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  • 1
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    Online Resource
    mTOR Inhibitor Rapamycin Interacts Synergistically with Farnesyltransferase Inhibitor FTI-277 To Induce Growth Inhibition in Human Leukemia Cells.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1821-1821
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1821-1821
    Abstract: Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin inhibits the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. However, it has been suggested that substantial proportion of acute myeloid leukemia (AML) cells showed resistance to rapamycin-induced growth inhibition. Aim: We aim to investigate the effects of the farnesyltransferase inhibitor (FTI)-277 on the rapamycin-induced growth inhibition of human leukemia cells. Patients and methods: Flow cytometric evaluation and Western blot analysis for mTOR and Ras-like GTPase Rheb expression in the leukemia cell lines (HL60,NB4,THP1,KG1,U937) and primary leukemia cells obtained from AML patients were performed. We also observed the inhibition of cell growth and the changes in expression of mTOR and up- or down-streams of mTOR after mTOR inhibitor rapamycin treatment with or without FTI-277. Results: Both flow cytometric evaluation and Western blot analysis demonstrated that mTOR expression in the leukemia cell lines (HL60, NB4, THP1, KG1, U937) and primary leukemia cells obtained from AML patients were significantly higher compared to normal bone marrow mononuclear cells (p & lt;0.001). Expression of Ras-like GTPase Rheb, a mTOR upstream, was also significantly increased in the leukemia cell lines and primary AML cells compared to normal bone marrow mononuclear (p & lt;0.001 and p & lt;0.005, respectively). We observed the inhibition rate of leukemia cell growth after treatment of cells with mTOR inhibitor rapamycin (100mM) in the absence or presence of farnesyltransferase inhibitor FTI-277 (10mM). Clonogenic cell growth in the leukemia cell lines was 69.3 ± 5.3% in the rapamycin group and 78.7 ± 4.4% in the FTI-277 group compared to that of the control group. Cotreatment of THP1 and HL-60 leukemia cells with rapamycin and FTI-277 exerted synergistic decrease in the clonogenic cell growth, as well as arrest at the G2/M phase of cell cycle, in a dose-and time-dependent manner (p & lt;0.01). This was associated with marked attenuation of protein levels of Rheb, phospho-mTOR, and mTOR downstreams phospho-p70S6 kinase, phospho-4E-BP1. Interestingly decreased expression of mTOR upstreams Akt/PKB activity, Akt/PKB phosphorylation and PTEN phosphorylation was also observed in these leukemia cells after cotreatment with FTI-277 and rapamycin. These findings were also observed in the primary leukemia cells obtained from untreated patients with AML. Conclusions: Taken together, these findings indicate that farnesyltransferase inhibitor FTI-277 potentially enhance the growth-inhibitory property of rapamycin, with inducing multiple perturbations in PI3K - Akt/PKB - mTOR signaling pathway in human leukemia cells. Combined rapamycin and FTI blockade can exert powerful anti-leukemia effects and could be developed into a novel therapeutic strategy for AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1821.1821
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    RNA Silencing of Aurora Kinase Genes Sensitizes Human Leukemia Cells to the Ara-C-Induced Cell Death Via Caspase-Independent Pathway.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2468-2468
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2468-2468
    Abstract: Aurora kinases play critical roles in chromosome segregation and cell division. Furthermore, Aurora A and B kinases are both frequently amplified and overexpressed in a various kinds of human cancers including leukemia disorders. To address its possibility as a therapeutic target for leukemia, we employed the RNA interference technique to knockdown Aurora kinase gene expression and analyzed its effect on the cell cycle distribution and the chemotherapy-induced cell death in leukemia cells. The expression of Aurora kinase A (AURKA) and Aurora kinase B (AURKB) was observed in all the leukemia cell lines evaluated and 15 out of 18 cultured leukemic cell specimens obtained from untreated patients with acute myeloid leukemia (AML). An arrest in the G(2)/M phase 24 h after specific knockdown of AURKA was shown in U937 leukemia cells. Following the silencing of AURKA, we observed a striking increase in the proportion of cells in the S phase, tetraploid state, and showing multi-nucleated morphologic changes. Cell death was observed in 17.0 ± 0.9% and 20.1 ± 2.5% of U937 cells after AURKA and AURKB silencing, respectively. The proportion of cells in the subG(0)/G(1) phase was 23% and 11% with AURKA and AURKB silencing, respectively. Although the disruption of mitochondrial membrane potential was observed after AURKA or AURKB silencing in U937 cells, the cleavage of caspase-3, -8, -9, and PARP was not observed in the apoptotic cells. Pretreatment of U937 cells with the caspase-3 inhibitor, DEVD-CHO, did not abrogate the AURKA or AURKB silencing-induced cell death. The U937 leukemia cells are resistant to Ara-C-induced cell death. However, we observed a striking synergistic enhancement of the cytotoxicity of Ara-C (10 μM), an important antimetabolic chemotherapeutic agent used for acute leukemia, by the RNA interference-mediated knockdown of AURKA and AURKB through a caspase-independent manner in U937 cells. Collectively, we demonstrate that the specific inhibition of either AURKA or AURKB can potentially regulate the cell cycle distribution of leukemia cells and induce synergistic interaction with Ara-C for inducing the cell death through the mechanism of mitotic catastrophe. These results indicate that Aurora kinase inhibition provides a novel approach for the treatment of human acute leukemia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2468.2468
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Protein Kinase CK2 Is Associated with Poor Clinical Outcome and Regulates the Expression of Anti-Apoptotic Proteins and PTEN Phosphorylation in Acute Myeloid Leukemia.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2356-2356
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2356-2356
    Abstract: We previously demonstrated that the phosphorylation of c-terminal regulatory domain of phosphatase and tensin homologue (PTEN) protein are frequently observed and significantly associated with poor clinical outcome in acute myeloid leukemia (AML). Phosphorylation of PTEN stabilizes the PTEN protein, but makes it less active towards its substrate, phosphatidylinositol 3,4,5-triphosphate, resulting in an antagonizing the apoptotic pathways. Protein kinase CK2 is implicated in many cellular processes including the cell proliferation, survival, and tumorigenesis. However, the biological significance of CK2 expression and its association with PTEN phosphorylation has not been evaluated. In this study, we evaluated the protein kinase CK2 activity/expression and PTEN phosphorylation simultaneously in leukemic blasts obtained from 59 patients with AML with normal karyotype. Western blot analysis revealed that PTEN phosphorylation was observed in 30 (50.9%) cases. CK2 expression was significantly associated with CK2 catalytic activity and PTEN phosphorylation. Levels of CK2 catalytic activity were significantly higher in AML cases with PTEN phosphorylation (p-PTEN-positive) compared with those without PTEN phosphorylation (p-PTEN-negative) (P & lt;0.05). Age, sex, white blood cell count, and complete remission rate were not different according to the CK2 expression. However, the overall survival was significantly shorter in AML cases with high CK2 expression (P & lt; 0.05). Treatment of p-PTEN-positive AML cells with apigenin, a specific inhibitor of CK2, abolished the phosphorylation of PTEN, as well as Ser473 phosphorylation of Akt/PKB, in a dose-dependent manner. CK2 overexpression induced an increase in the proportion of cells in the G(2)/M phase. Induced overexpression of CK2 in U937 leukemia cells led to PTEN phosphorylation, Ser473 Akt/PKB phosphorylation, in addition to an increased expression of Bcl-2, Bcl-xL, Mcl-1, Survivin, and XIAP proteins. Taken together, these results suggest that the phosphorylation of PTEN and expression of anti-apoptotic proteins were directly regulated by protein kinase CK2 in AML cells. We also demonstrate, for the first time, that CK2 is an independent prognostic variable in AML patients with normal karyotype. These findings additionally extend our understanding of the role of CK2 in AML, and suggest the CK2 molecule as a potential target for AML treatment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2356.2356
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Online Resource
    Factors associated with pulmonary toxicity after myeloablative conditioning using fractionated total body irradiation
    Korean Society for Therapeutic Radiology and Oncology ; 2017
    In:  Radiation Oncology Journal Vol. 35, No. 3 ( 2017-09-30), p. 257-267
    Details
    In: Radiation Oncology Journal, Korean Society for Therapeutic Radiology and Oncology, Vol. 35, No. 3 ( 2017-09-30), p. 257-267
    Type of Medium: Online Resource
    ISSN: 2234-1900 , 2234-3156
    URL: Article
    DOI: 10.3857/roj.2017.00290
    Language: English
    Publisher: Korean Society for Therapeutic Radiology and Oncology
    Publication Date: 2017
    detail.hit.zdb_id: 2712565-8
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  • 5
    Online Resource
    Online Resource
    Success Rate and Risk Factors for Failure of Empirical Antifungal Therapy with Itraconazole in Patients with Hematological Malignancies: A Multicenter, Prospective, Open-Label, Observational Study in Korea
    XMLink ; 2014
    In:  Journal of Korean Medical Science Vol. 29, No. 1 ( 2014), p. 61-
    Details
    In: Journal of Korean Medical Science, XMLink, Vol. 29, No. 1 ( 2014), p. 61-
    Type of Medium: Online Resource
    ISSN: 1011-8934 , 1598-6357
    URL: Article
    DOI: 10.3346/jkms.2014.29.1.61
    Language: English
    Publisher: XMLink
    Publication Date: 2014
    detail.hit.zdb_id: 2056822-8
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  • 6
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    The Role of Alemtuzumab Compared to Antitymocyte Globulin in Non-Myeloablative Stem Cell Transplantation; Especially for the Prevention of GVHD and Immune Recovery.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2739-2739
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2739-2739
    Abstract: Alemtuzumab is an anti-CD52 antibody, and has been used for lymphoid malignancies or as a member of non-myeloablative conditioning regimen in allogeneic transplantation. Especially, in non-myeloablative stem cell transplantation (NST), it has been reported that alemtuzumab is effective for graft-versus-host disease (GVHD), but the immune reconstruction after transplantation is delayed. In this study, we comparatively evaluated the efficacy of alemtuzumab for non-myeloablative conditioning, GVHD prophylaxis, and immune recovery in NST for hematologic diseases. We have compared the results in 28 recipients of a sibling or unrelated NST enrolled. The recipients were divided into 2 groups according to the use of alemtuzumab. In group A (n=21), the conditioning regimen was a combination of fludarabine, cyclophosphamide (or busulfan) and antithymocyte globulin (ATG), and group B (n=7) received fludarabine, cyclophosphamide (or busulfan), and alemtuzumab instead of ATG. GVHD prophylaxis was by cyclosporin A or FK506 plus methotrexate. There were no significant differences in the graft engraftment and period of granulocyte colony-stimulating factor infusion. Patients receiving alemtuzumab had a significantly lower incidence of acute GVHD (stage 2 or more) (14.3% versus 38.1%, P=0.03) and chronic GVHD (14.3% versus 52.4%, P=0.005). The relapse rate after transplantation was 28.6% (6 patients) in group A and 14.3 (1 patients) in group B (P=0.04). Flow cytometric analysis of peripheral mononuclear cells for evaluation of immune recovery showed that T-cell and NK-cell recovery were delayed in both groups. However, T-cell and NK-cell recovery after transplantation occurred earlier in patients received alemtuzumab. No significant differences were observed in disease-free or overall survival between two groups. In conclusion, alemtuzumab can be recommended for immune suppression in NST, with successful control over acute/chronic GVHD and inducing relatively earlier immune recovery after transplantation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2739.2739
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Online Resource
    Early Cytomegalovirus Reactivation and Expansion of CD56brightCD16dim/−DNAM1+ Natural Killer Cells Are Associated with Antileukemia Effect after Haploidentical Stem Cell Transplantation in Acute Leukemia
    Elsevier BV ; 2019
    In:  Biology of Blood and Marrow Transplantation Vol. 25, No. 10 ( 2019-10), p. 2070-2078
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 25, No. 10 ( 2019-10), p. 2070-2078
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2019.06.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 8
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    A Case of Serum Amino Acid Disturbance with Hyperammonemia in Patient with Primary Amyloidosis
    The Korean Society of Hematology ; 2005
    In:  The Korean Journal of Hematology Vol. 40, No. 1 ( 2005), p. 54-
    Details
    In: The Korean Journal of Hematology, The Korean Society of Hematology, Vol. 40, No. 1 ( 2005), p. 54-
    Type of Medium: Online Resource
    ISSN: 1738-7949
    URL: Article
    DOI: 10.5045/kjh.2005.40.1.54
    Language: Korean
    Publisher: The Korean Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 2711910-5
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  • 9
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    Online Resource
    Two Cases of Acquired Hemophilia A Successfully Treated with Oral Steroid or Danazol
    The Korean Society of Hematology ; 2005
    In:  The Korean Journal of Hematology Vol. 40, No. 1 ( 2005), p. 58-
    Details
    In: The Korean Journal of Hematology, The Korean Society of Hematology, Vol. 40, No. 1 ( 2005), p. 58-
    Type of Medium: Online Resource
    ISSN: 1738-7949
    URL: Article
    DOI: 10.5045/kjh.2005.40.1.58
    Language: Korean
    Publisher: The Korean Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 2711910-5
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  • 10
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    Online Resource
    PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells
    Springer Science and Business Media LLC ; 2020
    In:  Journal of Experimental & Clinical Cancer Research Vol. 39, No. 1 ( 2020-12)
    Details
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 39, No. 1 ( 2020-12)
    Abstract: The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. Methods We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34 + CD38 − leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. Results The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition. Conclusions PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-020-01565-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2430698-8
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