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)

To facilitate quantitation of cellular apoptotic responses to various antineoplastic agents, a laser-based technology, Optophoresis, has been developed to provide analysis of cells without any need for labeling or cell processing. Optophoresis is defined as the analysis of the motion of cells, where the motion is either induced or modified by a moving optical gradient field, which produces radiation pressure forces on the cells in an aqueous suspension. Quantitation of the induced motion provides a basis for distinguishing one population of cells from another. One Optophoretic technique, Fast Scan, measures the distribution of distances traversed by a population of cells when exposed to a fast-moving optical gradient. Fast Scan was validated using a cell-based model of chronic myeloid leukemia treated with Gleevec, a specific inhibitor of aberrant Bcr-Abl protein kinase. The Optophoretic measurements were quantitatively comparable to reference assays with regard to drug selectivity and potency and to target specificity, demonstrating the suitability of this technology for pharmaceutical and clinical applications.
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PMID:Use of moving optical gradient fields for analysis of apoptotic cellular responses in a chronic myeloid leukemia cell model. 1503 6

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl(+) human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor kappaB (NF-kappaB)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-beta-d-ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl(-) human leukemia cells. Collectively, these findings suggest that a strategy combining flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies.
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PMID:Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. 1503 84

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.
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PMID:Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells. 1505 60

The differentiation of K562 chronic myelogenous leukemia (CML) cells by smenospongine, which is a sesquiterpene aminoquinone isolated from a marine sponge, was examined. Smenospongine increased hemoglobin production in K562 cells at concentrations of 3-15 microM. In addition, flow cytometric analysis of smenospongine-treated K562 cells with FITC-labeled glycophorin A antibody showed an increase of glycophorin A expression, a marker for erythroid differentiation. Cell-cycle analysis showed G1 arrest in K562 cells after treatment with smenospongine for 24 h. The effect on expression of CIP/KIP family cyclin-dependent kinase inhibitors was investigated by Western blotting analysis and the result showed increased expression of p21, which is known to play an important role in differentiation. Furthermore, smenospongine was also found to inhibit the phosphorylation of Crkl, a substrate of Bcr-Abl tyrosine kinase, which is known as a causative protein of CML. In conclusion, our investigation indicated that smenospongine induced the differentiation of K562 cells into erythroblasts along with cell-cycle arrest at G1 phase and the mechanism might be attributed to the increased expression of p21.
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PMID:Smenospongine, a spongean sesquiterpene aminoquinone, induces erythroid differentiation in K562 cells. 1505 41

Chronic myelogenous leukaemia (CML) cells show expression of BCL-X(L), an anti-apoptotic oncogene. This expression is induced by BCR-ABL protein kinase through activation of the signal transducer and activator of transcription-5 protein (STAT5). To date, however, the contribution of BCL-X(L) and STAT5 to the transforming phenotype in CML is still unclear. This study was aimed at defining the status of activated STAT5 and BCL-X(L) expression and their relation to BCR-ABL rearrangement in CML cells derived from patients at different clinical stages. Twenty-seven consecutive patients with CML were enrolled in the study. Peripheral blood mononuclear cells were lysed and subjected to immunoprecipitation and Western blotting to analyse phosphorylated STAT5. The p210 BCR-ABL rearrangements were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and BCL-X(L) expression by semi-quantitative RT-PCR. We found that increased transcription of BCL-X(L) gene was associated with phosphorylated STAT5 in the majority of blast crisis patients and in a few accelerated and chronic phase patients. Moreover, BCL-X(L) expression levels were found to be decreased in chronic phase, contrary to a marked increase in blast crisis. We found no difference in expression of BCL-X(L) and phosphorylated STAT5 when related with b3a2 and b2a2 BCR-ABL rearrangements. These results suggest that STAT5 activity and BCL-X(L) overexpression may reflect a stage of differentiation among CML phases, and this could contribute to BCR-ABL-dependent transformation.
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PMID:Differences in BCL-X(L) expression and STAT5 phosphorylation in chronic myeloid leukaemia patients. 1508 59

Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the Bcr-Abl oncoprotein. An inhibitor of this tyrosine kinase, imatinib mesylate, is rapidly becoming the first-line therapy for CML. However, the development of resistance to this drug is a frequent setback, particularly in patients in advanced phases of the disease. Several mechanisms of resistance have been described, the most frequent of which are amplification and/or mutations of the BCR-ABL gene. To overcome resistance, several approaches have been studied in vitro and in vivo. They include dose escalation of imatinib, combination of imatinib with chemotherapeutic drugs, alternative Bcr-Abl inhibitors, inhibitors of kinases downstream of Bcr-Abl, farnesyl and geranylgeranyl transferase inhibitors, histone deacetylase, proteasome and cyclin-dependent kinase inhibitors, arsenic trioxide, hypomethylating agents, troxacitabine, targeting Bcr-Abl messenger RNA, and immunomodulatory strategies. It is important to understand that these approaches differ in efficiency, which is often dependent on the mechanisms of resistance. Further investigations into the molecular mechanisms of disease and how to specifically target the abnormal processes will guide the design of new treatment modalities in future clinical trials.
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PMID:Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. 1523 91

Indirubin, a 3, 2' bisindole isomer of indigo, has originally been identified as the active principle of a traditional Chinese preparation and has been proven to exhibit antileukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered our research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anticancer compounds accessible with strongly improved CDK inhibitory potential and with broad spectrum antitumour activity. This novel family of compounds holds strong promise for clinical anticancer activity and might be useful also in several important noncancer indications, including Alzheimer's disease or diabetes.
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PMID:Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine. 1534 Aug 40

Small molecule inhibitors belonging to the pyrido[2,3-d]pyrimidine class of compounds were developed as antagonists of protein tyrosine kinases implicated in cancer progression. Derivatives from this compound class are effective against most of the imatinib mesylate-resistant BCR-ABL mutants isolated from advanced chronic myeloid leukemia patients. Here, we established an efficient proteomics method employing an immobilized pyrido[2,3-d]pyrimidine ligand as an affinity probe and identified more than 30 human protein kinases affected by this class of compounds. Remarkably, in vitro kinase assays revealed that the serine/threonine kinases Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) and p38alpha were among the most potently inhibited kinase targets. Thus, pyrido[2,3-d]pyrimidines did not discriminate between tyrosine and serine/threonine kinases. Instead, we found that these inhibitors are quite selective for protein kinases possessing a conserved small amino acid residue such as threonine at a critical site of the ATP binding pocket. We further demonstrated inhibition of both p38 and RICK kinase activities in intact cells upon pyrido[2,3-d]pyrimidine inhibitor treatment. Moreover, the established functions of these two kinases as signal transducers of inflammatory responses could be correlated with a potent in vivo inhibition of cytokine production by a pyrido[2,3-d]pyrimidine compound. Thus, our data demonstrate the utility of proteomic methods employing immobilized kinase inhibitors for identifying new targets linked to previously unrecognized therapeutic applications.
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PMID:Chemical proteomic analysis reveals alternative modes of action for pyrido[2,3-d]pyrimidine kinase inhibitors. 1547 68

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.
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PMID:Putting the rap on Akt. 1548 33

Among novel promising approaches to anticancer therapy belongs the targeting inhibition of signal transduction. This review outlines present-day experiences with imatinib (Glivec), a potent inhibitor of the tyrosine kinases bcr-abl, c-kit and platelet-derived growth factor receptor kinase. Due to inhibition of bcr-abl tyroxine kinase, imatinib has rapidly become the standard therapy for chronic myelocytic leukemia; inhibition of c-kit receptor explains its effectivity in the treatment of patients with gastrointestinal stromal tumors. Another known target of imatinib is tyrosine kinase of PDGFR, which is activated in numerous malignancies, particularly in dermatofibrosarcoma protuberans. Discovery of the novel fusion gene in hypereosinophilic syndrome (FIPILI-PFGFRA, whose product is an imatinib sensitive protein kinase) permitted to treat successfully this event. Possible combination of imatinib with conventional chemotherapeutic drugs and other key signal transduction inhibitors are mentioned.
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PMID:[Imatinib--a new perspective in the treatment of tumors]. 1553 94


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