Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complexes of lanthanum (III) with bis-coumarins: bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-2-yl-methane; bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-3-yl-methane and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-4-yl-methane 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 ca. 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 13C-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 to the metal ion was also suggested. Cytotoxic screening by MTT assay was carried out. In the present study, we performed comparative evaluation of the cytotoxic effects of the three newly synthesized lanthanum complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia (CML)-derived BV-173. In addition the cytotoxic effects of La (III) complex with bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-piridin-2-yl-methane were evaluated on the SKW-3 cells. In order to elucidate some of the mechanistic aspects of the observed cytotoxic effects we evaluated the ability of this complex to trigger programmed cell death (apoptosis by means of agarose gel electrophoretic analysis of DNA), isolated from the cytosolic fraction of treated SKW-3 cells. In addition, microscopic morphological evaluation of the treated cells was carried out in order to establish morphological features indicative for programmed cell death.
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PMID:Cytotoxic activity of new lanthanum (III) complexes of bis-coumarins. 1592 38

To study the influence of IFN-alpha on function of CML-DC cultured in vitro and expression of chemokine and its chemokine receptor, bone marrow mononuclear cells from 13 CML patients were cultured in the fetal calf serum culture system supplemented with rhSCF, rhFlt-3L for expansion system, and adding rhGM-CSF, rhTNF-alpha, rhIL-4, with or without rhIFN-alpha to induce DCs. After incubation for two weeks, the phenotypes of CML-DC were analyzed by direct immunofluorescence and flow cytometry. The concentration of MIP-3beta expressed by CML-DC in the supernatant were analyzed by ELISA. The proliferative ability of T cells from healthy volunteers stimulated by CML-DCs were measured by MTT assay. The results showed that expression of CD86, CD83, CD40, MHC-I class molecules, CCR7, the concentration of MIP-3beta expressed by CML-DC, and the proliferative ability of T cells stimulated by CML-DCs in IFN-alpha group were all significantly higher than that in control group (P < 0.01). It is concluded that the immunophenotype of CML-DCs can be partially changed by IFN-alpha to accelerate the maturation of CML-DCs, enhance the capacity of CML-DCs, and stimulate allogeneic T lymphocyte proliferation.
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PMID:[Influence of IFN-alpha on function of CML-DC in vitro and expression of chemokine with its receptor]. 1597 48

Complexes of cerium (III) with bis-coumarins: 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) and bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane were synthesized by reaction of cerium (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 cerium (III) salt to an aqueous solution of the ligand subsequently raising the pH of the mixture gradually to ca. 5.0 by adding dilute solution of sodium hydroxide. The cerium (III) complexes with bis-coumarins were characterized by different physicochemical methods--elemental analysis, IR-, 1H- and 13C-NMR-spectroscopies and mass-spectral data. The spectral data of cerium (III) complexes were interpreted on the basis of comparison with the spectra of the free ligands. This analysis showed that in the Ce (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 to the metal ion was also suggested. Cytotoxic screening by MTT assay was carried out. In the present study we performed comparative evaluation of the cytotoxic effects of the two newly synthesized cerium complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia (CML)-derived BV-173. In addition the cytotoxic effects of Ce (III) complex with 3,3'-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one) were evaluated on the CML-derived K-562 and LAMA-84 cells, characterized by relative low responsiveness to chemotherapy. The DNA isolated from the cytosolic fraction of BV-173 cells after 24 h treatment with the same complex (at 100 and 200 microM) demonstrated a laddering phenomenon that is indicative for apoptotic cell death.
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PMID:Cytotoxic activity of new cerium (III) complexes of bis-coumarins. 1614 28

Imatinib mesylate (STI571), a specific inhibitor of BCR/ABL tyrosine kinase, exhibits potent antileukemic effects in the treatment of chronic myelogenous leukemia (CML). However, the precise mechanism by which inhibition of BCR/ABL activity results in pharmacological responses remains unknown. BCR/ABL-positive human K562 CML cells resistant to doxorubicin (K562DoxR) and their sensitive counterparts (K562DoxS) were used to determine the mechanism by which the STI571 inhibitor may overcome drug resistance. K562 wild type cells and CCRF-CEM lymphoblastic leukemia cells without BCR/ABL were used as controls. The STI571 specificity was examined by use of murine pro-B lymphoid Baf3 cells with or without BCR/ABL kinase expression. We examined kinetics of DNA repair after cell treatment with doxorubicin in the presence or absence of STI571 by the alkaline comet assay. The MTT assay was used to estimate resistance against doxorubicin and Western blot analysis with Crk-L antibody was performed to evaluate BCR/ABL kinase inhibition by STI571. We provide evidence that treatment of CML-derived BCR/ABL-expressing leukemia K562 cells with STI571 results in the inhibition of DNA repair and abrogation of the resistance of these cells to doxorubicin. We found that doxorubicin-resistant K562DoxR cells exhibited accelerated kinetics of DNA repair compared with doxorubicin-sensitive K562DoxS cells. Inhibition of BCR/ABL kinase in K562DoxR cells with 1 microM STI571 decreased the kinetics of DNA repair and abrogated drug resistance. The results suggest that STI571-mediated inhibition of BCR/ABL kinase activity can affect the effectiveness of the DNA-repair pathways, which in turn may enhance drug sensitivity of leukemia cells.
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PMID:Imatinib mesylate (STI571) abrogates the resistance to doxorubicin in human K562 chronic myeloid leukemia cells by inhibition of BCR/ABL kinase-mediated DNA repair. 1638 76

This study was aimed to investigate and compare the anti-leukemic effect mediated by dendritic cells (DC) derived from multidrug resistant (MDR) leukemia K562/A02 cells with high expression of p-glycoprotein (P-gp) and sensitive K562 cells. Multidrug resistant K562/A02 cell line and sensitive K562 cell line from chronic myeloid leukemia (CML) were induced for differentiating to DC in complete RPMI 1640 culture medium supplemented with GM-CSF (1 000 U/ml), IL-4 (500 U/ml) and TNF-alpha (100 ng/ml) for 14 days. The morphologic features of DC were observed by means of optical microscopy and the phenotype of DC was detected by flow cytometry. T-cell stimulating activity was determined by allogeneic lymphocyte reaction (allo-MLR). Cytotoxic activity was measured by MTT assay. The results indicated that DC derived from K562/A02 cells and K562 cells similarly showed the typical morphology of dendritic cell and expressed the surface differentiation antigens and costimulatory molecules CD1a, CD83, HLA-DR, CD80 and CD86 of DC. In allo-MLR, K562/A02-DC had a higher capacity to induce lymphocyte proliferation, compared with K562-DC (P < 0.05). K562/A02-DC and K562-DC could similarly generate specific cytotoxic activity against K562/A02 cells or K562 cells respectively, but low reactivity against HL-60 cells. More importantly, the cytotoxic activity mediated by K562/A02-DC was stronger than that by K562-DC against K562/A02 cells or HL-60/VCR cells (P < 0.01, respectively). It is concluded that functional DC can be differentiated from multidrug resistant leukemia K562/A02 cells as well as sensitive K562 cells in the presence of GM-CSF, IL-4 and TNF-alpha. Especially, DC derived from K562/A02 cells can induced a p-glycoprotein specific anti-leukemic immunity.
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PMID:[Induction of anti-leukemic immunity of dendritic cells derived from multidrug resistant leukemia K562/A02 cells with high expression of P-glycoprotein and sensitive K562 cells]. 1640 71

Indomethacin (IN) can inhibit cyclooxygenase activity and is considered to exert antitumor action in a variety of cancer cells. In the present study, we investigated the underlying mechanism of its antiproliferative effect on chronic myeloid leukemia (CML) cells. We studied the role of signal transducer and activator of transcription 1 or 5 (STAT(1) or STAT(5)) and Bcl-X(L) proteins in IN-induced proliferative inhibition on CML cells. Both K562 cells and fresh bone marrow mononuclear cells from five CML patients were exposed to IN. Cell proliferation was determined by MTT assay. The expression of JAK(2), STAT(1), STAT(5), and Bcl-X(L) proteins was probed with Western blotting. The level of phosphorylated STAT(1) (p-STAT(1)) or STAT(5) (p-STAT(5)) proteins was determined by coimmunoprecipitation combined with Western blotting. Intracellular localizations of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were observed by indirect immunofluorescence assay. Our results showed that IN could inhibit the proliferation of CML cells in a dose-dependent manner (36-288 microg/ml). The expression of STAT(1) and STAT(5) was suppressed by IN both in a concentration-dependent manner and a time-dependent (0-36 h) manner. The levels of p-STAT(1) and p-STAT(5) were down-regulated by IN. A similar result was obtained for Bcl-X(L) protein expression. The intracellular fluorescence signals representing STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were obviously weakened by IN. In contrast with IN, granulocyte-macrophage colony-stimulating factor could significantly promote the growth of CML cells and up-regulate the expression of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5). This data indicated that IN is able to suppress the proliferation of CML cells, and the mechanism is associated with the inhibition of STATs/ Bcl-X(L) signal transduction pathway.
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PMID:Antiproliferative effect of indomethacin on CML cells is related to the suppression of STATs/Bcl-XL signal pathway. 1657 23

The purpose of this study was to investigate the mechanism of effects of interferon-alpha (IFN-alpha) on chronic myeloid leukemia (CML). Bone marrow mononuclear cells (BMMNC) were obtained from heparinized blood of CML patients by Ficoll-Paque density gradient centrifugation. The expressions of CD1a, CD83, CD86, HLA-ABC, HLA-DR and CD54 on DC induced by IFN-alpha + GM-CSF, IFN-alpha + GM-CSF+IL-4 and IL-4 + GM-CSF for 7 days in vitro were assayed by flow cytometry. The morphologic features were observed by transmission and optical microscopy. The mixed lymphocyte reactions (MLR) with DC were evaluated by MTT assay. The results showed that the DC cultured in different cytokine combinations expressed significantly higher levels of CD1a, HLA-ABC, HLA-DR, CD86, CD54, and CD83 than those in the precultured. The DC growing with IFN-alpha + GM-CSF expressed significantly higher levels of HLA-ABC, HLA-DR than those in GM-CSF + IL-4. The CD86 expression and MLR levels in IFN-alpha + GM-CSF + IL-4 increased significantly. The expression rate of DC antigens and MLR in the IFN resistant group significantly lower than those in the newly diagnosed and the effectively treated groups after at least 6 months of IFN-alpha treatment (P < 0.05). The DC from the IFN resistant group did not express significantly CD86 and MLR in IFN-alpha + GM-CSF + IL-4 groups compared to those in the newly diagnosed and IFN effective treated groups. It is concluded that the BMMNC from CML cultured in combination with IFN-alpha and other cytokines can be induced into DC with typical morphologic and immunophenotypic characteristics. Addition of IFN-alpha + GM-CSF + IL-4 to DC cultures can significantly up-regulate the expression of major histocompatibility complex molecules, co-stimulatory molecules and various adhesion molecules. The deficiency of DC differentiation and function may play a role in the development of clinical resistance to IFN-alpha.
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PMID:[In vitro cytokines-induced differentiation in mononuclear cell derived dendritic cells from chronic myeloid leukemia]. 1658 10

Isothiocyanates (ITCs) are phytochemicals with promising cancer-preventive potential. To elucidate the mechanism of cytotoxicity of ITCs, their accumulation by cells and the role of intracellular glutathione, fluorescent 9-isothiocyanatoacridine (AcITC) was synthesized. The kinetic parameters for the reactions of AcITC with thiols were estimated and the influence of AcITC on human chronic myeloid leukemia cell line (K562) in regard to intracellular glutathione was studied. Cytotoxicity was evaluated by MTT assay, IC(50)=29.2 +/- 2.5 microM (48 h incubation). This acridine derivative was able to induce apoptosis of cells (morphological changes of cells and DNA fragmentation were observed) at least within certain dose that only decreased the level of intracellular glutathione, excessive doses (completely depleted intracellular pool of glutathione) induced necrosis rather than apoptosis. Our results indicated that apoptosis of leukemia cells induced by ITC is possible only if intracellular glutathione is not entirely depleted.
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PMID:Involvement of glutathione in the cytotoxicity of 9-isothiocyanatoacridine. 1660 1

Complexes of zirconium (IV) with some bis-coumarin ligands have been synthesized. The zirconium (IV) complexes with bis-coumarins were characterized by different physicochemical methods-elemental analysis, IR-, and (1)H-NMR-spectroscopies and mass spectral data. The spectral data of zirconium (IV) complexes were interpreted on the basis of comparison with the spectra of the free ligands. The results of the ligands and their complexes, based on spectral data are informative and useful for suggestion of the metal-ligand binding mode. Cytotoxic screening by MTT assay was carried out. In the present study we performed comparative evaluation of the cytotoxic effects of the three newly synthesized zirconium complexes against the acute myeloid leukemia derived HL-60 and the chronic myeloid leukemia LAMA-84. The preliminary cytotoxicity screening program revealed that the investigated zirconium complexes induced 50% inhibition of the cell viability of HL-60 and LAMA-84 cells at micromolar concentrations and thus could be considered as biologically active. Independently of the tumor test system evaluated the complex of bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane proved superior to the remaining agents with respect to the IC(50) values obtained. The complexes of both the other coumarins evaluated proved to be less potent than the corresponding free ligands, as evidenced by the IC(50) values obtained. Thus the zirconium complexes with coumarin ligands represent a novel class of antiproliferative agents, which deserve further attention in search of anticancer lead compounds.
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PMID:New zirconium (IV) complexes of coumarins with cytotoxic activity. 1669 91

FK228 is a novel antitumor depsipeptide that inhibits histone deacetylases and restores the expression of genes aberrantly suppressed in cancer cells. This agent was shown to have broad antitumor activity in preclinical studies, and is currently under phase I/II evaluations. Because of its wide spectrum of actions, it is reasonable to consider the combination with other anticancer drugs in clinical application. We studied the cytotoxic interaction of FK228 in combination with conventional antileukemic agents using human promyelocytic leukemia HL60, Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia KU-812, T-cell lymphoblastic leukemia MOLT3 and Burkitt's lymphoma Raji cell lines. For the combination of FK228 and imatinib, Ph(+) leukemia KU812, K562 and TCC-S cell lines were used. The cells were exposed simultaneously to FK228 and other agents for 4 days. Cell growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We used the isobologram method of Steel and Peckham to evaluate the cytotoxic interaction at the concentration of drugs that produced 80% cell growth inhibition (IC(80)). FK228 showed an additive effect with cytarabine, carboplatin, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, 6-mercaptopurine and SN-38 (active metabolite of irinotecan) in all cell lines studied. FK228 with methotrexate and vincristine showed an antagonistic effect in three and one of the four cell lines, respectively. FK228 was additive with imatinib in all three Ph(+) leukemia cells. Our findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.
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PMID:Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines. 1686 29


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