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)

Differentiation-inducing therapy with the DNA-methylation inhibitor Decitabine (5'-aza-deoxycytidine) and histone deacetylase (HDAC) inhibitors are now considered in acute myelogenous leukemia (AML). We investigated the in vitro effects of Decitabine and two structurally unrelated HDAC inhibitors (Sodium 4-phenyl butyrate, Tricostatin A) on clonogenic AML cells. Based on morphological criteria we identified four major colony types: (i) non-erythroid colonies, (ii) erythroid colonies that were detected only for a subset of patients and could be further sub classified into mature and immature forms, and (iii) intermediate colonies. Erythroid differentiation was associated with low CD34 expression. The colonies showed differences in morphology, viability, cell cycle distribution and expression of differentiation markers. Both Decitabine and the two HDAC inhibitors altered AML cell expression of differentiation markers, whereas the drugs did not have any major influence on cell cycle distribution. However, the pharmacological effects differed between the four colony subsets, and differences were also detected between the two HDAC inhibitors. We conclude that clonogenic AML cells can be classified into well-defined subsets based on their differentiation, and these subsets differ in their biological characteristics as well as their response to pharmacological targeting of epigenetic regulation.
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PMID:Clonogenic acute myelogenous leukemia cells are heterogeneous with regard to regulation of differentiation and effect of epigenetic pharmacological targeting. 1741 13

Complexes of lanthanum(III) with bis-coumarins: 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) (H(2)L1) and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane (H(2)L2) were synthesized by reaction of lanthanum(III) salt and the ligands, in amounts equal to metal : ligand molar ratio of 1 : 2. The complexes were prepared by adding an aqueous solution of lanthanum(III) salt to an aqueous solution of the ligand subsequently raising the pH of the mixture gradually to circa 5.0 by adding dilute solution of sodium hydroxide. The lanthanum(III) complexes with bis-coumarins were characterized by different physicochemical methods-elemental analysis, IR-, (1)H-, and (13)C-NMR-spectroscopies, and mass spectral data. The spectral data of lanthanum(III) complexes were interpreted on the basis of comparison with the spectra of the free ligands. This analysis showed that in the La(III) complexes, the ligands coordinated to the metal ion through both deprotonated hydroxyl groups. On the basis of the nu(C=O) red shift observed, participation of the carbonyl groups in the coordination with the metal ion was also suggested. In the present study, we performed a cytotoxic-effects screening of the lanthanum complexes with H(2)L1 and H(2)L2 in a panel of human tumor cell lines, using the standard MTT-dye reduction assay for cell viability. The panel consisted of the acute myeloid leukemia-derived HL-60 and the chronic myeloid leukemia-derived BV-173. Following a 24- hour treatment of BV-173 cells with lanthanum complex of H(2)L1 at 100 or 200 microM led to a DNA-laddering. The findings suggest that the observed cytotoxicity of the lanthanum complex of H(2)L1 on BV-173 is at least partly mediated through induction of programmed cell death.
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PMID:Synthesis, characterization, and cytotoxic activity of new lanthanum(III) complexes of bis-coumarins. 1749 5

Modulation of gene expression through histone deacetylase (HDAC) inhibition is considered a possible therapeutic strategy in acute myeloid leukaemia (AML). In vitro effects and basal gene expression of structurally different HDAC inhibitors were examined. Primary human AML cells were derived from 59 consecutive patients. The HDAC inhibitors valproic acid, PXD101, trichostatin A and sodium butyrate inhibited leukaemic and clonogenic cell proliferation and increased apoptosis in a dose-dependent manner when tested at high concentrations. However, at lower concentrations proliferation increased for a subset of patients. This divergence was also observed in the presence of all-trans retinoic acid, theophylline and decitabine, and in cocultures with bone marrow stromal cells. Levels of IL-1beta, IL-6, GM-CSF and TNFalpha increased. Based on the basal expression of 100 genes the patients with growth enhancement at intermediate HDAC inhibitor concentrations and those without this response were clustered into two mutually exclusive groups. Functional characterization and gene expression analyses identify AML patient subsets that differ in their response to HDAC inhibitors. These observations may explain why HDAC inhibitor therapy affects only a subset of patients.
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PMID:Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors. 1798 80

We report the case of a 75-year-old man with acute myeloid leukemia who developed hyponatremia after linezolid administration. Because induction therapy did not achieve complete remission for this man, we initiated re-induction therapy with enocitabin and daunomycin. Seven days after chemotherapy, the patient experienced a catheter-related blood stream infection (CRBSI) due to methicilin resistant staphylococcus aureus (MRSA). When treatment with albekacin and fosfomycin was in effective, linezolid was administrated intravenously and he became afebrile. On day 8 after linezolid administration, however, he reported general fatigue and slight consciousness disturbance. His serum sodium concentration was 119 mEq/L and his urinary sodium excretion rose to 143 mEq/day, although intravenous sodium intake was 98 mEq/day. Because of the sufficiency of urine volume and weight loss, we surmise that inappropriate ADH secretion (SIADH) syndrome was unlikely. We diagnosed renal salt wasting syndrome (RSWS) based on calculation of the amount of sodium intake and the amount of sodium excreted from the kidneys. After linezolid was discontinued and aggressive treatment with sodium supplement begun, his consciousness cleared as his low serum sodium level rose. This is, to the best of our knowledge, the first case reported on the development of RSWS after linezolid treatment. Although the process remains unclear, our case suggests that linezolid may induce RSWS after intensive chemotherapy.
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PMID:[Marked hyponatremia with consciousness disturbance probably caused by linezolid in a patient with acute myeloid leukemia]. 1830 78

Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
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PMID:Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells. 1866 Mar 79

LY573636-sodium is a promising anti-tumor agent, which causes growth arrest and apoptosis of a variety of human solid tumors in vitro and in vivo. Moreover, studies have shown that the compound is selectively toxic towards tumor cells over their normal counterparts. This targeted effect makes LY573636 a candidate for combined therapy regimens in patients with advanced or resistant cancers. We studied for the first time, the anti-tumor properties of LY573636 against a variety of human hematopoietic malignancies, including AML, B-ALL, large B-cell and mantle cell lymphoma cell lines. Cells were treated with the compound in vitro and its effect on cell proliferation, apoptosis and differentiation was determined. The cell lines underwent growth arrest in response to treatment with LY573636 in a dose-dependent manner. This antiproliferative activity was associated with the induction of apoptosis, loss of mitochondrial membrane potential and induction of reactive oxygen species. Furthermore, we showed that LY573636 was able to induce granulocytic/monocytic differentiation of HL60 and U937 cells. LY573636, as shown before in solid tumors, is effective in hematopoietic cell lines as well. These data suggest the use of LY573636 alone or in combination with conventional chemotherapeutic regimens in hematopoietic malignancies.
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PMID:Novel acyl sulfonamide LY573636-sodium: effect on hematopoietic malignant cells. 1894 27

Histone deacetylase inhibitors (HDIs) are emerging as valuable new agents in the treatment of acute myeloid leukaemia (AML). However, since response rates to these agents alone are low, we sought to identify markers associated with responsiveness. In a trial of 20 patients treated with the HDI sodium valproate (VPA) in combination with all trans retinoic acid and theophylline, three patients responded clinically with one complete remission (CR) and two partial remissions. The in vivo response of the CR patient was mirrored by high in vitro sensitivity of their blasts to VPA, indicating that similar factors determine both in vivo and in vitro sensitivity. Microarray analysis of the primary AMLs and a panel of haemato-lymphoid cell lines, with a similar range of VPA sensitivities as the primary leukaemic blasts, identified elevated FOSB-expression as a potential marker of VPA sensitivity. Quantitative polymerase chain reaction confirmed overexpression of FOSB in the CR patient blasts compared to patients failing to achieve CR, and in a subset of a larger panel of AML samples. Overexpression of FOSB in K562 myeloid cells significantly increased in vitro sensitivity to VPA. Thus, we propose that FOSB is a novel, potential marker of VPA sensitivity in AML.
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PMID:Elevated FOSB-expression; a potential marker of valproate sensitivity in AML. 1903 90

Engagement of NKG2D by their ligands (NKG2D-L), as the human major histocompatibility complex class I-related molecules MIC-A and the UL16-binding proteins, on cytolytic lymphocytes leads to the enhancement of antitumour effector functions. These ligands are missing or expressed at very low levels on leukaemic cells; furthermore, they can be shed by tumour cells and inhibit cytolytic activity of lymphocytes. Herein, we show that in vivo administration of all-trans-retinoic acid (ATRA) or the histone deacetylase inhibitor sodium valproate (VPA) to patients affected with acute myeloid leukaemia (AML) M3 or M1 respectively, leads to the induction of transcription and expression of NKG2D-L at the surface of leukaemic cells. Apparently, no detectable shedding of the soluble form of these molecules was found in patients' sera. Conversely, AML blasts from patients treated with chemotherapy not including ATRA or VPA did not show any induction of NKG2D-L transcription. Furthermore, upon therapy with ATRA or VPA, leukaemic blasts become able to trigger lytic granule exocytosis by autologous CD8(+) T and natural killer lymphocytes, as shown by CD107a mobilization assay, followed by leukaemic cell lysis. These findings indicate that ATRA and VPA may contribute to the activation of cytolytic effector lymphocytes in vivo, possibly enhancing their anti-leukaemic effect.
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PMID:Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate. 1915 70

The effects of common inorganic ions found in freshwater on the infectivity of Romanomermis culicivorax and the survival of its host, Culex pipiens, were tested. In general, the median lethal concentrations found for R. culicivorax were greater than the reported median concentrations of these ions in freshwater but less than the reported maximum natural concentrations. The ion toxicity for R. culicivorax (on a molar basis) increased in the following order: sodium < potassium < calcium; aml chloride < carbonate = sulfate < nitrate < nitrite < phosphate. The larvae of C. pipiens were generally 20 to 75 times as tolerant of higher ion concentrations as were the preparasitic stages of R. culicivorax.
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PMID:Salts and the infectivity of Romanomermis culicivorax. 1930 14

Cortactin is an F-actin binding protein, regulating cell movement and adhesive junction assembly. However, the function of cortactin in epithelial-mesenchymal transition (EMT) remains elusive. Here we found that during transforming growth factor-beta1 (TGF-beta1)- induced EMT in AML-12 murine hepatocytes, cortactin underwent tyrosine dephosphorylation. Inhibition of the dephosphorylation of cortactin by sodium vanadate blocked TGF-beta1-induced EMT. Knockdown of cortactin by RNAi led to decrease of intercellular junction proteins E-cadherin and Zonula occludens-1 and induced expression of mesenchymal protein fibronectin. Additionally, knockdown of cortactin further promoted TGF-beta1-induced EMT in AML-12 cells, as determined by EMT markers and cell morphological changes. Moreover, migration assay showed that cortactin knockdown promoted the migration of AML-12 cells, and also enhanced TGF-beta1-induced migration. Our study showed the involvement of cortactin in the TGFbeta1- induced EMT.
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PMID:Cortactin is involved in transforming growth factor-beta1-induced epithelial-mesenchymal transition in AML-12 cells. 1977 49


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