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

Studies on the mechanism of apoptosis in this laboratory support a model in which signal transduction involving caspase 3 leads to activation of a serine protease called Mr 24,000 apoptotic protease (AP24), which then induces internucleosomal DNA fragmentation in the nucleus. This study examined the effect of Bcl-2 overexpression on activation of AP24 and the induction of DNA fragmentation by AP24 in isolated nuclei. It was demonstrated that overexpression of Bcl-2 in either HL-60 or PW leukemia cell lines suppressed activation of AP24 induced by either tumor necrosis factor or UV light and protected cells from apoptosis. Furthermore, nuclei isolated from Bcl-2-overexpressing cells were relatively resistant to internucleosomal DNA fragmentation induced by AP24 isolated from apoptotic cells. Bcl-2-overexpressing cells that were nutritionally depleted of glutathione (GSH) became sensitive to tumor necrosis factor- or UV light-induced activation of AP24 and underwent apoptotic cell death. Moreover, nuclei isolated from Bcl-2-overexpressing cells that were depleted of GSH became sensitive to AP24-induced DNA fragmentation. The addition of exogenous GSH blocked the proteolytic activity of AP24, as well as its ability to induce DNA fragmentation in normal isolated nuclei. These results indicate that Bcl-2 can attenuate at least two events in the AP24 apoptotic pathway: activation of AP24 and induction of DNA fragmentation by activated AP24. Furthermore, agents that deplete intracellular levels of GSH may have therapeutic use in the sensitization of Bcl-2-overexpressing cancer cells to apoptotic cell death.
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PMID:Bcl-2-mediated resistance to apoptosis is associated with glutathione-induced inhibition of AP24 activation of nuclear DNA fragmentation. 985 96

Antioxidant defence was investigated in red blood cells (RBC) in 56 patients with 3 different haemoblastoses: polycythemia vera (PV), chronic myelogenous leukaemia (CML), chronic lymphoid leukemia (CLL) with and without anaemia, in 12 iron deficiency anaemia (A) patients and 50 healthy persons. The activities were determined of the following antioxidant enzymes: glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and MDA levels. Antioxidant defence is decreased and the level of lipid peroxidation are increased in RBC in all patients (PV, CML, CLL, A). Different changes were detected in the antioxidative defence between normal red blood cells and those formed from leukaemic cells clone. In normal RBC in anaemia (CLL, A) opposite deviation of G6PD and GSSG-R activities was observed. In RBC formed from leukaemic cell clone (PV, CML), a simultaneous significant increase in G6PD and GSSG-R activities was found, which indicated activisation of pentose phosphate pathways (PPP) in these pathologies; in anaemia they function less effectively.
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PMID:Anaemia and antioxidant defence of the red blood cells. 1021 69

Human leukemia promyelocytic HL-60 cells differentiate into granulocytes when cultured with 1.25% dimethyl sulfoxide for 3 d. The radioactive Na2 75SeO3 incorporation and the amount of total proteins were interrelated in both promyelocytic and granulocytic HL-60. Promyelocytic cells had four times higher 75Se incorporation and 34% more protein synthesis than the granulocytic cells on the fifth culturing day. The enzyme activities of glutathione peroxidase (GSH-Px, E.C. 1.11.1.9) and thioredoxin reductase (TrxR, E.C. 1.6.4.5) in both types of cells increased significantly and approached steady stage on the third day. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (PAGE) analysis and autoradiography of the proteins from the cells revealed three proteins with molecular weights of 57, 28, and 21 kDa, respectively. These three 75Se-labeled proteins were present in both types of cells. The proteins from HL-60 cells were separated by DEAE-Sepharose and 2'5'-ADP-Sepharose columns. The purified 57-kDa protein had TrxR activity of 0.744 micromol 5'-thionitrobenzoic acid (TNB) formed/min/mg protein and two isoelectric points at pH 5.9 and 6.0. These results suggest that TrxR is one of the selenoproteins in both promyelocytic and granulocytic HL-60 cells.
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PMID:Thioredoxin reductase is one of the selenoproteins in both promyelocytic and granulocytic HL-60 cells. 1032 37

The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM-1 min-1 (100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (kapp = 1. 41 +/- 0.03 min-1 (37 degrees C)) and inhibition of cell growth (GI50 = 0.5 +/- 0.1 microM). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.
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PMID:A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides. 1034 34

Etoposide (VP-16) is extensively used to treat cancer, yet its efficacy is calamitously associated with an increased risk of secondary acute myelogenous leukemia. The mechanisms for the extremely high susceptibility of myeloid stem cells to the leukemogenic effects of etoposide have not been elucidated. We propose a mechanism to account for the etoposide-induced secondary acute myelogenous leukemia and nutritional strategies to prevent this complication of etoposide therapy. We hypothesize that etoposide phenoxyl radicals (etoposide-O(.)) formed from etoposide by myeloperoxidase are responsible for its genotoxic effects in bone marrow progenitor cells, which contain constitutively high myeloperoxidase activity. Here, we used purified human myeloperoxidase, as well as human leukemia HL60 cells with high myeloperoxidase activity and provide evidence of the following. 1) Etoposide undergoes one-electron oxidation to etoposide-O(.) catalyzed by both purified myeloperoxidase and myeloperoxidase activity in HL60 cells; formation of etoposide-O(.)radicals is completely blocked by myeloperoxidase inhibitors, cyanide and azide. 2) Intracellular reductants, GSH and protein sulfhydryls (but not phospholipids), are involved in myeloperoxidase-catalyzed etoposide redox-cycling that oxidizes endogenous thiols; pretreatment of HL60 cells with a maleimide thiol reagent, ThioGlo1, prevents redox-cycling of etoposide-O(.) radicals and permits their direct electron paramagnetic resonance detection in cell homogenates. VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts. 3) Ascorbate directly reduces etoposide-O(.), thus competitively inhibiting etoposide-O(.)-induced thiol oxidation. Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone). 4) A vitamin E homolog, 2,2,5,7, 8-pentamethyl-6-hydroxychromane, a hindered phenolic compound whose phenoxyl radicals do not oxidize endogenous thiols, effectively competes with etoposide as a substrate for myeloperoxidase, thus preventing etoposide-O(.)-induced redox-cycling. We conclude that nutritional antioxidant strategies can be targeted at minimizing etoposide conversion to etoposide-O(.), thus minimizing the genotoxic effects of the radicals in bone marrow myelogenous progenitor cells, i.e., chemoprevention of etoposide-induced acute myelogenous leukemia.
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PMID:Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. 1046 37

In order to test the hypothesis that glutathione (GSH) is an important determinant of treatment response in childhood acute leukaemia, blast cell GSH levels were studied in a cohort of children with acute lymphoblastic (ALL) and acute myeloid (AML) leukaemia. In both ALL and AML, several indicators of poor prognosis are well established but the underlying molecular mechanisms leading to resistant disease are still poorly understood. GSH is an intracellular thiol implicated in the development of cytotoxic drug resistance and appears to be involved in the control of cell proliferation and apoptosis. In this study, total GSH was measured in cryopreserved blasts from 62 childhood ALL and 13 AML patients. In ALL, high GSH levels were associated with a relatively poor prognosis. A positive correlation was demonstrated between the GSH level and presenting white cell count (WCC). GSH levels were significantly higher in T lineage ALL compared with B lineage and in AML blasts compared with ALL. These results are supportive of GSH as prognostic indicator in childhood leukaemia and may suggest one mechanism of treatment failure. They imply that it may be possible to improve chemosensitivity by the use of known modulators of GSH synthesis.
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PMID:Glutathione in childhood acute leukaemias. 1050 Jul 96

Curcumin, an antioxidant present in the spice turmeric (Curcuma longa), has been shown to inhibit chemical carcinogenesis in animal models and has been shown to be an anti-inflammatory agent. While mechanisms of its biological activities are not understood, previous studies have shown that it modulates glutathione (GSH)-linked detoxification mechanisms in rats. In the present studies, we have examined the effects of curcumin on GSH-linked enzymes in K562 human leukemia cells. One micromolar curcumin in medium (16 h) did not cause any noticeable change in glutathione peroxidase (GPx), glutathione reductase, and glucose-6-phosphate dehydrogenase activities. Gamma-glutamyl-cysteinyl synthetase activity was induced 1.6-fold accompanied by a 1.2-fold increase in GSH levels. GSH S-transferase (GST) activities towards 1-chloro-2,4-dinitrobenzene, and 4-hydroxynonenal (4HNE) were increased in curcumin-treated cells 1.3- and 1.6-fold, respectively (P = 0.05). The GST isozyme composition of K562 cells was determined as follows: 66% of GST Pl-1, 31% of Mu class GST(s), and 3% of an anionic Alpha-class isozyme hGST 5.8, which was immunologically similar to mouse GSTA4-4 and displayed substrate preference for 4HNE. The isozyme hGST 5.8 appeared to be preferentially induced by curcumin, as indicated by a relatively greater increase in activity toward 4HNE. Immunoprecipitation showed that GPx activity expressed by GST 5.8 contributed significantly (approximately 50%) to the total cytosolic GPx activity of K562 cells to lipid hydroperoxides. Taken together, these results suggest that GSTs play a major role in detoxification of lipid peroxidation products in K562 cells, and that these enzymes are modulated by curcumin.
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PMID:The effect of curcumin on glutathione-linked enzymes in K562 human leukemia cells. 1051 34

Free radicals are highly reactive species that have been implicated in the pathogenesis of many diseases. Reactive oxygen species can initiate lipid peroxidation and DNA damage leading to mutagenesis, carcinogenesis and cell death, if the antioxidant system is impaired. This study was undertaken to examine the prevalence of oxidative stress and the role of antioxidant defence in untreated leukemia patients. The generation of superoxide anion and hydrogen peroxide by leukocytes, plasma malondialdehyde levels, red cell copper zinc superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GSH-PX) activities were determined in 30 patients with different types of leukemias prior to therapy. The superoxide anion generation by polymorphonuclear leukocytes was found to be significantly increased in leukemia patients especially those with acute lymphocytic and nonlymphocytic leukemias, while the hydrogen peroxide levels were comparable to the control values. Plasma lipid peroxidation products in untreated leukemia patients were in the normal range. Red cell Cu-Zn SOD and GSH-PX activities were significantly increased and showed no correlation with the hemoglobin content. Although superoxide generation was high, lipid peroxide levels were normal in these patients. This might be due to the increased activities of the antioxidant enzymes (SOD, GSH-PX) which counteract lipid peroxidation. Increased free radical generation, especially superoxide anion in leukemia patients and increased antioxidant defence enzymes, which is an adaptive protective response, are indicative of mild oxidative stress. There were no significant differences for the parameters cited above between different types of leukemias, suggesting that the changes are not specific to the type of leukemia.
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PMID:Free radicals antioxidant enzymes and lipid peroxidation in different types of leukemias. 1069 22

Arsenic trioxide (As2O3)-treatment is effective in acute promyelocytic leukemia (APL) patients with t(15;17). Clinically achievable concentrations of As2O3 induce apoptosis in NB4, an APL cell line, in vitro. Here, to study the mechanism of As2O3-induced apoptosis, we established an As2O3-resistant subline, NB4/As. Growth of NB4/As was inhibited by 50% after 2 day-treatment (IC50) at 1.6 microM As2O3, whereas IC50 of NB4 was 0.3 microM. Degradation of PML-RARalpha and change of the PML-subcellular localization were similarly induced by As2O3 in NB4 and NB4/As, suggesting that their contribution to apoptosis is small. Treatment with 1 microM As2O3 induced the activation of caspase 3 as well as a loss of mitochondrial transmembrane potential (deltapsim) in NB4 but not in NB4/As. Caspase 8 and Bid were also activated by As2O3 in NB4 but not in NB4/As. In NB4, an inhibitor of caspase 8 blocked not only the activation of caspase 3 but also the loss of deltapsim. Neither cell line expressed CD95/Fas, and agonistic anti-Fas antibody (CH-11) failed to cause apoptosis. Neither antagonistic anti-CD95/Fas antibody nor anti-Fas ligand antibodies influenced the As2O3-induced apoptosis. NB4/As had a higher concentration of intracellular glutathione (GSH) than NB4 (96 vs 32 nmol/mg). Reduction of the GSH level by buthionine sulfoxide (BSO) completely restored the sensitivity to As2O3 in NB4/As. Furthermore, caspase activation and the loss of deltapsim were recovered by combination treatment with BSO. These findings suggest that the As2O3 treatment activates caspase 8 in a CD95-independent but GSH concentration-dependent manner. In combination with BSO, As2O3 might be applied to therapy of leukemia/cancers which are insensitive to the clinically achievable concentrations of As2O3.
Leukemia 2000 Oct
PMID:Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis. 1102 49

The dietary isothiocyanate and cancer chemopreventive agent, phenethyl isothiocyanate, induced apoptosis of human leukaemia HL60 and human myeloblastic leukaemia ML-1 cells in vitro. Cytotoxicity was associated with an initial decrease in GSH and GSSG, with a concomitant formation of the GSH adduct S-(N-phenethylthiocarbamoyl)glutathione inside cells, which was then exported from cells. After 12 hr, the cellular concentration of GSH recovered and then declined after 24 hr. Buthionine sulphoximine prevented the recovery of cellular GSH concentration and potentiated the cytotoxicity of phenethyl isothiocyanate. S-(N-phenethylthiocarbamoyl)glutathione spontaneously fragmented to GSH and phenethyl isothiocyanate, GSH oxidized to GSSG and glutathionyl-protein disulphides, and phenethyl isothiocyanate hydrolyzed to phenylethylamine. GSH and GSSG depletion was more marked in ML-1 cells than in HL60 cells. Studies with [(14)C]-labelled phenethyl isothiocyanate gave evidence of phenethylthiocarbamoylation of cells that maximized after 2-3 hr. This occurred later than the maximum concentration of S-(N-phenethylthiocarbamoyl)glutathione, but coincided with the commitment to apoptosis and cytotoxicity which developed later. The cytotoxicity of phenethyl isothiocyanate was prevented by a high concentration of GSH (15 mM) and delayed by the antioxidant and c-Jun N-terminal kinase signalling pathway inhibitor curcumin. GSH prevented and curcumin partly prevented the decrease in cellular GSH. These studies show that the cysteinyl thiol group of GSH is an important site of thiocarbamoylation by phenethyl isothiocyanate during induction of apoptosis and that this may lead to depletion of cellular GSH by efflux of the GSH conjugate. Thiocarbamoylation also occurred at other sites. The recent demonstration of a critical role for activation of caspase-8 in phenethyl isothiocyanate-induced apoptosis suggests that this thiocarbamoylation directly or indirectly leads to functional activation of a cell death receptor/adaptor protein complex.
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PMID:Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. 1116 31


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