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)

Low doses of oxidative stress can induce cellular resistance to subsequent higher doses of the same stress. By using human U937 leukemia cells, we previously demonstrated that H(2)O(2) can induce such an adaptive response without elevating the cellular capacity to degrade H(2)O(2), and were able to confer the cells a cross-resistance to an H(2)O(2)-independent lethal stimulus, C(2)-ceramide. In this study, it was found that the adaptation is accompanied by the translocation of cytoplasmic NF-kappa B to the nuclei. This event was promoted or abolished when either IKK alpha or a dominant negative mutant of I kappa B, respectively, was overexpressed. The overexpression of IKK alpha also resulted in the suppression of H(2)O(2)-induced cell death and DNA fragmentation, whereas these events were accelerated by the expression of the I kappa B mutant. The protective effect of IKK alpha was accompanied neither by an elevation of protein levels of various antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase, nor by an increase in the cellular capacity to consume H(2)O(2). Moreover, the overexpression of IKK alpha resulted in an enhancement of H(2)O(2)-induced resistance to C(2)-ceramide. The overall data suggest that NF-kappa B mediates the H(2)O(2) adaptation induced in a manner independent of H(2)O(2)-degrading activity.
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PMID:NF-kappa B mediates the adaptation of human U937 cells to hydrogen peroxide. 1118 27

The imbalance between oxidants and antioxidants in cells often results in pathological processes and/or diseases. This delicate balance is achieved in part by antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase (SOD), as well as by low-molecular-weight reductants such as glutathione. We evaluated the effect of thiol reagents on the proliferation of the Jurkat human T-cell leukemia-derived cell line. The cells show a multiphasic behavior when grown in the presence of thiols. Low concentrations of N-2-mercaptopropionyl glycine (0.03 mM) cause growth arrest, and intermediate concentrations (0.3-1.0 mM) induce apoptosis. Similarly, 1 mM N-acetylcysteine or glutathione induce apoptosis in more than 40% of the cells. Surprisingly, the cells grow well in higher concentrations (3-10 mM) of these reagents. Because the I58T variant of human SOD2 is thiol-sensitive, we measured SOD in Jurkat cells grown in the presence of thiol agents, observing markedly less SOD activity. In cell-free extracts, thiols quickly eliminated the SOD2 activity. Jurkat cells contain little SOD2 activity, with a different electrophoretic mobility from that of normal lymphocytes. Single-strand conformational polymorphism analysis of the Jurkat sod2 gene revealed a pattern different from the wild-type gene, suggesting a mutation in the sod2 gene. This was confirmed by cloning and sequencing the gene. Jurkat cells are heterozygous for a new mutation, L60F, in exon 3 of the mature protein. Our findings suggest a possible association between decreased SOD2 activity and malignant phenotype.
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PMID:Paradoxical effects of thiol reagents on Jurkat cells and a new thiol-sensitive mutant form of human mitochondrial superoxide dismutase. 1251 93

Treatment with arsenic trioxide (As(2)O(3)) by inducing apoptosis and partial differentiation of acute promyelocytic leukemia (APL) cells results in clinical remission in APL patients resistant to chemotherapy and all-trans-retinoic acid. As(2)O(3) (iAs(III)) is methylated in the liver to mono- and dimethylated metabolites, including methylarsonic acid, methylarsonous acid, dimethylarsinic acid, and dimethylarsinous acid. Methylated trivalent metabolites that are potent cytotoxins, genotoxins, and enzyme inhibitors may contribute to the in vivo therapeutic effect of iAs(III). Therefore, we compared the potency of iAs(III) and trivalent metabolites using chemical precursors of methylarsonous acid and dimethylarsinous acid to induce differentiation, growth inhibition, and apoptosis. Methylarsine oxide (MAs(III)O) and to a lesser extent iododimethylarsine were more potent growth inhibitors and apoptotic inducers than iAs(III) in NB4 cells, an APL cell line. This was also observed in K562 human leukemia, lymphoma cell lines, and in primary culture of chronic lymphocytic leukemia cells, but not human bone marrow progenitor cells. Apoptosis was associated with greater hydrogen peroxide accumulation and inhibition of glutathione peroxidase activity. MAs(III)O, in contrast to iAs(III), did not induce PML-retinoic acid receptor alpha degradation, or restore PML nuclear bodies or differentiation in NB4 cells. In a cocultivation experiment, hepatoma-derived HepG2 cells, but not NB4 cells, methylate radiolabeled iAs(III). Methylated metabolites released from HepG2 cells are preferentially accumulated by NB4 cells. This experimental model suggests that in vivo hepatic methylation of iAs(III) may contribute to As(2)O(3)-induced apoptosis but not differentiation of APL cells. MAs(III)O as an apoptotic inducer should be considered in the treatment of other hematologic malignancies like lymphoma.
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PMID:Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. 1270 73

Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As2O3) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As2O3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As2O3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As2O3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As2O3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As2O3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROS-related compounds demonstrated that hydrogen peroxide (H2O2) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As2O3 and BSO blocked H2O2-scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As2O3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As2O3 with BSO is a valid means of blockade of H2O2-scavenging system, and that the combination of a ROS-generating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.
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PMID:Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. 1500 36

The neuroimmunodegenerative syndrome that develops in mice infected with ts1, a mutant of Moloney murine leukemia virus, resembles human AIDS. Both ts1 and human immunodeficiency virus type 1 infect astrocytes, microglia, and oligodendrocytes but do not infect neurons. Oxidative stress has been implicated in the neuropathology of AIDS dementia and other neurodegenerative diseases. We report here that ts1 infection of astrocytes (both transformed C1 cells and primary cultures) also induces thiol (i.e., glutathione and cysteine) depletion and reactive oxygen species (ROS) accumulation, events occurring in parallel with viral envelope precursor gPr80(env) accumulation and upregulated expression of endoplasmic reticulum chaperones GRP78 and GRP94. Furthermore, ts1-infected astrocytes mobilize their thiol redox defenses by upregulating levels of the Nrf-2 transcription factor, as well its targets, the xCT cystine/glutamate antiporter, gamma-glutamylcysteine ligase, and glutathione peroxidase. Depleting intracellular thiols by treating uninfected astrocytes with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, or by culturing in cystine-deficient medium, also induces ROS accumulation, activates Nrf-2, and upregulates Nrf-2 target gene expression in these astrocytes. Overexpression of Nrf-2 in astrocytes specifically increases expression of the above thiol synthesis-related proteins. Further treatment with BSO or N-acetylcysteine in transfected cells modulates this expression. Thiol depletion also accelerates cell death, while thiol supplementation promotes survival of ts1-infected cells. Together, our results indicate that ts1 infection of astrocytes, along with ts1-induced gPr80(env) accumulation, endoplasmic reticulum stress, thiol depletion, and oxidative stress, accelerates cell death; in response to the thiol depletion and oxidative stress, astrocytes activate their Nrf-2-mediated thiol antioxidant defenses, promoting cell survival.
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PMID:Activation of transcription factor Nrf-2 and its downstream targets in response to moloney murine leukemia virus ts1-induced thiol depletion and oxidative stress in astrocytes. 1547 33

The response of three human leukemia cell lines, the proliferative promonocyte THP-1 and the promyeloid HL60 cells and the non-proliferative phorbol ester-treated HL60 cells (HL60/PMA), to oxidative stress induced by tert-butylhydroperoxide (t-BHP) treatment was analyzed by fluorescence microplate assay, anti-oxidant enzyme activity measurements, high performance liquid chromatography, yopro-1/PI incorporation, poly (ADP-ribose) polymerase and caspase 3 cleavages. After t-BHP treatment, the non-proliferative HL60/PMA cells exhibited a weak increase in reactive oxygen species (ROS) production, a better preservation of thiol content, a decrease of glutathione peroxidase activity and a high ability to undergo necrosis rather than apoptosis. Submitted to the same treatment, the proliferative HL60 and THP-1 cells exhibited a high increase of ROS production, a moderate thiol depletion and a high percentage of apoptosis. Under thiol depleting conditions, the oxidative treatment of the HL60/PMA cells resulted in a high ROS production that reached levels similar to those of the two other cell lines and in cell death mainly by necrosis. In conclusion, these results that show proliferative phenotype is essential for cell response towards oxidative stress, are of particular interest in chemotherapy involving an oxidative mechanism.
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PMID:Differential responses of proliferative and non-proliferative leukemia cells to oxidative stress. 1587 6

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which approximately 40% of the patients respond well to current chemotherapy, but the prognosis for the other 60% is poor. The Leukemia/Lymphoma Molecular Profiling Project (LLMPP) used microarray technology to define a molecular profile for each of 240 patients with DLBCL and develop a molecular outcome predictor score that accurately predicted patient survival. Data from our laboratory and others suggest that alterations in antioxidant defense enzyme levels and redox environment can be oncogenic and affect the response to glucocorticoid treatment, one of the components of combination chemotherapy regimens for lymphoma. The goal of the current study was to reanalyze the LLMPP microarray data to determine whether the levels of antioxidant defense enzymes and redox proteins were correlated with prognosis in DLBCL. We found that patients with DLBCL with the worst prognosis, according to the outcome predictor score, had decreased expression of catalase, glutathione peroxidase, manganese superoxide dismutase, and VDUP1, a protein that inhibits thioredoxin activity. The data suggest that the patients with the worst prognosis combine a decrease in antioxidant defense enzyme expression with an increase in thioredoxin system function (the redox signature score).
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PMID:A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis. 1608 86

Interactions between the endogenous estradiol metabolite 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors (HDACIs) have been investigated in human leukemia cells. Coadministration of subtoxic or marginally toxic concentrations of 2-ME and SAHA or sodium butyrate in diverse human leukemia-cell types resulted in a marked increase in oxidative damage (eg, generation of reactive oxygen species [ROSs]), mitochondrial injury (eg, cytochrome c release and Bax translocation), caspase activation, and apoptosis. These interactions were also noted in primary human leukemia cells but not in normal bone marrow CD34+ cells. Synergistic interactions between these agents were associated with inactivation of Akt and activation of c-Jun N-terminal kinase (JNK). Essentially all of these events were reversed by free radical scavengers such as the manganese superoxide dismutase (MnSOD) mimetic TBAP and catalase. Notably, treatment with 2-ME/HDACIs resulted in down-regulation of thioredoxin, MnSOD, and glutathione peroxidase. Enforced activation of Akt blocked 2-ME/HDACI-mediated mitochondrial injury, caspase activation, and JNK up-regulation, but not generation of ROSs. Pharmacologic or genetic (siRNA) interruption of the JNK pathway also significantly attenuated the lethality of this regimen. Together, these findings support a model in which antileukemic synergism between 2-ME and HDACIs stems primarily from induction of oxidative damage, leading in turn to Akt inactivation and JNK activation, culminating in mitochondrial injury and apoptosis. They also raise the possibility that these events may preferentially occur in leukemic versus normal hematopoietic cells.
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PMID:Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress. 1614 49

Essential elements, mainly selenium and zinc, were involved in protection against oxidative stress in cells. Oxidation could lead to the formation of free radicals that have been implicated in the pathogenesis of many diseases, including leukemia. Leukemia is a neoplastic disease that is susceptible to antioxidant enzyme and essential elements alterations. This study was undertaken to examine the levels of essential elements, antioxidant enzymes activities, and their relationships with different types of leukemia. Serum selenium, zinc, and copper concentrations, red blood cell glutathione peroxidase (GPx) activities, plasma Cu-Zn superoxide dismutase (Cu-Zn SOD) activities and lipid peroxidation (LPO) levels were determined in 49 patients with different types of leukemia before initial treatment. Serum selenium and zinc concentrations were lower in leukemia patients than those of controls (p<0.01). Serum copper concentration was higher in leukemia patients than that of controls (p<0.01). The activities GPx and Cu-Zn SOD were significantly increased in leukemia patients, especially with acute leukemia (AL), acute lymphoid leukemia (ALL), and acute nonlymphoid leukemia (ANLL) (p<0.05), whereas no difference was found between those of chronic myelogenous leukemia and the controls. The levels of LPO were normal as controls. Serum selenium concentration was not correlated with GPx, and serum levels of zinc and copper were not related to Cu-Zn SOD. Serum zinc levels had a negative correlation with the absolute peripheral blast cells, whereas serum copper had a positive correlation with the absolute peripheral blast cells. Increased GPx and Cu-Zn SOD activities and normal levels of LPO, which were a protective responses, were an indicator of mild oxidative stress; it might indicate that the essentials elements alterations in leukemia patients were mostly dependent on tumor activity. Changes of their levels demonstrated that there are low selenium, zinc, and high copper status in leukemia patients. The decrease of plasma zinc and increase of the Cu/Zn ratio could be the index that showed an unfavorable prognosis of acute leukemia.
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PMID:Levels of selenium, zinc, copper, and antioxidant enzyme activity in patients with leukemia. 1720 86

Neurotropin, a nonprotein extract from inflamed rabbit skin inoculated with vaccinia virus, is well known as an analgesic drug, but its cytoprotective effects have not been explored. Because infection by viruses, such as human T-cell leukemia virus type I and Epstein-Barr virus, induces expression of the redox-regulating molecule, thioredoxin (TRX), we hypothesized that neurotropin would also be capable of regulating the redox balance and could be applied for the therapeutics of lung diseases caused by oxidative stress, such as chronic obstructive pulmonary disease. Neurotropin enhanced mRNA expression of the redox-regulating molecules, glutathione peroxidase and catalase and, particularly, TRX, in human lung adenocarcinoma A549 cells. Neurotropin also increased the cellular TRX content and regulated TRX release from cells. The cytoprotective effects of neurotropin against hydrogen peroxide and cigarette smoke extracts was demonstrated by an attenuation of lactate dehydrogenase release from oxidant-exposed A549 cells and the inhibition of apoptosis. This cytoprotection was linked with reduced activity of intracellular oxidants. Furthermore, neurotropin enhanced TRX expression in mouse lungs and ameliorated cigarette smoke-induced lung injury in mice, suggesting that its cytoprotective effects in lung epithelial cells are mediated through the induction of redox-regulating molecules that reduce intracellular oxidative activity.
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PMID:Neurotropin demonstrates cytoprotective effects in lung cells through the induction of thioredoxin-1. 1758 12


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