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)

The relationship between the Src kinase Lyn and Bcl-2 expression was examined in chronic myelogenous leukemia cells (K562 and LAMA84) displaying a Bcr/Abl-independent form of imatinib mesylate resistance. K562-R and LAMA-R cells that were markedly resistant to induction of mitochondrial dysfunction (e.g. loss of mitochondrial membrane potential, Bax translocation, cytochrome c, and apoptosis-inducing factor release) and apoptosis by imatinib mesylate exhibited a pronounced reduction in expression of Bcr/Abl, Bcl-x(L), and STAT5 but a striking increase in levels of activated Lyn. Whereas basal expression of Bcl-2 protein was very low in parental cells, imatinib-resistant cells displayed a marked increase in Bcl-2 mRNA and/or protein levels. Treatment of LAMA-R cells with the Src kinase inhibitor PP2 significantly reduced Lyn activation as well as Bcl-2 mRNA and protein levels. Transient or stable transfection of LAMA84 or K562 cells with a constitutively active Lyn (Y508F), but not with a kinase-dead mutant (K275D), significantly increased Bcl-2 protein expression and protected cells from lethality of imatinib mesylate. Ectopic expression of Bcl-2 protected K562 and LAMA84 cells from imatinib mesylate- and PP2-mediated lethality. Conversely, interference with Bcl-2 function by co-administration of the small molecule Bcl-2 inhibitor HA14-1 or down-regulation of Bcl-2 expression by small interfering RNA or antisense strategies significantly increased mitochondrial dysfunction and apoptosis induced by imatinib mesylate and the topoisomerase inhibitor VP-16 in LAMA-R cells. In marked contrast, these interventions had little effect in parental LAMA84 cells that display low basal levels of Bcl-2. Together, these findings indicate that activation of Lyn in leukemia cells displaying a Bcr/Abl-independent form of imatinib mesylate resistance plays a functional role in Bcl-2 up-regulation and provide a theoretical basis for the development of therapeutic strategies targeting Bcl-2 in such a setting.
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PMID:A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2. 1517 50

Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34+ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34+ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21CIP1, Bcr/Abl, and cyclin D1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.
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PMID:Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. 2773 68

BCR/ABL-kinase mutations frequently mediate clinical resistance to the selective tyrosine kinase inhibitor Imatinib mesylate (IM, Gleevec). However, mechanisms that promote survival of BCR/ABL-positive cells before clinically overt IM resistance occurs have poorly been defined so far. Here, we demonstrate that IM-treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTor)-pathway in BCR/ABL-positive LAMA-cells and primary leukemia cells in vitro, as well as in a chronic phase CML patient in vivo. In fact, PI3K/Akt-activation critically mediated survival during the early phase of IM resistance development before manifestation of BCR/ABL-dependent strong IM resistance such as through a kinase mutation. Accordingly, inhibition of IM-induced Akt activation using mTor inhibitors and Akt-specific siRNA effectively antagonized development of incipient IM-resistance in vitro. In contrast, IM-resistant chronic myeloid leukemia (CML) patients with BCR/ABL kinase mutations (n=15), and IM-refractory BCR/ABL-positive acute lymphatic leukemia patients (n=2) displayed inconsistent and kinase mutation-independent autonomous patterns of Akt-pathway activation, and mTor-inhibition overcame IM resistance only if Akt was strongly activated. Together, an IM-induced compensatory Akt/mTor activation may represent a novel mechanism for the persistence of BCR/ABL-positive cells in IM-treated patients. Treatment with mTor inhibitors may thus be particularly effective in IM-sensitive patients, whereas Akt-pathway activation variably contributes to clinically overt IM resistance.
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PMID:Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. 1613 69

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

AMN107 (Novartis Pharmaceuticals, Basel, Switzerland) has potent in vitro and in vivo activity against the unmutated and most common mutant forms of Bcr-Abl. Treatment with the histone deacetylase inhibitor LBH589 (Novartis) depletes Bcr-Abl levels. We determined the effects of AMN107 and/or LBH589 in Bcr-Abl-expressing human K562 and LAMA-84 cells, as well as in primary chronic myelogenous leukemia (CML) cells. AMN107 was more potent than imatinib mesylate (IM) in inhibiting Bcr-Abl tyrosine kinase (TK) activity and attenuating p-STAT5, p-AKT, Bcl-x(L), and c-Myc levels in K562 and LAMA-84 cells. Cotreatment with LBH589 and AMN107 exerted synergistic apoptotic effects with more attenuation of p-STAT5, p-ERK1/2, c-Myc, and Bcl-x(L) and increases in p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of Bcr-Abl or the IM-resistant, point-mutant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis of IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared with either agent alone, cotreatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Thus, cotreatment with LBH589 and AMN107 is active against cultured or primary IM-resistant CML cells, including those with expression of Bcr-AblT315I.
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PMID:Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. 1653 4

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

Callus and hairy root cultures of Linum leonii were established. The genetic transformation in hairy roots was proven by PCR analysis, which showed integration of rol A and rol C genes into the plant genome. Calli and hairy roots accumulate the arylnaphthalene lignan justicidin B as a major constituent. Hairy roots produce 5-fold higher yields of justicidin B (10.8 mg g(-1) DW) compared to calli. Justicidin B shows strong cytotoxicity on the chronic myeloid leukemia LAMA-8 and K-562 cell lines and on the chronic lymphoid leukemia SKW-3 cell line with IC(50) values of 1.11, 6.08, and 1.62 microM, respectively. Apoptotic properties of justicidin B are reported for the first time.
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PMID:Production of justicidin B, a cytotoxic arylnaphthalene lignan from genetically transformed root cultures of Linum leonii. 1687 35

The tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia, but the occurrence of resistance phenomena can significantly limit therapeutic impact. Imatinib shows synergistic effects with cisplatin, suggesting that the coadministration of different cytostatics might reestablish the efficacy of treatment. We recently demonstrated that cobalt alkyne (or acetylenehexacarbonyldicobalt) complexes induce antiproliferative activity in human leukemia and lymphoma cells. The present study evaluates the effects of cobalt alkyne compounds containing propargylic acid esters on human acute (HL-60) and chronic myeloid (LAMA-84 and CML-T1) leukemia cell lines. The cell growth inhibitory activities (IC(50) values of 9.5 microM and higher) and induction of apoptosis (maximum 5.5-fold increase of single-stranded DNA at a drug concentration of 50 microM) achieved with the single agents were moderate. Interestingly, suboptimal concentrations of the cobalt complexes (10 microM) together with imatinib (0.1 microM), when coadministered, showed an additive or synergistic effect on cellular proliferation inhibition. The most promising results were obtained with complexes containing ligands derived from the nonsteroidal antiinflammatory drugs acetylsalicylic acid and naproxene.
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PMID:Synergistic and additive antiproliferative effects on human leukemia cell lines induced by combining acetylenehexacarbonyldicobalt complexes with the tyrosine kinase inhibitor imatinib. 1690 70

Overcoming imatinib mesylate (IM) resistance and disease persistence in patients with chronic myeloid leukemia (CML) is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL+ cells in the presence of IM and nilotinib (NI; AMN107), a novel, more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84 cell clones (R-CM) was found to substantially protect IM-naive LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony-stimulating factor (GM-CSF), which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the janus kinases 2 (JAK-2)/signal transducer and activator of transcription 5 (STAT-5) signaling pathway in GM-CSF receptor alpha receptor (CD116)-expressing cells, including primary CD34+/CD116+ GM progenitors (GMPs). Elevated mRNA and protein levels of GM-CSF were detected in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF-mediated STAT-5 phosphorylation and NI resistance in vitro. Together, adaptive autocrine secretion of GM-CSF mediates BCR/ABL-independent IM and NI resistance via activation of the antiapoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance, providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
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PMID:Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. 1709 Jun 51

Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell lines (K562 and LAMA-84) than either drug alone (P < 0.01). Cell cycle analysis of propidium iodide-stained cells showed that STI-571 significantly reduced PBOX-6-induced G2M arrest and polyploid formation with a concomitant increase in apoptosis. Similar results were obtained in K562 CML cells using lead MTAs (paclitaxel and nocodazole) in combination with STI-571. Potentiation of PBOX-6-induced apoptosis by STI-571 was specific to Bcr-Abl-positive leukemia cells with no cytoxic effects observed on normal peripheral blood cells. The combined treatment of STI-571 and PBOX-6 was associated with the down-regulation of Bcr-Abl and repression of proteins involved in Bcr-Abl transformation, namely the antiapoptotic proteins Bcl-x(L) and Mcl-1. Importantly, PBOX-6/STI-571 combinations were also effective in STI-571-resistant cells. Together, these findings highlight the potential clinical benefits in simultaneously targeting the microtubules and the Bcr-Abl oncoprotein in STI-571-sensitive and -resistant CML cells.
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PMID:STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells. 1720


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