Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic occupational exposure to benzene has been correlated with aplastic aneamia and acute myelogenous leukemia, however mechanisms behind benzene toxicity remain unknown. Interestingly, benzene-initiated hematotoxicity is absent in mice lacking the aryl hydrocarbon receptor (AhR) suggesting an imperative role for this receptor in benzene toxicities. This study investigated two potential roles for the AhR in benzene toxicity using hepa 1c1c7 wild type and AhR deficient cells. Considering that many toxic effects of AhR ligands are dependent on AhR activation, our first objective was to determine if benzene, hydroquinone (HQ) or benzoquinone (BQ) could activate the AhR. Secondly, because the AhR regulates a number of enzymes involved in oxidative stress pathways, we sought to determine if the AhR had a role in HQ and BQ induced production of reactive oxygen species (ROS). Dual luciferase assays measuring dioxin response element (DRE) activation showed no significant change in DRE activity after exposure to benzene, HQ or BQ for 24h. Immunofluorescence staining showed cytosolic localization of the AhR after 2h incubations with benzene, HQ or BQ. Western blot analysis of cells exposed to benzene, HQ or BQ for 1, 12 and 24h did not demonstrate induction of CYP1A1 protein expression. Dichlorodihydrofluorescein staining of cells exposed to benzene, HQ or BQ revealed that the presence of the AhR did not affect BQ and HQ induced ROS production. These results indicate that the involvement of the AhR in benzene toxicity does not seem to be through classical activation of this receptor or through interference of oxidative stress pathways.
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PMID:Investigating the role of the aryl hydrocarbon receptor in benzene-initiated toxicity in vitro. 1716 14

This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.
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PMID:Balance of NF-kappaB and p38 MAPK is a determinant of radiosensitivity of the AML-2 and its doxorubicin-resistant cell lines. 1721 10

Acute myeloid leukemia (AML) cell lines treated by genotoxic agents or by Tumor Necrosis Factor alpha (TNFalpha) acquire potent cytotoxicity towards myeloid cells through activation of granzyme B (GrB)/perforin (PFN) system. Here we first extend this observation to another death receptor activator, Fas Ligand (FasL). Moreover, we analyzed GrB induction signalling pathway in TNFalpha- and FasL-stimulated AML cells. The effects of TNFalpha and FasL on GrB expression were specifically mediated by p38MAPK (Mitogen-activated-protein-kinase) activation. Otherwise, TNFalpha and FasL stimulation led to radical oxygen species (ROS) generation and ASK1 (Apoptosis-signal-regulating-kinase-1) activation. Endogenous activation of ASK1 by either H2O2 or thioredoxin (Trx) reductase inhibition had the same effects as TNFalpha and FasL on GrB up regulation. Altogether, our results suggest that TNFalpha- and FasL-stimulated AML cell lytic induction is regulated by a signalling pathway involving sequentially, ROS generation, Trx oxidation, ASK1 activation, p38MAPK stimulation and GrB induction at mRNA and protein levels.
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PMID:Granzyme B induction signalling pathway in acute myeloid leukemia cell lines stimulated by tumor necrosis factor alpha and Fas ligand. 1725 90

Troxacitabine (BCH-4556; [-]-2'-deoxy-3'-oxacytidine) is a synthetic dioxolane that represents the first nucleoside analog with an L-isomer configuration to have shown important cytotoxic activity. Troxacitabine was obtained by exchanging the sulfur endocyclic atom with oxygen in the structure of lamivudine (3TC). Its unnatural stereochemistry renders it insensitive to some mechanisms of resistance of tumor cells to D-nucleosides, such as deamination by deoxycytidine deaminase and decreased active uptake by nucleoside transporters. These characteristics make troxacitabine a suitable alternative for patients with acute myelogenous leukemia as a potential way for overcoming resistance to ara-C therapy, which is the mainstay of acute myelogenous leukemia therapy at present. Clinically significant activity has been reported in Phase I studies in patients with advanced hematologic malignancies and has prompted troxacitabine to enter a series of Phase II trials in patients with refractory and relapsed acute myelogenous leukemia.
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PMID:Evaluation of the L-stereoisomeric nucleoside analog troxacitabine for the treatment of acute myeloid leukemia. 1737 Dec 1

Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H(2)O(2), transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H(2)O(2) is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H(2)O(2) does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H(2)O(2) activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.
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PMID:Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. 1754 Jul 68

Melissoidesin G (MOG) is a new diterpenoid purified from Isodon melissoides, a plant used in Chinese traditional medicine as antitumor and anti-inflammatory agents. In our study, MOG was shown to specifically inhibit the growth of human leukemia cell lines and primary acute myeloid leukemia (AML) blasts via induction of apoptosis, with the evidence of mitochondrial DeltaPsim loss, reactive oxygen species production, caspases activation and nuclear fragmentation. Furthermore, it was shown that thiol-containing antioxidants completely blocked MOG-induced mitochondrial DeltaPsim loss and subsequent cell apoptosis, while the inhibition of apoptosis by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone only partially attenuated mitochondrial DeltaPsim loss, indicating that MOG-induced redox imbalance is an early event upstream to mitochondrial DeltaPsim loss and caspase-3 activation. Consistently, it was found that MOG rapidly decreased the intracellular glutathione (GSH) content in a dose-dependent manner and the significance of GSH depletion in MOG-induced apoptosis was further supported by the protective effects of tert-butylhydroquinone (tBHQ) and the facilitative effects of DL-buthionine (S,R)-sulfoximine (BSO). Furthermore, it was showed that GSH depletion induced by MOG rendered some leukemia cell lines more sensitive to arsenic trioxide (As2O3), doxorubicin or cisplatin. Additionally, the synergistic apoptotic effects of MOG with As2O3 were detected in HL-60 and primary AML cells, but not in normal cells, suggesting the selective toxicity of their combination to the malignant cells. Together, we proposed that MOG alone or administered with other anticancer agents may provide a novel therapeutic strategy for leukemia.
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PMID:Melissoidesin G, a diterpenoid purified from Isodon melissoides, induces leukemic-cell apoptosis through induction of redox imbalance and exhibits synergy with other anticancer agents. 1764 57

Angiogenesis and hematopoiesis are closely linked and interactive with each other, but few studies were given to identify possible links between angiogenesis-promoting proteins and hematopoiesis-related transcription factors. Here we investigated the potential relationship of oxygen-sensitive alpha-subunit of angiogenesis-related hypoxia-inducible factor-1alpha (HIF-1alpha) with Runt-related protein 1 (Runx1, also known as acute myeloid leukemia-1, AML-1), an important hematopoietic transcription factor. The results demonstrated that Runx1 and HIF-1alpha proteins directly interacted with each other to a degree, in which Runt homology domain of Runx1 was mainly involved. Leukemia-related abnormal Runx1 fusion protein AML1-ETO, which fuses the N-terminal 177 amino acid residues of the Runx1 protein in frame to ETO (eight-twenty-one) protein, also interacted with HIF-1alpha protein with greater ability than Runx1 itself. More intriguingly, Runx1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1 protein with reduced expression of HIF-1-targeted genes such as vascular endothelial growth factor, while silence of Runx1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1 protein, suggesting that Runx1 inhibited transcription-dependent function of HIF-1. Vice versa, HIF-1alpha increased DNA-binding ability and transcriptional activity of Runx1 protein. All these data would shed new insight to understanding Runx1 and HIF-1alpha-related hematopoietic cell differentiation and angiogenesis.
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PMID:Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1alpha. 1768 92

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.
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PMID:Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia? 1787 17

A young man who presented with fever, altered sensorium and sudden onset tachypnea, is described. Arterial blood gas analysis, revealed the presence of severe high anion gap metabolic acidosis, with compensatory respiratory alkalosis and normal oxygen saturation. A detailed neurological, nephrological, biochemical and hematological evaluation, revealed the presence of Acute myeloid leukemia, with lactic acidosis and hyponatremia. There are very few reports of presentation of leukemia as lactic acidosis. This case report highlights the need for emergency room physicians, to consider the possibility of lactic acidosis, as one of the causes of high anion gap acidosis and to meticulously investigate the cause of lactic acidosis. We describe a rare clinical instance of lactic acidosis as the presenting manifestation of Acute myeloid leukemia.
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PMID:A typical presentation of acute myeloid leukemia. 1799 83

Adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents. We hypothesized that disruption of leukemic cell cytoskeletal stability and interference with vascular cell interactions would promote leukemic cell death. We demonstrate that low and nontoxic doses of microtubule-destabilizing agent combretastatin-A4-phosphate (CA4P) inhibit leukemic cell proliferation in vitro and induce mitotic arrest and cell death. Treatment of acute myeloid leukemias (AMLs) with CA4P leads to disruption of mitochondrial membrane potential, release of proapoptotic mitochondrial membrane proteins, and DNA fragmentation, resulting in cell death in part through a caspase-dependent manner. Furthermore, CA4P increases intracellular reactive oxygen species (ROS), and antioxidant treatment imparts partial protection from cell death, suggesting that ROS accumulation contributes to CA4P-induced cytotoxicity in AML. In vivo, CA4P inhibited proliferation and circulation of leukemic cells and diminished the extent of perivascular leukemic infiltrates, prolonging survival of mice that underwent xenotransplantation without inducing hematologic toxicity. CA4P decreases the interaction of leukemic cells with neovessels by down-regulating the expression of the adhesion molecule VCAM-1 thereby augmenting leukemic cell death. These data suggest that CA4P targets both circulating and vascular-adherent leukemic cells through mitochondrial damage and down-regulation of VCAM-1 without incurring hematologic toxicities. As such, CA4P provides for an effective means to treat refractory organ-infiltrating leukemias.
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PMID:The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death. 1802 94


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