Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-13C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC50, 0.69 +/- 0.06 micromol/L) and K562 cells (IC50, 0.47 +/- 0.04 micromol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 micromol/L) decreased glucose uptake from the media by suppressing glycolytic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 micromol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 micromol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.
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PMID:Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. 1547 56

BCR-ABL oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3'-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an overactive mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy.
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PMID:Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species. 1548 67

NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.
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PMID:Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. 1549 78

Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-d]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL(+) KIT(+)-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL(+) KIT(+)-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor's ability to suppress protein kinases in addition to the dominant target.
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PMID:Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. 1550 16

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.
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PMID:Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study. 1554 Sep 2

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), which inhibits the BCR-ABL, PDGF-R alpha and c-kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
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PMID:[A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)]. 1555 17

The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor (TCR)-mediated activation of human T cells. Following stimulation with the anti-CD3 antibody 12F6, proliferation of activated T cells was almost completely inhibited by 10 microM imatinib. Furthermore, antigen-triggered expansion of CD8+ T cells in response to immunodominant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) peptides was significantly reduced. Up-regulation of the activation markers CD25 and CD69 in response to TCR cross-linking was suppressed by imatinib at a mean inhibitory concentration 50% (IC50) of 5.4 microM and 7.3 microM, respectively; interleukin 2 (IL-2) production was also impaired. Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the adenosine triphosphate (ATP) binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib. The IC50 for LCK inhibition by imatinib was 0.6 microM to 0.8 microM in an in vitro tyrosine kinase assay. In summary, imatinib can interfere with T-cell activation in vitro, and its impact on the frequency of opportunistic infections and graft-versus-host or graft-versus-leukemia reactions after transplantation should be investigated in clinical trials.
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PMID:Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. 1557 91

Imatinib mesylate, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.
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PMID:Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. 1558 22

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
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PMID:Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. 1573 62

Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.
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PMID:Glivec and CML: a lucky date. 1573 79


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