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)

Amyloid-beta, (Abeta) is a cytotoxic peptide implicated in the pathology of Alzheimers disease. The antioxidant enzyme catalase has been suggested to protect against Abeta cytotoxicity in both neuronal and non-neuronal cell types. Inhibition of endogenous catalase using 3-amino-1,2,4-triazole (3AT) in neuronal (NT-2) and myeloma (SP2/0-Ag-14) cell lines increases Abeta toxicity, suggesting that any protective role for endogenous catalase requires active enzyme. In Abeta treated mveloma cells there was a significant decrease in the total cell catalase activity and immunoreactivity. However, when the surviving live cell population was isolated following Abeta treatment the levels of catalase were significantly increased. The surviving live cell population from groups treated with both 3AT and Abeta contain elevated immunoreactive catalase levels suggesting that the protective role for endogenous catalase may have a component independent of the antioxidant activity, possibly by acting as an Abeta binding protein. Amyloid-beta (Abeta) cytotoxicity can be prevented by Vitamin E treatment or an anti-Abeta monoclonal antibody (ALIOI), both of which also prevent Abeta cytotoxicity in cells treated with 3AT These observations suggest that Abeta mediated cell death in both neuronal and non-neuronal cells is mediated in part by actions to increase hydrogen peroxide. Catalase has a protective role, as a hydrogen peroxide-degrading enzyme and catalase inhibition by Abeta is not the direct cause of cytotoxicity.
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PMID:Inhibition of catalase activity with 3-amino-triazole enhances the cytotoxicity of the Alzheimer's amyloid-beta peptide. 1182 10

The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.
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PMID:Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid. 1474 74

Multiple myeloma (MM) is a neoplastic disorder characterized by monoclonal multiplying of plasma cells. Although radiation, environmental factors, viruses and other factors have been suggested as potential causes of the disease, the aetiopathogenesis of MM is still obscure. This clinical study was designed to investigate the role of reactive oxygen species (ROS) in the aetiopathogenesis of the disease and the possible relationships between treatment and ROS production. For this purpose, erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities as well as plasma nitric oxide (NO) and malondialdehyde (MDA) levels were measured in 14 MM patients newly diagnosed at stage III. The relationship between the above-mentioned parameters and vincristine-adriamycin-dexamethasone (VAD) therapy were also investigated in the same patients. All the enzyme activities and the parameters of oxidative stress were found to be significantly reduced after VAD therapy. These findings suggest that ROS may be involved in the aetiopathogenesis of MM. Further investigations with a larger cohort of MM patients are needed to provide definitive data about the role of ROS in MM and the alternative therapeutic approaches to MM.
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PMID:Oxidant/antioxidant parameters and their relationship with medical treatment in multiple myeloma. 1538 38

Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 muM MGd and 50 to 100 microM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
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PMID:Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. 1538 78

Staging and monitoring of multiple myeloma (MM) is mainly based on monoclonal component quantification; the absence of such a parameter renders difficult follow up of patients with nonsecretory MM (nsMM). In this study our aims were to determine the specificity and sensitivity of Tc99m-sestaMIBI scintigraphy at diagnosis and during follow up of nsMM patients. Nine nsMM patients were prospectively studied at diagnosis and during treatment for a mean time of 33 months (range: 12-65+). Tc99m-sestaMIBI (MIBI) scintigraphy was compared to conventional imaging (CI: X ray with CAT or NMR details) at diagnosis and during follow up. At diagnosis, CI and MIBI were concordant in three patients; CI showed more focal lesions than MIBI in four patients, while MIBI revealed more focal lesions than CI in two patients. During the follow up, MIBI uptake was normal in the four patients who achieved remission. Five patients did not achieve remission: CI and MIBI were concordant in three, while MIBI was falsely negative in two patients. In conclusion, Tc99m-sestaMIBI scintigraphy has high sensitivity (no false positive cases) and 78% specificity (2/9 false negative cases) in tracing active nsMM lesions; it should be considered complementary to CI for monitoring this rare disease.
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PMID:Tc99m-sestaMIBI uptake in nonsecretory multiple myeloma. 1608 47

SPAN-Xb is a novel cancer-testis antigen in multiple myeloma (MM). In this study, we determined the mechanisms regulating SPAN-Xb expression in MM. SPAN-Xb promoter sequence was first cloned into the CAT-reporter vector to determine the role of promoter methylation in the regulation of gene expression. Tumor cells were treated with 5-azacytidine and a panel of cytokines were used to determine their ability to induce SPAN-Xb expression. Bisulfite conversion with sequence analysis was applied to a panel of tumor cells and normal tissues to correlate the CpG dinucleotide hypomethylation and SPAN-Xb expression. We found that SPAN-Xb promoter function could be silenced by methylation. 5-Azacytidine induced promoter hypomethylation and resulted in SPAN-Xb expression, at both the transcript and protein levels. Hypomethylation of the CpG dinucleotides at positions -310, -307, -299 and -221 within the SPAN-Xb promoter strongly predict for SPAN-Xb expression. Both IL-7 and GM-CSF were also able to upregulate the expression of SPAN-Xb in myeloma cells, but only after the promoter sequence has been hypomethylated. Our results provide the first evidence showing the role of promoter methylation in the primary regulation of SPAN-Xb and the ability of IL-7 and GM-CSF to further enhance SPAN-Xb gene and protein expression in myeloma cells.
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PMID:SPAN-Xb expression in myeloma cells is dependent on promoter hypomethylation and can be upregulated pharmacologically. 1618 75

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

Bortezomib (1) is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor employed in the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. The potency of 1 is owed primarily to the presence of the boronic acid moiety, one which is suited to establish a tetrahedral intermediate with the active site N-terminal threonine residue of the proteasome. Hence, deboronation of 1 represents a deactivation pathway for this chemotherapeutic agent. Deboronation of 1 affords a near equal mixture of diastereomeric carbinolamide metabolites (M1/M2) and represents the principal metabolic pathway observed in humans. In vitro results from human liver microsomes and human cDNA-expressed cytochrome P450 enzymes (P450) indicate a role for P450 in the deboronation of 1. Use of 18O-labeled oxygen under controlled atmospheres confirmed an oxidative mechanism in the P450-mediated deboronation of 1, as 18O was found incorporated in both M1 and M2. Chemically generated reactive oxygen species (ROS), such as those generated as byproducts during P450 catalysis, were also found to deboronate 1 resulting in the formation of M1 and M2. Known to undergo efficient redox cycling, P450 2E1 was found to catalyze the deboronation of 1 predominantly to the carbinolamide metabolites M1 and M2, as well as to a pair of peroxycarbinolamides, 2 and 3. The presence of superoxide dismutase (SOD) and catalase prevented the deboronation of 1, thus, supporting the involvement of ROS in the P450 2E1-catalyzed deboronation reaction. The presence of SOD and catalase also protected 1 against P450 3A4-catalyzed deboronation, albeit to a lesser extent. The remaining deboronation activity observed in the P450 3A4 reaction may suggest the involvement of the more conventional activated enzyme-oxidants previously described for P450. Our present findings indicate that the oxidase activity of P450 (i.e., formation of ROS) represents a mechanism of deboronation.
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PMID:Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. 1660 65

The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38(+) high), but barely induced death in normal lymphocytes (CD38(-/+)low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL.
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PMID:Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. 1705 30

Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thalidomide's specific effects on gamma-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on gamma-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34+ cells. We found that thalidomide induced gamma-globin mRNA expression in a dose-dependent manner, but had no effect on beta-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thalidomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced gamma-globin gene expression. These data indicate that thalidomide induces increased expression of the gamma-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation.
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PMID:Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. 1762 Apr 52


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