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)

Benzene is an established human and animal carcinogen. While many of the key mechanisms underlying its carcinogenic effects remain unknown, there is increasing evidence that chromosomal alterations play an important role in the development of the induced leukemias. Inhibition of enzymes involved in DNA replication and maintenance such as topoisomerases by benzene metabolites represents a potential mechanism by which benzene may induce its chromosome-altering effects. Previous work from our laboratory and others has demonstrated that bioactivated benzene metabolites are capable of inhibiting topoisomerase II (topo II) in isolated enzyme and cell systems as well as in mice administered benzene in vivo. The current studies were designed to build upon this hypothesis, and show that in the presence of human myeloperoxidase and H2O2, hydroquinone can be activated to a potent topo II inhibitor. In the absence of dithiothreitol, partial inhibition can be seen at hydroquinone concentrations as low as 50 nM. The potential role of topo II inhibition in the development of benzene-induced leukemia is also discussed in the context of other known leukemia-inducing agents. Current evidence indicates that multiple mechanisms are likely to contribute to benzene-induced leukemias, and that inhibition of topo II could represent an important step in the development of certain leukemia subtypes.
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PMID:Topoisomerase II inhibition by myeloperoxidase-activated hydroquinone: a potential mechanism underlying the genotoxic and carcinogenic effects of benzene. 1593 18

Since the higher redox potential of quinone molecules has been correlated with enhanced cellular deleterious effects, we studied the ability of the association of ascorbate with several quinones derivatives (having different redox potentials) to cause cell death in K562 human leukaemia cell line. The rationale is that the reduction of quinone by ascorbate should be dependent of the quinone half-redox potential thus determining if reactive oxygen species (ROS) are formed or not, leading ultimately to cell death or cell survival. Among different ROS that may be formed during redox cycling between ascorbate and the quinone, the use of different antioxidant compounds (mannitol, desferal, N-acetylcysteine, catalase and superoxide dismutase) led to support H2O2 as the main oxidizing agent. We observed that standard redox potentials, oxygen uptake, free ascorbyl radical formation and cell survival were linked. The oxidative stress induced by the mixture of ascorbate and the different quinones decreases cellular contents of ATP and GSH while caspase-3-like activity remains unchanged. Again, we observed that quinones having higher values of half-redox potential provoke a severe depletion of ATP and GSH when they were associated with ascorbate. Such a drop in ATP content may explain the lack of activation of caspase-3. In conclusion, our results indicate that the cytotoxicity of the association quinone/ascorbate on K562 cancer cells may be predicted on the basis of half-redox potentials of quinones.
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PMID:Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study. 1603 43

Vitamin K2 (VK2) effectively induces apoptosis in leukemia cell lines, including HL-60 and U937. However, combined treatment of cells with VK2 plus 1alpha,25-dihydroxy vitamin D3 (VD3) resulted in suppression of VK2-inducing apoptosis and pronounced induction of monocytic differentiation as compared with that by VD3 alone. After achieving monocytic differentiation by pre-exposure to VK2 and VD3, the cells became resistant to various apoptotic stimuli including VK2- and H2O2-treatment and serum deprivation. Accumulation of cytoplasm p21CIP1 along with disappearance of nuclear p21CIP1 was detected in cells in response to 96-h treatment with VK2 plus VD3. A stable transfectant, U937-deltaNLS-p21CIP1, which lacked the nuclear localization signal of p21CIP1 and showed overexpression of cytoplasm p21CIP1 without monocytic differentiation, was resistant to apoptosis. These data suggest that a change of intracellular distribution of p21CIP1 from nucleus to cytoplasm along with differentiation appears to be anti-apoptotic. Clinical benefits of using VK2 for treatment of patients with leukemia and myelodysplastic syndrome (MDS) have been reported. Our data suggest that VK2 plus VD3 may be an effective combination for differentiation-based therapy for leukemia and also MDS whose cytopenias are mediated though apoptosis.
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PMID:Combined treatment of leukemia cells with vitamin K2 and 1alpha,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21CIP1. 1614 3

Procyanidin B2 (epicatechin-(4beta-8)-epicatechin), which is present in grape seeds, apples, and cacao beans, has antioxidant properties. We investigated the mechanism of preventive action of procyanidin B2 against oxidative DNA damage in human cultured cells and isolated DNA. Procyanidin B2 inhibited the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in the human leukemia cell line HL-60 treated with an H2O2-generating system. In contrast, a high concentration of procyanidin B2 increased the formation of 8-oxodG in HL-60 cells. Experiments with calf thymus DNA also revealed that procyanidin B2 decreased 8-oxodG formation by Fe(II)/H2O2, whereas procyanidin B2 induced DNA damage in the presence of Cu(II), and H2O2 extensively enhanced it. An electron spin resonance spin trapping study utilizing 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) demonstrated that procyanidin B2 decreased the signal of M4PO-OH from H2O2 and Fe(II), whereas procyanidin B2 enhanced the signal from H2O2 and Cu(II). As an antioxidant mechanism, UV-visible spectroscopy showed that procyanidin B2 chelated Fe(II) at equivalent concentrations. As a pro-oxidant property, we examined DNA damage induced by procyanidin B2, using 32P-labeled DNA fragments obtained from genes relevant to human cancer. Our results raise the possibility that procyanidin B2 exerts both antioxidant and pro-oxidant properties by interacting with H2O2 and metal ions.
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PMID:Procyanidin B2 has anti- and pro-oxidant effects on metal-mediated DNA damage. 1619 31

Salicylate and jasmonates are two different types of plant hormone that play critical roles in plant defense responses against insect herbivores and microbial pathogens, through activating defense genes. These two natural products have been shown to have similar activities in animal cells: the compounds are able to induce cell cycle arrest or apoptosis in a variety of human cancer cells including those of colon, prostate, breast, and leukemia, suggesting the chemicals may potentially be a novel class of anti-cancer drugs. Since sodium salicylate can induce the heat shock response in animals, we examined the effects of jasmonates on the heat shock response in C6 glioma cells. Here, we show that brief exposure to methyl jasmonate (MeJA), but not to jasmonic acid, induces heat shock protein 72 (HSP72), but not HSP73 and HSP90, via heat shock factor I (HSF1) activation in C6 glioma cells without affecting cell viability. Intracellular H2O2 and O2-, and mitochondrial ROS were prominently increased in response to 5 mM MeJA in C6 cells. MeJA-induced HSP72 expression, HSF1 DNA binding, and human HSP70 promoter-driven CAT activity were prevented by N-acetyl-L-cysteine (a general antioxidant), catalase (a specific antioxidant for H2O2), and sodium formate (an inhibitor of OH.), but not by Rac1 dominant negative mutant Rac1N17 and diphenyleneiodonium (a NADPH oxidase inhibitor), indicating that MeJA induces HSP72 expression though HSF1 that is activated via Rac1-NADPH oxidase-independent ROS production pathway. These results suggest that the plant stress hormones share the ability to induce heat shock response in animal cells.
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PMID:Induction of heat shock protein 72 in C6 glioma cells by methyl jasmonate through ROS-dependent heat shock factor 1 activation. 1621 Dec 52

Vitamin K3 (VK3) is a well-known anticancer agent, but its mechanism remains elusive. In the present study, VK3 was found to simultaneously induce cell death, reactive oxygen species (ROS) generation, including superoxide anion (O2*-) and hydrogen peroxide (H2O2) generation, and histone hyperacetylation in human leukemia HL-60 cells in a concentration- and time-dependent manner. Catalase (CAT), an antioxidant enzyme that specifically scavenges H2O2, could significantly diminish both histone acetylation increase and cell death caused by VK3, whereas superoxide dismutase (SOD), an enzyme that specifically eliminates O2*-, showed no effect on both of these, leading to the conclusion that H2O2 generation, but not O2*- generation, contributes to VK3-induced histone hyperacetylation and cell death. This conclusion was confirmed by the finding that enhancement of VK3-induced H2O2 generation by vitamin C (VC) could significantly promote both the histone hyperacetylation and cell death. Further studies suggested that histone hyperacetylation played an important role in VK3-induced cell death, since sodium butyrate, a histone deacetylase (HDAC) inhibitor, showed no effect on ROS generation, but obviously potentiated VK3-induced histone hyperacetylation and cell death. Collectively, these results demonstrate a novel mechanism for the anticancer activity of VK3, i.e., VK3 induced tumor cell death through H2O2 generation, which then further induced histone hyperacetylation.
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PMID:Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation. 1625 25

Polyphenols have been shown to induce apoptosis in a variety of tumor cells including leukemia both in vitro and in vivo. However, their action on normal human peripheral blood mononuclear cells (PBMCs) during oxidative stress remains to be explored. In this study, we have evaluated the anti-apoptotic and radical scavenging activities of dietary phenolics, namely caffeic acid (CA), ellagic acid (EA) and ferulic acid (FA). H2O2-induced apoptosis in normal human PBMCs was assayed by phosphotidylserine externalization, nucleosomal damage and DNA fragmentation. Incubation of PBMCs with 5 mM H2O2 led to increased Annexin-V binding to externalized phosphatidyl serine (PS), an event of pre-apoptotic stage of the cell. Peripheral blood mononuclear cells pretreated with phenolics could resist H2O2-induced apoptotic damage. Caffeic acid (60 and 120 microM) and EA (100 and 200 microM) caused no change in externalization of PS, whereas FA (100 and 200 microM) increased externalization of PS in PBMCs treated with H2O2. The effects of phenolics were abolished to a large extent by culturing the PBMCs for 24 h after washing the phenolics from the medium. Inhibitory activities of these phenolics on lipid peroxidation were in the order of EA<CA<FA. DPPH-scavenging activities of EA, CA and FA were found to be 31.2+/-1.36, 50+/-1.86 and 73.0+/-1.58 microM respectively. Although, the phenolics significantly inhibited DNA damage and lipid peroxidation, they could not alter the Bcl-2 expression in PBMCs. In conclusion, the anti-apoptotic effect of EA, CA and FA in PBMCs seems to be through the Bcl-2 independent mechanism.
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PMID:Anti-apoptotic activity of caffeic acid, ellagic acid and ferulic acid in normal human peripheral blood mononuclear cells: a Bcl-2 independent mechanism. 1645 21

The ts1 mutant of Moloney murine leukemia virus (MoMuLV) induces a neurodegenerative disease in mice, in which glial cells are infected by the retrovirus but neurons are not. ts1 infection of primary astrocytes, or of the immortalized astrocytic cell line C1, results in accumulation of the ts1 gPr80(env) envelope protein in the endoplasmic reticulum (ER), with ER and oxidative stress. Notably, only about half of the infected astrocytes die in these cultures, while the other half survive, continue to proliferate, and continue to produce virus. To determine how these astrocytes survive ts1 infection in culture, we established a chronically infected subline of the living cells remaining after the death of all acutely infected cells in an infected C1 cell culture (C1-ts1-S). We report here that C1-ts1-S cells proliferate more slowly, produce less virus, show reduced H2O2 levels, increase their uptake of cystine, and maintain higher levels of intracellular GSH and cysteine compared to acutely infected or uninfected C1 cells. C1-ts1-S cells also upregulate their thiol antioxidant defenses by activation of the transcription factor NF-E2-related factor 2 (Nrf2) and its target genes. Interestingly, despite maintenance of higher levels of intracellular reduced thiols, C1-ts1-S cells are more sensitive to cystine deprivation than uninfected C1 cells. We conclude that some ts1-infected astrocytes survive and adapt to virus-induced oxidative stress by successfully mobilizing their thiol redox defenses.
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PMID:Astrocytes survive chronic infection and cytopathic effects of the ts1 mutant of the retrovirus Moloney murine leukemia virus by upregulation of antioxidant defenses. 1653 94

Heat stress and nitroxides induce reactive oxygen species (ROS) and proapoptotic effects. The underlying mechanisms remain largely elusive. Here we report that Tempo (2,2,6,6-tetramethylpiperidine-N-oxyl) is a potent thermosensitizer for promoting cell death in human leukemia U937 cells. Treatment with Tempo (10 mM, 37 degrees C/30 min) and hyperthermia (44 degrees C/30 min) induced 30 and 70-80% apoptosis, respectively, through Bax-mediated cytochrome c release and DEVDase activation. The Tempo/heat combination also caused Bax-mediated cytochrome c release, but switched heat-induced apoptosis to the particular pyknotic cell death, resulting in the irreparable inhibition of proliferation. Tempo and heat stress, but not the combination, caused an early transient elevation of H2O2/O2*- and a late induction of only O2*-, respectively. Mitochondrial Ca2+ overloads were indistinguishable after any treatment. Heat stress induced the pan-caspase inhibitor zVAD-fmk-suppressible low-Deltapsi (mitochondrial membrane potential) in 75% of cells as a result of DEVDase activation. In contrast, Tempo yielded low-Deltapsi by deprivation of the mitochondrial H+ gradient. The combined treatment induced 97% zVAD-resistant low-Deltapsi cells through irreversible mitochondrial dysfunction. Together, thus, Tempo or heat stress induced Bax-mediated mitochondrial apoptosis with the possible help of ROS or mitochondrial Ca2+, and Tempo when combined with hyperthermia acts a sensitizer by inducing irreparable pyknotic cell death through irreversible mitochondrial dysfunction.
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PMID:Mechanism of cell death induction by nitroxide and hyperthermia. 1654 80

Recent studies have suggested that antibodies can catalyze the generation of unknown oxidants including hydrogen peroxide (H2O2) and ozone (O3) from singlet oxygen (1O2) and water. This study is aimed to detect the effect of antibody-catalyzed water oxidation on atherosclerosis. Our results showed that both H2O2 and O3 were produced in human leukemia THP-1 monocytes incubated with human immunoglobulin G and phorbol myristate acetate. In the THP-1 monocytes incubated with human immunoglobulin G, phorbol myristate acetate and low density lipoprotein, the intracellular total cholesterol, free cholesterol, cholesteryl ester and lipid peroxides clearly increased, and a larger number of foam cells were observed by oil red O staining. The accumulation of all intracellular lipids was significantly inhibited by vinylbenzoic acid, and only slightly affected by catalase. These findings suggested that the production of O3, rather than H2O2, might be involved in the pathogenesis of atherosclerosis through the antibody-catalyzed water oxidation pathway.
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PMID:Effect of ozone produced from antibody-catalyzed water oxidation on pathogenesis of atherosclerosis. 1676 Nov


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