythropoietin (epoetin) has become the standard of care in the treatment of anaemia resulting from cancer and its treatment, and chronic kidney disease. The discovery that erythropoietin and its receptor are located in regions outside the erythropoietic system has led to interest in the potential role of epoetin in other tissues, such as the central nervous system. Animal studies have shown that systemically applied epoetin can cross the blood-brain barrier, where it reduces tissue injury associated with stroke, blunt trauma and experimental autoimmune encephalomyelitis. Pilot studies in humans have shown that epoetin treatment given within 8 h of stroke reduces infarct size and results in a significantly better outcome when compared with placebo treatment. Studies also suggest that epoetin has the potential to improve cognitive impairment associated with adjuvant chemotherapy in patients with cancer. Anaemia is a major factor causing tumour hypoxia, a condition that can promote changes within neoplastic cells that further tumour survival and malignant progression and also reduces the effectiveness of several anticancer therapies including radiotherapy and oxygen-dependent cytotoxic agents. Use of epoetin to prevent or correct anaemia has the potential to reduce tumour hypoxia and improve treatment outcome. Several therapeutic studies in anaemic animals with experimental tumours have shown a beneficial effect of epoetin on delaying tumour growth. Furthermore, clinical observations in patients with multiple myeloma and animal studies have suggested that epoetin has an antimyeloma effect, mediated via the immune system through activation of CD8+ T cells. Therefore, the role of epoetin may go well beyond that of increasing haemoglobin levels in anaemic patients, although additional studies are required to confirm these promising results.
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PMID:Beyond anaemia management: evolving role of erythropoietin therapy in neurological disorders, multiple myeloma and tumour hypoxia models. 1624 7

Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45(+) U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45(+) myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45(-) cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45(+) U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45(+) U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.
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PMID:Increased susceptibility to apoptosis in CD45(+) myeloma cells accompanied by the increased expression of VDAC1. 1624 87

Imexon (NSC-714597) is an aziridine-containing imminopyrolidone in Phase I clinical trials. The current studies compared biological indices of cytotoxicity in 7 human multiple myeloma (MM) cell lines to develop a correlative model for imexon sensitivity. In the MM cell lines there was a wide range of sensitivity to imexon measured by standard cytotoxicity assays (MTT) and by viability/apoptosis/necrosis (Annexin-V-FITC/PI) measurements. The following sensitivity pattern was observed in order of decreasing sensitivity: IM-9 > 8226/S > MM.1S, ARH-77, H929 > 8226/I > U266. The same descending rank order was seen for loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS) and, at high drug concentrations, thiol depletion. Cell cycle analysis showed imexon sensitive cells accumulate at the G2/M interphase. Although there was a positive correlation between increasing CuZnSOD levels and imexon resistance, no relationship was found for catalase, Bcl-2, mitochondrial thioredoxin or MnSOD levels. These findings suggest consistent phenotypes for imexon sensitivity and resistance in human MM cell lines exposed to drug for 48 h, with a combination of apoptosis and necrosis. Resistance is correlated with CuZnSOD expression, reduced drug accumulation, lack of ROS generation and maintenance of MMP. Oxidation of cellular thiols occurs only at high (supra-cytotoxic) drug levels and is, therefore, weakly correlated with cytotoxicity. This unique mechanism involving oxidation and the previously reported absence of myelosuppression suggests that imexon may be rationally combined with existing cytotoxic agents to improve therapeutic activity in MM.
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PMID:Correlates of imexon sensitivity in human multiple myeloma cell lines. 1632 33

Cell culture optimization is a labor-intensive process requiring a large number of experiments to be conducted under varying conditions. Here we describe a high-throughput bioreactor system that allows 12 mini stirred-tank bioreactors to be operated simultaneously. All bioreactors are monitored by low-cost minimally invasive optical sensors for pH and dissolved oxygen. The sensors consist of single-use patches affixed inside the bioreactors and monitored optically from the outside. Experimental results show that different sensing patches with the same composition respond consistently. The discrepancy between different pH sensors is less than 0.1 pH units over most of their responsive range. The discrepancy between different dissolved oxygen sensors is less than 10% over the whole range from 0% to 100% dissolved oxygen. The consistency of the sensing system ensures that only an initial one-time calibration is required for the sensing patches. After that, a calibration code is generated and sensing patches of the same composition can be used directly. This greatly reduces the time and cost required for monitored multi-bioreactor operations. We used SP2/0 myeloma/mouse hybridoma cell cultures to demonstrate reactor performance consistency. Transcriptional profiling, HPLC analysis, viable cell count, and viability inspection show that the presence of sensing patches and the use of optical monitoring have no apparent effect on the metabolism of the cells.
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PMID:Validation of an optical sensor-based high-throughput bioreactor system for mammalian cell culture. 1642 20

Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies. In primary myeloma cells, IMP dehydrogenase (IMPDH) was shown to be consistently overexpressed. We therefore tested the IMPDH inhibitor mycophenolate mofetil (MMF) currently available as a clinical therapeutic agent for its antimyeloma activity in vitro. MMF depleted intracellular guanosine 5'-triphosphate (GTP) levels in myeloma cells. We showed apoptosis induction in myeloma cell lines and primary myeloma cells between 1 and 5 mumol/L MMF. MMF was also cytotoxic at this concentration in dexamethasone-resistant and Mcl-1-overexpressed myeloma cell lines shown by the tetrazolium salt XTT assay along with cell survival measured by a modified flow cytometric assay. Apoptosis was not inhibited by the presence of an antioxidant, suggesting that MMF-induced apoptosis is less likely to be associated with reactive oxygen species. However, apoptosis was abrogated by exogenously added guanosine, which activates an alternative pathway for GTP formation, implicating that this effect is directly mediated by IMPDH inhibition. MMF-induced G1-S phase cell cycle arrest and its apoptosis induction mechanism were associated with a caspase-dependent pathway as shown by alteration of mitochondrial membrane potential and cytochrome c release followed by activation of the caspases. MMF-induced apoptosis was also inhibited by a pan-caspase inhibitor Z-VAD-fmk. MMF-treated myeloma cells showed an up-regulation of Bak, which most likely together with Bax resulted in the release of cytochrome c. In summary, MMF attenuates G1-S phase cell cycle progression and activates the pathway of mitochondrial dysfunction, leading to cytochrome c release followed by activation of caspases.
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PMID:IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells. 1650 21


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