Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine leukemia L1210 cells grown for 2-3 weeks in the presence of 1% serum without selenium supplementation [L.Se(-) cells] typically exhibited < 10% of the glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) activity of selenium-satisfied controls [L.Se(+) cells]. Concomitant with diminished GPX and PHGPX activity was a 1.5- to 2.0-fold increase in catalase (CAT) activity, which reverted to control levels when L.Se(-) cells were given sufficient Se for full expression of selenoperoxidase activity. Selenium manipulation affected total glutathione content similarly, but had no effect on glutathione-S-transferase or superoxide dismutase activity. Long-term growth under Se-deficient conditions resulted in a progressive additional increase in CAT activity, which maximized after ca. 5 months. These cells [referred to as L'.Se(-)] attained CAT activity levels at least 100-times greater than those of Se-supplemented [L'.Se(+)] controls, whereas their glutathione content remained elevated by approximately 70%. Supplying L'.Se(-) cells with Se resulted in a rapid elevation to full GPX activity; however, CAT failed to decline in this case, suggesting that a selection for stable CAT hyperexpressing variants had been accomplished. Quantitative immunoblot analysis indicated that the high CAT activity of L'.Se(-) cells is accounted for by an elevated level of enzyme protein. Induction of CAT and selection for CAT-rich phenotypes, as apparent for Se-starved L1210 cells, was not observed in human K562 counterparts, which lack GPX and express only a low level of PHGPX. L.Se(-) cells were found to be more sensitive to H2O2-induced killing than L.Se(+) controls, whereas L'.Se(-) cells were exceedingly more resistant to H2O2 than L'.Se(+) counterparts. By contrast, L.Se(-) and L'.Se(-) cells were both more sensitive to t-butyl hydroperoxide than Se(+) controls, consistent with CAT being unimportant in the detoxification of this peroxide compared with GPX. This appears to be the first reported evidence for CAT hyperexpression in response to selenium deprivation.
 ...
PMID:Hyperexpression of catalase in selenium-deprived murine L1210 cells. 834 49

In this study, we measured hydrogen peroxide (H2O2) release as one of the functions of mature eosinophils, and utilized it as a quantitative index. We demonstrated that 1) the human eosinophilic leukemia cell line, EoL-1, did not release H2O2 when stimulated with phorbol myristate acetate (PMA), but after culturing with tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) it acquired the ability to release H2O2; 2) the ability to release H2O2 was time dependent and reached a peak after 4 days of culture; 3) administration of TGF-beta or GM-CSF, with TNF and IFN-gamma enhanced the PMA-induced release of H2O2 from EoL-1. To examine the potential relationship between c-myc gene expression and induction of the ability to release H2O2, Northern analysis of c-myc gene expression in EoL-1 cocultured with TNF and IFN-gamma was performed. The results showed that the c-myc gene was spontaneously expressed in EoL-1, and the level of c-myc mRNA was markedly reduced after the cells were cocultured with TNF and IFN-gamma, suggesting that the decrease of the c-myc mRNA level is closely associated with induction of the ability to release H2O2.
 ...
PMID:The effect of cytokines on the differentiation of an eosinophilic leukemia cell line (EoL-1) is associated with down regulation of c-myc gene expression. 836 80

We have investigated the effects of 1,25-dihydroxyvitamin D3 (D3) and/or transforming growth factor (TGF)-beta on one monocytic (U-937) and two human promyelocytic (HL-60 and AML-193) leukemic cell lines. D3 addition induces a partial monocytic maturation of the cell lines, whereas TGF-beta treatment is largely ineffective. Combined treatment with TGF-beta and D3 causes terminal monocytic maturation, as evaluated both by assessment of a large spectrum of membrane Ag and by functional assays. Furthermore, sequential addition of the two inducers showed that pretreatment with TGF-beta 1 followed by incubation with D3, but not vice versa, induces monocytic maturation as effectively as simultaneous treatment with both agents. In liquid culture the proliferative activity of these cell lines is slightly decreased by D3 and virtually unaffected by TGF-beta, whereas combined treatment with D3 and TGF-beta induces a markedly potentiated inhibitory effect. Furthermore, TGF-beta/D3 treatment (but not D3 alone) elicits the expression of membrane CD14, FcRI, FcRII, CD11a, CD11b, CD11c, ICAM-1, and PECAM-1 Ag at a level comparable to that observed on normal human monocytes. It is noteworthy that several of these Ag play an important role in monocyte physiology (e.g., CD14 Ag mediates the binding of bacterial LPS to monocytes). Treatment with both TGF-beta and D3 (but not D3 alone) induces superoxide anions and H2O2 production similar to that of circulating monocytes. In semisolid culture, D3 and TGF-beta alone cause, respectively, a marked and slight loss of cloning efficiency of the cell lines, whereas their combined addition synergistically results in a complete loss of the cloning capacity. These findings suggest a physiologic role for TGF-beta in monocyte maturation. Furthermore, they may pave the way to the design of clinical protocols combining D3 and TGF-beta in the differentiation therapy of acute promyelocytic/myelomonocytic leukemia.
 ...
PMID:Transforming growth factor-beta potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines. 838 19

The myelotoxicity, including leukemia, associated with benzene exposure has been attributed to the further activation of benzene-derived metabolites. In a previous study, we observed that (Cu(II) strongly mediates the oxidation of hydroquinone (HQ) producing benzoquinone (BQ) and H2O2 through Cu(II)/Cu(I) redox mechanism. Since copper exists in the nucleus and is closely associated with chromosomes and DNA, in this study we investigated whether this chemical--metal redox system induces strand breaks in phi X-174 RFI plasmid DNA. In the presence of micromolar concentrations of Cu(II) and HQ, both single and double strand breaks were induced, whereas HQ, Cu(II), H2O2 or BQ alone at the employed concentrations elicited no significant damage to DNA. The HQ/Cu(II) system was at least twice as efficient as a H2O2/Cu(II) system at inducing DNA strand breaks. Of Cu(II), Fe(III), Mn(II), Cd(II) and Zn(II), only HQ/Cu(II) induced extensive DNA strand breaks. Among HQ, 1,2,4-benzenetriol (BT), catechol and phenol, HQ/Cu(II) and BT/Cu(II) were the two most efficient DNA cleaving systems. The presence of bathocuproinedisulfonic acid (BCS) or catalase prevented the HQ/Cu(II)-induced DNA strand breaks. In addition, the HQ/Cu(II)-induced DNA strand breaks could be completely blocked by reduced glutathione and dithiothreitol, but not by L-cysteine. The interaction of L-cysteine with copper in the absence of HQ induced significant DNA strand breaks with the same pattern of DNA strand breaks as that of HQ/Cu(II) plus L-cysteine. In contrast to the HQ/Cu(II) system, a HQ/myeloperoxidase (MPO)/H2O2 system did not induce any DNA strand breaks, and furthermore, the presence of MPO inhibited the HQ/Cu(II)-induced DNA strand breaks. When DNA pretreated with Cu(II) was exposed to HQ, DNA strand breaks were formed that could be prevented by BCS or catalase, indicating that DNA-bound copper can undergo redox cycling in the presence of HQ, generating H2O2. Similar to the H2O2/Cu(II) system, the HQ/Cu(II)-induced DNA strand breaks could not be efficiently inhibited by hydroxyl radical scavengers but could be protected by singlet oxygen scavengers, indicating that the localized generation of singlet oxygen or a singlet oxygen-like entity, possibly a copper-peroxide complex, rather than free hydroxyl radical probably plays a role in the HQ/Cu(II)-induced DNA strand breaks. The above results suggest that macromolecule-associated copper and reactive oxygen generation may be important factors in the mechanism of HQ-induced DNA damage in target cells.
 ...
PMID:DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation. 839 44

Exposure of humans and experimental animals to benzene has been shown to result in hematotoxicity such as pancytopenia, aplastic anemia, and leukemia. The oxidative activation of the benzene metabolite, hydroquinone (HQ), in the bone marrow to the electrophilic benzoquinone (BQ) has been suggested to play an important role in benzene-induced hematotoxicity. Since the interaction of several xenobiotics with copper has been shown to result in their metabolism, in this study we have investigated the role of copper in the oxidation of HQ and HQ-induced toxicity to mice bone marrow stromal cells, target cells of HQ in the bone marrow. In phosphate-buffered saline, HQ underwent autoxidation slowly to BQ, while the presence of Cu(II) ions (1, 2.5, 5, 10, 50 microM) strongly accelerated the oxidation of HQ to BQ in a concentration-dependent manner. Reaction of HQ with Cu(II) was also accompanied by the reduction of Cu(II) to Cu(I), the utilization of O2, and the concomitant generation of H2O2. The oxidation of HQ by Cu(II) could be blocked by the Cu(I)-specific chelator bathocuproinedisulfonic acid (BCS), particularly when the ratio of BCS to Cu(II) was 4:1. By observing the kinetics of the reactions derived from mixing 100 microM HQ and 100 microM Cu(II), it was found that all of the Cu(II) was reduced to Cu(I) within 5 s, followed by consumption of O2 and the generation of BQ, which reached maximum levels at 4 min after mixing HQ and Cu(II). In addition, oxidation of HQ by Cu(II) also generated chemiluminescence. In the presence of myeloperoxidase, Cu(II)-mediated oxidation of HQ was increased. Addition of Cu(II) to primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity. The enhanced cytotoxicity of HQ by Cu(II) could be completely prevented by adding BCS, glutathione (GSH), or dithiothreitol but not by catalase. Supplementation of stromal cells with 20 microM BCS in the absence of exogenously added Cu(II) significantly abated HQ-induced cellular GSH depletion and cytotoxicity, suggesting a possible involvement of endogenous copper in the activation of HQ. The above results indicate that Cu(II) strongly induces the oxidation of HQ and as such may be a factor involved in the oxidative activation and toxicity of HQ in target cells.
 ...
PMID:Oxidation of hydroquinone by copper: chemical mechanism and biological effects. 842 68

The influence of exogenous iron on merocyanine 540 (MC540)-sensitized photoinactivation of leukemia cells has been investigated. Irradiation of murine L1210 or human HL-60 cells (approximately 10(6)/mL in 1% serum/RPMI medium) with broadband visible light in the presence of MC540 (2 microM) resulted in a progressive loss of clonally assessed cell viability. When added to cells 30 min before irradiation, the low polarity chelate, ferric 8-hydroxyquinoline [Fe(HQ)2, 0.5 microM] stimulated dye-sensitized photokilling, whereas high polarity chelates such as ferric 8-hydroxyquinoline-5-sulfonate [Fe(HQS)2, 0.5 microM] or ferric ethylenediaminetetraacetate (Fe.EDTA, 0.5 microM) had no no effect. A striking reversal of Fe(HQ)2-enhanced photokilling was observed upon increasing the preirradiation incubation time with Fe(HQ)2 such that a marked resistance (relative to non-iron-treated controls) was evident after 24 h. Cells exposed for 24 h to Fe(HQS)2 or Fe.EDTA showed similar or even greater resistance to photokilling. Like phototoxicity, H2O2-induced cytotoxicity was enhanced after a 30 min exposure of cells to Fe(HQ)2 but strongly repressed after 24 h. Immunoblot (western) analysis, using a polyclonal antibody to ferritin, revealed that cells exposed to Fe(HQ)2 for 24 h contained at least 12 times as much ferritin heavy chain as non-Fe(HQ)2-treated controls. Preincubating cells with emetine, an inhibitor of protein synthesis, prevented both ferritin induction and the development of hyperresistance. These findings, along with the observation that exogenous apoferritin protected L1210 cells against photokilling, suggest a possible role for ferritin in iron-stimulated photoresistance.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Stimulatory and inhibitory effects of iron on photodynamic inactivation of leukemia cells. 857 Jul 8

Effects of selenium (Se) deficiency on the sensitivity of murine leukemia L1210 cells to broad band UVA/B radiation (310-400 nm) have been investigated. Cells rendered glutathione peroxidase (GPX) deficient by shortterm (2-3 week) growth in 1%, serum/RPMI medium without added Se [L.Se(-) cells] were found to be much less resistant to clonally assessed UVA/B lethality than Se-supplemented controls [L.Se(+) cells]. By contrast, long-term ( > 20 week) Se-deprived [L'.Se(-)] cells whose catalase (CAT) activity was elevated > 100-fold were far more resistant to UVA/B than L.Se(+) cells. Similar trends were observed for cells irradiated in 1% serum/RPMI or Hank's medium. Whereas the CAT inhibitor 3-amino-1,2,4-triazole had no effect on L.Se(+) photosensitivity, it produced a large increase in L'.Se(-) photosensitivity. These findings are consistent with H2O2 intermediacy in photokilling and suggest that L1210 cells depend mainly on GPX for protection against this species but switch to overexpressed CAT after chronic Se deprivation. In agreement with this, steady-state H2O2 levels measured by H2O2 electrode during UVA/B exposure were higher in L.Se(-) than L.Se(+) suspensions but much lower (barely detectable) in L'.Se(-) suspensions. Cytotoxic effects of UVA/B and variations thereof resulting from Se manipulation could be mimicked by treating cells with glucose oxidase in the presence of D-glucose, providing further support for H2O2 involvement. Whether UVA/B-generated H2O2 is directly cytotoxic or gives rise to a more damaging species such as hydroxyl radical (HO) is presently unknown.
 ...
PMID:Role of hydrogen peroxide in the cytotoxic effects of UVA/B radiation on mammalian cells. 878 7

Mitoxantrone [1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl] amino]-9,10-anthracenedione, MXH2] is a novel anticancer agent frequently employed in the chemotherapy of leukemia and breast cancer. Earlier studies have shown that metabolic oxidation to reactive 1,4-quinone or/and 5,8-diiminequinone intermediates may be an important mechanism of activation of this agent, pertinent to its cytotoxic action in vivo. Here we report that in the presence of nitrite ions (NO2-), MXH2 undergoes oxidation by the mammalian enzyme lactoperoxidase (LPO) and hydrogen peroxide and that the process proceeds at a rate that is proportional to NO2- concentration. In contrast, when MXH2 was exposed to LPO/H2O2 in the absence of nitrite, oxidation of the drug was either completely absent or markedly inhibited. These experiments were carried out using concentrated solutions of MXH2 (approximately 100 microM) at near neutral pH where dimers of the drug predominate. We propose that oxidation of MXH2 is mediated by an LPO/ H2O2 metabolite of NO2-, most likely the .NO2 radical. Because in mitoxantrone therapy the drug is administered intravenously, it is directly exposed to nitrogen oxides and other free radicals produced by blood components. It is therefore possible that the ability of mitoxantrone to react with the nitrogen dioxide radical may be relevant to the biological action of the drug in vivo.
 ...
PMID:Lactoperoxidase-catalyzed oxidation of the anticancer agent mitoxantrone by nitrogen dioxide (NO2.) radicals. 943 21

Beta-Lapachone a novel topoisomerase inhibitor, has been found to induce apoptosis in various human cancer cells. In this study we report that a dramatic elevation of hydrogen peroxide (H2O2) in human leukemia HL-60 cells following 1 microM beta-lapachone treatment and that this increase was effectively inhibited by treatment with antioxidant N-acetyl-L-cysteine (NAC), ascorbic acid, alpha-tocopherol. NAC strongly prevented beta-lapachone-induced apoptotic characteristics such as DNA fragmentation and apoptotic morphology. However, treatment of HL-60 cells with another topoisomerase inhibitor camptothecin (CPT) did not induce H2O2 production as compared to untreated cells. NAC also failed to block CPT-induced apoptosis. Correlated with these findings, we found that cancer cell lines K562, MCF-7, and SW620, contained high level of intracellular glutathione (GSH), were not elevated in H2O2 and were resistant to apoptosis after treatment with beta-lapachone. In contrast, cancer cell lines such as, HL-60, U937, and Molt-4 which have lower level of GSH, were readily increased of H2O2 and were sensitive to this drug. Furthermore, ectopic overexpression of Bcl-2 in HL-60 cells also attenuated beta-lapachone-induced H2O2 and conferred resistance to beta-lapachone-induced cell death. Beta-Lapachone at the concentration as low as 0.25 microM effectively induced HL-60 cells to undergo monocytic differentiation, as evidenced by CD14 antigenicity and alpha-naphthyl acetate esterase activity. Again, the beta-lapachone-induced monocytic differentiation was suppressed by NAC. These results suggest that intracellular H2O2 generation plays a crucial role in beta-lapachone-induced cell death and differentiation.
 ...
PMID:Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone-induced apoptosis and differentiation in human leukemia cells. 955 79

The aim of these studies was to investigate the ability of cysteamine and its congeners to arrest the proliferation of leukemic cells and to determine the physico-chemical properties responsible for this ability. Fifteen low molecular weight thiol-bearing compounds were shown to arrest the proliferation of CCRF-CEM cells and a methotrexate-resistant subline, with IC50 values between 10(-5) and 10(-4) M. Cysteamine arrested proliferation by slowing the passage of cells through S phase. These cells subsequently resumed cycling, although a proportion went on to die by apoptosis. The antiproliferative action of cysteamine was shown to depend, in part, on H2O2 production. This ability to generate peroxide is shared by many thiol compounds, and molecular modeling indicated that thiol groups were required for the antiproliferative actions of the congeners of cysteamine. Molecular modeling also revealed that the most efficacious antiproliferative agents were those that had their amino acid and thiol moieties separated by an intramolecular distance of 3.17 to 5.9 A, as exemplified by WR 1065 and the aminothiophenols. These findings indicate that thiol-bearing compounds may have some efficacy in the treatment of drug-naive and -resistant leukemia cells.
 ...
PMID:Inhibition of drug-naive and -resistant leukemia cell proliferation by low molecular weight thiols. 958 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>