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International journal of hematology 06/2011; 93(6):830-1. · 1.17 Impact Factor
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ABSTRACT: Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRalpha/beta). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G(0)/G(1) cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRalpha fusion gene. Ki11502 decreased levels of p-PDGFRalpha and its downstream signals, including p-Akt, p-ERK, and p-STAT5, in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRalphaT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.
Blood 06/2008; 111(10):5086-92. · 9.90 Impact Factor
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ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with a poor prognosis in which nuclear factor kappa B (NF-kappaB) is thought to play a role. This study explored the effects of histone deacetylase inhibitors (HDACIs) MS-275, suberoylanilide hydroxamic acid (SAHA), and LBH589 on both human T-cell lymphotropic virus type I (HTLV-1)-infected T cells (MT-1, -2, -4, and HUT102) and freshly isolated ATL cells harvested from patients. HDACIs effectively inhibited the proliferation of these cells. For example, MS-275, SAHA, and LBH589 effectively inhibited the proliferation of MT-1 cells with ED(50s) of 6microM, 2.5microM, and 100nM, respectively, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay on day 2 of culture. In addition, HDACIs induced cell cycle arrest at the G2/M phase and apoptosis of HTLV-1-infected T-cells in conjunction with regulation of apoptosis-related proteins. Electrophoretic mobility shift assay showed that exposure of HTLV-1-infected T-cells to HDACIs for 48h inhibited formation of the NF-kappaB/DNA binding complex. Moreover, we found that HDACIs accumulated NF-kappaB and inhibitory subunit of NF-kappaB in the cytoplasm in conjunction with the down-regulation of NF-kappaB in the nucleus, suggesting that HDACIs blocked nuclear translocation of NF-kappaB. Based on these findings, we believe HDACIs can be useful for treating patients with ATL or other types of cancer in which NF-kappaB plays a role.
Leukemia Research 03/2008; 32(2):287-96. · 2.92 Impact Factor
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Jing Yang,
Takayuki Ikezoe,
Chie Nishioka,
Taizo Tasaka,
Ayuko Taniguchi, Yoshio Kuwayama,
Naoki Komatsu,
Kentaro Bandobashi,
Kazuto Togitani,
H Phillip Koeffler,
Hirokuni Taguchi,
Akihito Yokoyama
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ABSTRACT: Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.
Blood 10/2007; 110(6):2034-40. · 9.90 Impact Factor
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Takayuki Ikezoe,
Jing Yang,
Chie Nishioka,
Taizo Tasaka,
Ayuko Taniguchi, Yoshio Kuwayama,
Naoki Komatsu,
Kentaro Bandobashi,
Kazuto Togitani,
H Phillip Koeffler,
Hirokuni Taguchi
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ABSTRACT: The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.
Molecular Cancer Therapeutics 07/2007; 6(6):1851-7. · 5.23 Impact Factor
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ABSTRACT: This study found that phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling was activated in human T-cell lymphotropic virus type I (HTLV-1)-infected leukemia cells. Rapamycin (1-100 nM, 48h), the inhibitor of mTOR and its analog RAD001 (1-100 nM, 48 h)-induced growth inhibition and G0/G1 cell cycle arrest of these cells in association with de-phosphorylation of p70S6K and 4E-BP-1, although IC50 was not achieved. Paradoxically, rapamycin-stimulated phosphorylation of Akt at Ser473. Blockade of Akt signaling by the PI3K inhibitor LY294002 (1-20 microM, 48 h) also resulted in the growth inhibition and G0/G1 cell cycle arrest of HTLV-1-infected cells, with IC50 ranging from 5 to 20muM, and it caused de-phosphorylation of p70S6K and 4E-BP-1. Of note, when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Moreover, both LY294002 and rapamycin down-regulated the levels of c-Myc and cyclin D1 proteins in these cells, and their combination further decreased levels of these cell cycle-regulating proteins. Taken together, longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with adult T-cell leukemia.
Leukemia Research 06/2007; 31(5):673-82. · 2.92 Impact Factor
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ABSTRACT: We describe a 27-year-old man with hypereosinophilc syndrome (HES) presenting acute abdomen due to acute thrombosis of the mesenteric artery, who had a past history of eosinophilic pneumonia followed by multiple arterial thromboses of the extremities. At the recurrence of eosinophilia, he was treated with high-dose corticosteroids. Immediately after the reduction of peripheral blood eosinophils, he suddenly developed perforation of the intestine due to acute thromboses of mesenteric arteries despite sustained anticoagulation therapy. Molecular analysis demonstrated that the FIP1L1-PDGFRA fusion gene was negative. Histopathology showed thrombi and eosinophilic inflammation of arteries. It is important to recognize that HES could be a cause of acute abdomen.
Internal Medicine 02/2007; 46(10):675-8. · 0.94 Impact Factor
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Internal Medicine 02/2007; 46(7):429-30. · 0.94 Impact Factor
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Daisuke Wakao,
Nobutaka Kawai, Yoshio Kuwayama,
Motohiro Misumi,
Yasutaka Satoh,
Tsuneyuki Shimada,
Miki Akiba,
Kuniya Kishimoto,
Katsuhiko Yoshida,
Naoki Wakimoto,
Naoki Takahashi,
Yuichi Sugahara,
Fumiharu Yagasaki,
Yoshihiro Itoh,
Tohru Sakata,
Toshiya Suzuki,
Akira Matsuda,
Masami Bessho
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ABSTRACT: Systemic capillary leak syndrome (SCLS) is a disorder characterized by hypotension, edema, and an increased hematocrit (Ht) due to sudden leakage of plasma into the extravascular space through some unknown mechanism, in which monoclonal gammopathy is observed. A 30-year-old man visited our emergency department because of abdominal pain, and was admitted to our hematology department because of a markedly increased hemoglobin concentration reaching 26.2 g/dl. The polycythemia was thought to be pseudo-polycythemia due to hemoconcentration, and we diagnosed the patient as having SCLS based on the triad of increased hematocrit, whole-body edema which was especially marked in the lower extremities, and monoclonal gammopathy. The patient recovered after administration of extracellular fluids and albumin, but the attacks recurred. Prophylaxis with terbutaline sulfate, theophylline and corticosteroid reduced the frequency of severe attacks. Because there is possibility that patients with SCLS may be admitted to hematology departments due to severe erythrocytosis, we report this case to increase the awareness of hematologists that SCLS is one of the important differential diagnoses of erythrocytosis.
[Rinshō ketsueki] The Japanese journal of clinical hematology 03/2002; 43(2):122-7.
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