134 results on '"Okabe-Kado, J"'
Search Results
2. Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma
- Author
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Niitsu, N, Honma, Y, Iijima, K, Takagi, T, Higashihara, M, Sawada, U, and Okabe-Kado, J
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- 2003
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3. Elevated plasma level of differentiation inhibitory factor nm23-H1 protein correlates with risk factors for myelodysplastic syndrome
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Ito, Y, Okabe-Kado, J, Honma, Y, Iwase, O, Shimamoto, T, Ohyashiki, JH, and Ohyashiki, K
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- 2002
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4. Serum nm23-H1 protein as a prognostic factor for indolent non-Hodgkin's lymphoma
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Niitsu, N, Okamoto, M, Okabe-Kado, J, Takagi, T, Yoshida, T, Aoki, S, Honma, Y, and Hirano, M
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- 2001
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5. Regulation by Prostaglandins of Differentiation of Mouse Myeloid Leukemia M1 Cells
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Hozumi, M., Honma, Y., Kasukabe, T., Okabe-Kado, J., Takenaga, K., Garaci, Enrico, editor, Paoletti, Rodolfo, editor, and Santoro, M. Gabriella, editor
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- 1987
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6. Combined analysis of differentiation inhibitory factor nm23-H1 and nm23-H2 as prognostic factors in acute myeloid leukaemia
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Wakimoto, N, primary, Yokoyama, A, additional, Okabe-Kado, J, additional, Nagata, N, additional, Motoyoshi, K, additional, and Honma, Y, additional
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- 1998
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7. Growth inhibition and differentiation induction in human monoblastic leukaemia cells by 1alpha-hydroxyvitamin D derivatives and their enhancement by combination with hydroxyurea
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Makishima, M, primary, Okabe-Kado, J, additional, and Honma, Y, additional
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- 1998
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8. Differentiation inhibitory factor nm23 as a new prognostic factor in acute monocytic leukemia
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Yokoyama, A, primary, Okabe-Kado, J, additional, Sakashita, A, additional, Maseki, N, additional, Kaneko, Y, additional, Hino, K, additional, Tomoyasu, S, additional, Tsuruoka, N, additional, Kasukabe, T, additional, and Honma, Y, additional
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- 1996
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9. Identity of differentiation inhibiting factor for mouse myeloid leukemia cells with Nm23/nucleoside diphosphate kinase
- Author
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Okabe-Kado, J, primary and Hozumi, M, additional
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- 1992
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10. 61. Identity of differentiation inhibiting factor for mouse myeloid leukemia cells with Nm23/nucleoside diphosphate kinase
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Okabe-Kado, J, primary and Hozumi, M, additional
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- 1992
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11. Antileukemic effect of alkyl phospholipids. I. Inhibition of proliferation and induction of differentiation of cultured myeloid leukemia cells by alkyl ethyleneglycophospholipids.
- Author
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Honma, Y, Kasukabe, T, Okabe-Kado, J, Hozumi, M, Tsushima, S, and Nomura, H
- Abstract
Various alkyl ethyleneglycophospholipids, i.e., alkyl phospholipids, with ethyleneglycol or its congener in place of glycerol as a molecular backcone, were synthesized and their effects on cell proliferation and differentiation of cultured human (HL-60) and mosue (Ml) myeloid leukemia cells were studied. On incubation with alkyl ethyleneglycophospholipids, proliferation of both cell lines was inhibited and the cells were induced to differentiate into morphologically and functionally mature granulocytes and macrophages. Among the compounds tested, dodecyl ethyleneglycophospholipid with a pyridinioethyl group was the most effective in induction of differentiation of both cell lines. [ABSTRACT FROM AUTHOR]
- Published
- 1983
12. Induction of differentiation of human myeloid leukemia cells by immunosuppressant macrolides (rapamycin and FK506) and calcium/calmodulin-dependent kinase inhibitors
- Author
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Yamamoto-Yamaguchi, Y., Okabe-Kado, J., Kasukabe, T., and Honma, Y.
- Published
- 2001
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13. Induction of differentiation of human myeloid leukemia cells by novel synthetic neurotrophic pyrimidine derivatives
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Honma, Y., Ishii, Y., Kasukabe, T., Okabe-Kado, J., Yamamoto-Yamaguchi, Y., Kakegawa, T., and Awaya, A.
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- 2001
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14. Induction of differentiation of myelogenous leukemia cells by humulone, a bitter in the hop
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Honma, Y., Tobe, H., Makishima, M., Yokoyama, A., and Okabe-Kado, J.
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- 1998
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15. Bromelain Induces the Differentiation of Leukemic Cells in Vitro: An Explanation for its Cytostatic Effects?
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Maurer, H. R., Hozumi, M., Honma, Y., and Okabe-Kado, J.
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- 1988
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16. Purification of a factor inhibiting differentiation from conditioned medium of nondifferentiating mouse myeloid leukemia cells.
- Author
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Okabe-Kado, J, Kasukabe, T, Honma, Y, Hayashi, M, and Hozumi, M
- Abstract
Mouse myeloid leukemic M1 cells are induced to differentiate by various differentiation inducers. Activity for inhibition of induction of differentiation of M1 cells (I-factor activity) was detected in conditioned medium of variant M1 cell clones that were resistant to differentiation inducers, and this I-factor activity was shown to be closely associated with resistance of the cells to differentiation inducers. In this work, the I-factor was purified to apparent homogeneity from conditioned medium of resistant M1 cells. The purification procedure consisted of ammonium sulfate precipitation, CM-Sepharose CL-6B, Sephadex G-200, reverse-phase high performance liquid chromatography on a C18 hydrophobic support, and high-performance liquid chromatography on a gel filtration column. The factor was analyzed by radioiodination, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and autoradiography. The purified factor gave a single band of protein with a molecular weight of 68,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis which coincided with its biological activity. The concentration of I-factor required for 50% inhibition of dexamethasone-induced differentiation of M1 cells was 24 pM. At its effective concentration it had no effect on cell proliferation, and even at 1.2 nM it did not inhibit colony formation of normal bone marrow cells, suggesting that it was distinct from the inhibitor of normal precursors of macrophages and/or granulocytes.
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- 1988
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17. Angelmicin B, a new inhibitor of oncogenic signal transduction, inhibits growth and induces myelomonocytic differentiation of human myeloid leukemia HL-60 cells
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Yokoyama, A., Okabe-Kado, J., Uehara, Y., Oki, T., Tomoyasu, S., Tsuruoka, N., and Honma, Y.
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- 1996
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18. Purification of a novel growth inhibitory factor for partially differentiated myeloid leukemic cells.
- Author
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Kasukabe, T, Okabe-Kado, J, Honma, Y, and Hozumi, M
- Abstract
A novel factor termed growth inhibitory (GI) factor, which specifically inhibits the growth of mouse monocytic leukemia cells including monocytic cell lines (Mm-A and J774.1) and other partially differentiated myeloid leukemic cells, has been purified from conditioned medium of some clones of mouse myeloblastic leukemia M1 cells. The procedure for purification of the GI factor included ammonium sulfate precipitation, CM-Sepharose CL-6B and Sephadex G-200 chromatographies, reverse-phase high-performance liquid chromatography on a C18 hydrophobic support, and high-performance liquid chromatography on a gel filtration column. The purified factor gave a single band of protein with a molecular weight of 25,000 on sodium dodecyl sulfate-polyacrylamide gel. A concentration of 8 X 10(-10) M GI factor was required for 50% inhibition of growth of Mm-A cells. On chromatofocusing, the GI activity was eluted with Polybuffer 96/acetic acid at pH 8.2-8.4. The purified GI factor markedly inhibited growth of mouse bone marrow cells stimulated by macrophage colony-stimulating factor. The GI factor appeared to be a unique cytokine unrelated to known cytokines such as the tumor necrosis factor, interferons, and oncostatin M.
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- 1988
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19. Antileukemic effect of alkyl phospholipids. II. Prolongation of survival times of leukemic mice by alkyl ethyleneglycophospholipids.
- Author
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Honma, Y, Kasukabe, T, Okabe-Kado, J, Hozumi, M, Tsushima, S, and Nomura, H
- Abstract
Alkyl ethyleneglycophospholipids induced differentiation in vitro of mouse myeloid leukemia M1 cells into mature granulocytes and macrophages. The compounds also prolonged the survival of syngeneic SL mice inoculated with M1 cells. Although in mice with florid leukemia these compounds alone scarcely affected survival, administration of dodecyl ethyleneglycophospholipid with pyridinioethyl as a polar group plus actinomycin D significantly prolonged survival. [ABSTRACT FROM AUTHOR]
- Published
- 1983
20. Bromelain Induces the Differentiation of Leukemic Cellsin Vitro: An Explanation for its Cytostatic Effects?
- Author
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Maurer, H., primary, Hozumi, M., additional, Honma, Y., additional, and Okabe-Kado, J., additional
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- 1988
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21. Induction of differentiation of human promyelocytic leukemia cells (HL-60) by arginase
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Honma, Y., primary, Fujita, Y., additional, Okabe-Kado, J., additional, Kasukabe, T., additional, and Hozumi, M., additional
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- 1980
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22. Interleukin 4 potentiates the antiproliferative effect of 1a,25-dihydroxyvitamin D~3 on mouse monocytic leukemia cells but antagonizes the antiproliferative effects of interferona, and interleukin 6
- Author
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Kasukabe, T., Okabe-Kado, J., Honma, Y., and Hozumi, M.
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- 1992
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23. A new function of Nm23/NDP kinase as a differentiation inhibitory factor, which does not require it's kinase activity
- Author
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Okabe-Kado, J., Kasukabe, T., Hozumi, M., and Honn, Y.
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- 1995
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24. NM23 downregulation and lysophosphatidic acid receptor EDG2/lpa1 upregulation during myeloid differentiation of human leukemia cells.
- Author
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Okabe-Kado J, Hagiwara-Watanabe Y, Niitsu N, Kasukabe T, and Kaneko Y
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Female, HL-60 Cells, Humans, K562 Cells, Leukemia genetics, Leukemia pathology, Lysophospholipids pharmacology, MCF-7 Cells, Myeloid Cells pathology, NM23 Nucleoside Diphosphate Kinases genetics, Receptors, Lysophosphatidic Acid genetics, Tretinoin pharmacology, U937 Cells, Cell Differentiation, Down-Regulation, Gene Expression Regulation, Leukemic, Leukemia metabolism, Myeloid Cells metabolism, NM23 Nucleoside Diphosphate Kinases biosynthesis, Neoplasm Proteins biosynthesis, Receptors, Lysophosphatidic Acid biosynthesis, Up-Regulation
- Abstract
The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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25. Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells.
- Author
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Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N, and Kumakura S
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- Acetylcysteine metabolism, Amino Acid Chloromethyl Ketones pharmacology, Antioxidants metabolism, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Glycosides pharmacology, Humans, Pancreatic Neoplasms metabolism, Quinolines pharmacology, Reactive Oxygen Species metabolism, Antineoplastic Agents pharmacology, Cell Death drug effects, Cyclohexylamines metabolism, Diterpenes pharmacology, Isothiocyanates pharmacology, Pancreatic Neoplasms drug therapy, Phenylenediamines metabolism
- Abstract
The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and the necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer.
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- 2016
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26. Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells.
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Kasukabe T, Okabe-Kado J, Kato N, Honma Y, and Kumakura S
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- Arsenic Trioxide, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Cycle drug effects, Cell Differentiation drug effects, Cell Proliferation drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Apoptosis drug effects, Arsenicals administration & dosage, Breast Neoplasms drug therapy, Diterpenes administration & dosage, Oxides administration & dosage
- Abstract
Arsenic trioxide (ATO) is an approved treatment for acute promyelocytic leukemia (APL). It has also shown potential for treatment of multiple myeloma and various solid tumors including breast cancer. The requirement of high, toxic concentrations for the induction of apoptosis in non-APL and solid tumor cells is a major limitation for its use in other hematological malignancies and solid tumors. We have examined whether inducers of differentiation of leukemia cells can control the growth of solid tumor cells. In the present study, we found that cotylenin A, a plant growth regulator and a potent inducer of differentiation in myeloid leukemia cells, significantly potentiated both ATO-induced inhibition of cell growth in a liquid culture, and ATO-induced inhibition of anchorage-independent growth in a semi-solid culture in human breast cancer MCF-7 and MDA-MB-231 cells. ISIR-005 (a synthetic cotylenin A-derivative) was also able to enhance ATO-induced growth inhibition. The combined treatment with cotylenin A and ATO induced cleaved caspase-7 in MCF-7 cells at the concentrations which ATO alone scarcely induced and cotylenin A alone only weakly induced. Expression of survivin in MCF-7 cells was markedly decreased with the presence of both cotylenin A and ATO, although the expression of survivin was only slightly decreased by cotylenin A or ATO alone. The pretreatment with N-acetylcysteine significantly reduced the combination treatment-induced cell growth inhibition. These data suggest that induction of cleaved caspase-7, inhibition of survivin and oxidative responses are important events in the corporative inhibition in the growth of MCF-7 cells induced by both cotylenin A and ATO. Furthermore, we found that the combined treatment with cotylenin A and ATO also could be effective in suppressing the invasive capacity of MDA-MB-231 cells determined with the impedance-based xCELLigence Real-Time Cell Analysis technology. These results suggest that cotylenin A is an attractive enhancer for the ATO-induced anticancer activities in human breast cancer.
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- 2015
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27. Cytokine profiles, signalling pathways and effects of fluticasone propionate in respiratory syncytial virus-infected human foetal lung fibroblasts.
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Seki E, Yoshizumi M, Tanaka R, Ryo A, Ishioka T, Tsukagoshi H, Kozawa K, Okayama Y, Okabe-Kado J, Goya T, and Kimura H
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- Anti-Inflammatory Agents pharmacology, Cell Line, Drug Evaluation, Preclinical, Fibroblasts drug effects, Fibroblasts immunology, Fibroblasts virology, Fluticasone, Host-Pathogen Interactions, Humans, Intracellular Signaling Peptides and Proteins metabolism, Lung cytology, Phosphorylation, Protein Processing, Post-Translational, Toll-Like Receptors metabolism, Androstadienes pharmacology, Cytokines metabolism, Fibroblasts metabolism, Respiratory Syncytial Viruses physiology, Signal Transduction
- Abstract
To examine cytokine production in response to RSV infection, we assessed the levels of 29 cytokines released from RSV-infected human foetal lung fibroblasts. We also examined the relationships between the effects of fluticasone propionate and various signalling pathways in the cells. Twenty-four hours after infection (1MOI), RSV-infected cells released cytokines, for example proinflammatory cytokines (IL-1β, IL-6 and TNF-α), anti-inflammatory (IL-1ra), Th1 (IFN-γ, IFN-λ1a, IL-2 and IL-12), Th2 (IL-4, IL-5, IL-10 and IL-13), granulopoiesis-inducing (G-CSF and GM-CSF), eosinophil recruitment-inducing (eotaxin and RANTES) and neutrophil recruitment-inducing cytokines (IL-8, IP-10, MCP-1 and MIP-1α). Aberrant release of most was significantly suppressed by fluticasone propionate. Twelve hours after RSV infection, increased phosphorylation of Akt, p38 MAPK, ERK1/2 and IκB-α was noted. Fluticasone propionate suppressed the phosphorylation of Akt, p38 MAPK, and ERK1/2, but not IκB-α, in virus-infected cells. TLR-4 expression was unchanged in control and RSV-infected cells, and TLR-3 and RIG-I expression was not detected. The results indicate that RSV infection induces aberrant production and release of certain cytokines through these signalling pathways in human lung fibroblasts. Overproduction and imbalance of these cytokines may be associated with the pathophysiology of RSV-induced excessive and allergic inflammation., (© 2013 International Federation for Cell Biology.)
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- 2013
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28. Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells.
- Author
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Kasukabe T, Okabe-Kado J, Haranosono Y, Kato N, and Honma Y
- Subjects
- Benzoquinones pharmacology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation drug effects, Chromones pharmacology, Drug Synergism, Female, HSP90 Heat-Shock Proteins antagonists & inhibitors, Humans, Lactams, Macrocyclic pharmacology, Lung Neoplasms metabolism, Lung Neoplasms pathology, MCF-7 Cells, Morpholines pharmacology, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Breast Neoplasms drug therapy, Diterpenes administration & dosage, Lung Neoplasms drug therapy, Sirolimus administration & dosage
- Abstract
Cotylenin A, a plant growth regulator, and rapa-mycin, an inhibitor of the mammalian target of rapamycin, are potent inducers of differentiation in myeloid leukemia cells and also synergistically inhibit the proliferation of several human breast cancer cell lines including MCF-7 in vitro and in vivo. However, the mechanisms of the combined effects of cotylenin A and rapamycin are still unknown. Activated Akt induced by rapamycin has been suggested to attenuate the growth-inhibitory effects of rapamycin, serving as a negative feedback mechanism. In this study, we found that cotylenin A could suppress rapamycin-induced phosphorylation of Akt (Ser473) in MCF-7 cells and lung carcinoma A549 cells and that cotylenin A also enhanced the rapamycin-induced growth inhibition of MCF-7 and A549 cells. ISIR-005 (a synthetic cotylenin A-derivative) was able to enhance rapamycin‑induced growth inhibition and could also markedly inhibit rapamycin-induced phosphorylation of Akt. We also found that the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) or arsenic trioxide (ATO) in combination with rapamycin markedly inhibited the growth of MCF-7 cells and 17-AAG or ATO suppressed rapamycin-induced phosphorylation of Akt. The PI3K inhibitor LY294002 also suppressed rapamycin-induced phosphorylation of Akt and combined treatment showed synergistic growth inhibition of MCF-7 cells. Rapamycin inhibited growth more significantly in Akt siRNA-transfected MCF-7 cells than in control siRNA-transfected MCF-7 cells. These results suggest that the inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their effective growth inhibition of cancer cells.
- Published
- 2013
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29. Extracellular NM23 Protein as a Therapeutic Target for Hematologic Malignancies.
- Author
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Okabe-Kado J, Kasukabe T, and Kaneko Y
- Abstract
An elevated serum level of NM23-H1 protein is a poor prognostic factor in patients with various hematologic malignancies. The extracellular NM23-H1 protein promotes the in vitro growth and survival of acute myelogenous leukemia (AML) cells and inversely inhibits the in vitro survival of normal peripheral blood monocytes in primary culture at concentrations equivalent to the levels found in the serum of AML patients. The growth and survival promoting activity to AML cells is associated with cytokine production and activation of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways. Inhibitors specific for MAPK signaling pathways inhibit the growth/survival-promoting activity of NM23-H1. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
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- 2012
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30. Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells.
- Author
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Hagiwara Y, Kasukabe T, Kaneko Y, Niitsu N, and Okabe-Kado J
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- Antineoplastic Agents pharmacology, Drug Synergism, Flavonoids, HL-60 Cells, Humans, Phenols, Polyphenols, Apoptosis drug effects, Cell Differentiation drug effects, Ellagic Acid pharmacology, Tretinoin pharmacology
- Abstract
All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK. EA activated the caspase-3 pathway and enhanced the expressions of myeloid differentiation markers (CD11b, MRP-14 protein, granulocytic morphology) induced by ATRA treatment. These results indicate that EA is a potent apoptosis inducer and also effectively potentiates ATRA-induced myeloid differentiation of HL-60 cells.
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- 2010
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31. Extracellular NM23 protein promotes the growth and survival of primary cultured human acute myelogenous leukemia cells.
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Okabe-Kado J, Kasukabe T, Honma Y, Kobayashi H, Maseki N, and Kaneko Y
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- Biomarkers, Tumor analysis, Blotting, Western, Cell Line, Tumor, Cell Survival physiology, Cytokines metabolism, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, NM23 Nucleoside Diphosphate Kinases genetics, Prognosis, Recombinant Proteins genetics, Recombinant Proteins metabolism, Cell Proliferation, Extracellular Fluid chemistry, Leukemia, Myeloid, Acute metabolism, NM23 Nucleoside Diphosphate Kinases metabolism, Signal Transduction physiology
- Abstract
An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML), and predicts a poor treatment outcome in AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro growth and survival of primary cultured AML cells at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein promoted the in vitro growth and survival of AML cells and this activity was associated with the cytokine production and activation of the MAPK and signal transducers and activators of transcription signaling pathways. Inhibitors specific to MAPK signaling pathways inhibited the growth- and survival-promoting activity of NM23-H1. These findings indicate the novel biological action of extracellular NM23-H1 and its association with poor prognosis, and suggest an important role for extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
- Published
- 2009
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32. Extracellular NM23-H1 protein inhibits the survival of primary cultured normal human peripheral blood mononuclear cells and activates the cytokine production.
- Author
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Okabe-Kado J, Kasukabe T, Honma Y, Kobayashi H, Maseki N, and Kaneko Y
- Subjects
- Autoantibodies blood, Cell Survival drug effects, Cytokines blood, Cytokines immunology, Granulocyte-Macrophage Colony-Stimulating Factor blood, Humans, In Vitro Techniques, Leukemia, Monocytic, Acute immunology, Leukemia, Monocytic, Acute pathology, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute pathology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, NM23 Nucleoside Diphosphate Kinases genetics, NM23 Nucleoside Diphosphate Kinases pharmacology, Prognosis, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Tumor Cells, Cultured, Cell Survival immunology, Leukemia, Monocytic, Acute metabolism, Leukemia, Myeloid, Acute metabolism, Leukocytes, Mononuclear cytology, NM23 Nucleoside Diphosphate Kinases blood
- Abstract
An elevated serum level of NM23-H1 protein is found in acute myelogenous leukemia (AML) and predicts a poor treatment outcome for AML patients. To investigate the potential pathological link between the elevated serum level of this protein and poor prognosis, we examined the extracellular effects of recombinant NM23-H1 protein on the in vitro survival of primary cultured normal peripheral blood mononuclear cells (PBMNC) at concentrations equivalent to the levels found in the serum of AML patients. Extracellular NM23-H1 protein inhibited the in vitro survival of PBMNC and promoted the production of various cytokines, such as GM-CSF and IL-1beta, which in fact promoted the growth of primary cultured AML cells. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis of patients with elevated serum levels of NM23-H1 protein. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
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- 2009
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33. Cotylenin A, a new differentiation inducer, and rapamycin cooperatively inhibit growth of cancer cells through induction of cyclin G2.
- Author
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Kasukabe T, Okabe-Kado J, and Honma Y
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Differentiation drug effects, Cell Line, Tumor, Cyclin G2, Gene Expression drug effects, Humans, Antibiotics, Antineoplastic pharmacology, Cyclins biosynthesis, Diterpenes pharmacology, Gene Expression Regulation, Neoplastic drug effects, Sirolimus pharmacology
- Abstract
Cotylenin A, a plant growth regulator, and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), are potent inducers of differentiation of myeloid leukemia cells. Recently, we found that cotylenin A and rapamycin effectively inhibited the proliferation of several human breast cancer cell lines including MCF-7. Herein, we demonstrate that cotylenin A and rapamycin rapidly and markedly induced the cyclin G2 gene expression in several cancer cells including MCF-7 cells. The growth arrest of the MCF-7 cells at the G1 phase, induced by the treatment with cotylenin A and rapamycin or the culture in low serum medium, markedly induced the cyclin G2 gene expression. Anticancer drugs including doxorubicin, etoposide and 5-fluorouracil also induced cyclin G2 expression during induction of growth arrest of the MCF-7 cell at the G1 phase or G2/M phase. Ectopically inducible cyclin G2 expression potently inhibited the proliferation of MCF-7 cells. Furthermore, cyclin G2 knockdown induced by cyclin G2 small interfering RNA markedly reduced the potency of cotylenin A plus rapamycin to induce growth inhibition. Taken together, our results suggest that cotylenin A and rapamycin induce inhibition of cancer cell growth through the induction of cyclin G2.
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- 2008
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34. Clinical significance of serum NM23-H1 protein in neuroblastoma.
- Author
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Okabe-Kado J, Kasukabe T, Honma Y, Hanada R, Nakagawara A, and Kaneko Y
- Subjects
- Age Factors, Case-Control Studies, Child, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infant, Infant, Newborn, Male, N-Myc Proto-Oncogene Protein, NM23 Nucleoside Diphosphate Kinases, Neuroblastoma therapy, Nuclear Proteins analysis, Oncogene Proteins analysis, Prognosis, Biomarkers, Tumor blood, Gene Dosage, Neuroblastoma genetics, Neuroblastoma pathology, Nucleoside-Diphosphate Kinase blood
- Abstract
We have previously reported that NM23 genes are overexpressed in various hematological malignancies and that serum NM23-H1 protein levels are useful for predicting patient outcomes. In this study we assessed the clinical implications of serum NM23-H1 protein on neuroblastoma. We examined serum NM23-H1 protein levels in 217 patients with neuroblastoma, including 131 found by mass-screening and 86 found clinically by an enzyme-linked immunosorbent assay, and determined the association between levels of this protein, and known prognostic factors or the clinical outcome. The serum NM23-H1 protein level was higher in neuroblastoma patients than in control children (P < 0.0001). Patients with MYCN amplification had higher serum NM23-H1 levels than those with a single copy of MYCN. Overall survival was assessed in the 86 patients found clinically, and was found to be worse in patients with higher serum MN23-H1 levels (> or = 250 ng/mL) than in those with lower levels (< 250 ng/mL; P = 0.034). The higher level of NM23-H1 was correlated with a worse outcome in patients with a single MYCN copy, or in those younger than 12 months of age. Serum NM23-H1 protein levels may contribute to predictions of clinical outcome in patients with neuroblastoma.
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- 2005
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35. Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts.
- Author
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Kasukabe T, Okabe-Kado J, Kato N, Sassa T, and Honma Y
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Drug Interactions, Female, Gene Expression Regulation, Neoplastic drug effects, Genes, Neoplasm, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Transplantation, Heterologous, Antibiotics, Antineoplastic pharmacology, Breast Neoplasms pathology, Carcinoma pathology, Diterpenes pharmacology, Sirolimus pharmacology
- Abstract
Introduction: Rapamycin, an inhibitor of the serine/threonine kinase target of rapamycin, induces G1 arrest and/or apoptosis. Although rapamycin and its analogues are attractive candidates for cancer therapy, their sensitivities with respect to growth inhibition differ markedly among various cancer cells. Using human breast carcinoma cell line MCF-7 as an experimental model system, we examined the growth-inhibitory effects of combinations of various agents and rapamycin to find the agent that most potently enhances the growth-inhibitory effect of rapamycin., Method: We evaluated the growth-inhibitory effect of rapamycin plus various agents, including cotylenin A (a novel inducer of differentiation of myeloid leukaemia cells) to MCF-7 cells, using either MTT assay or trypan blue dye exclusion test. The cell cycle was analyzed using propidium iodide-stained nuclei. Expressions of several genes in MCF-7 cells with rapamycin plus cotylenin A were studied using cDNA microarray analysis and RT-PCR. The in vitro results of MCF-7 cells treated with rapamycin plus cotylenin A were further confirmed in vivo in a mouse xenograft model., Results: We found that the sensitivity of rapamycin to MCF-7 cells was markedly affected by cotylenin A. This treatment induced growth arrest of the cells at the G1 phase, rather than apoptosis, and induced senescence-associated beta-galactosidase activity. We examined the gene expression profiles associated with exposure to rapamycin and cotylenin A using cDNA microarrays. We found that expressions of cyclin G2, transforming growth factor-beta-induced 68 kDa protein, BCL2-interacting killer, and growth factor receptor-bound 7 were markedly induced in MCF-7 cells treated with rapamycin plus cotylenin A. Furthermore, combined treatment with rapamycin and cotylenin A significantly inhibited the growth of MCF-7 cells as xenografts, without apparent adverse effects., Conclusion: Rapamycin and cotylenin A cooperatively induced growth arrest in breast carcinoma MCF-7 cells in vitro, and treatment with rapamycin and cotylenin A combined more strongly inhibited the growth of MCF-7 cells as xenografts in vivo than treatment with rapamycin or cotylenin A alone, suggesting that this combination may have therapeutic value in treating breast cancer. We also identified several genes that were markedly modulated in MCF-7 cells treated with rapamycin plus cotylenin A.
- Published
- 2005
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36. Clinical significance of intracytoplasmic nm23-H1 expression in diffuse large B-cell lymphoma.
- Author
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Niitsu N, Nakamine H, Okamoto M, Akamatsu H, Higashihara M, Honma Y, Okabe-Kado J, and Hirano M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, C-Reactive Protein biosynthesis, Cytoplasm metabolism, Disease Progression, Disease-Free Survival, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Lymph Nodes pathology, Lymphoma metabolism, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell mortality, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse mortality, Middle Aged, Multivariate Analysis, NM23 Nucleoside Diphosphate Kinases, Nucleoside-Diphosphate Kinase physiology, Prognosis, Time Factors, Lymphoma, B-Cell metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Nucleoside-Diphosphate Kinase biosynthesis
- Abstract
Purpose: Recently, we established an ELISA technique for measuring nm23-H1 protein in serum and found that the serum nm23-H1 level is a potential prognostic factor for patients with non-Hodgkin's lymphoma., Experimental Design: We used immunohistochemistry to examine the expression of nm23-H1 by the lymphoma cells in patients with diffuse large B-cell lymphoma (DLBCL)., Results: By analyzing a consecutive series of 172 untreated DLBCL patients, we found that 100 (58.1%) were strongly positive. The cytoplasmic nm23 expression in lymphoma cells correlated significantly with the serum nm23-H1 level. There was a significant correlation between patients with cytoplasmic nm23-positive lymphoma and those with performance status 2-4, stage III/IV, bulky mass, B symptoms, elevated serum level of soluble interleukin 2 receptor, and elevated serum level of C-reactive protein. Overall and progression-free survival rates were significantly lower in patients with nm23-H1-positive lymphomas than in those with nm23-H1-negative lymphomas. Similar difference was seen between patients with high and low serum levels of nm23-H1. Thus, the correlation between presence or absence of cytoplasmic nm23-H1 expression and serum nm23-H1 levels suggests that serum nm23-H1 is produced directly by lymphoma cells., Conclusion: We suggest that nm23-H1 expression is a prognostic factor for DLBCL, and that it is as important as serum nm23-H1, both of which are useful for planning a treatment strategy.
- Published
- 2004
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37. MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia.
- Author
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Yokoyama A, Yamashita T, Shiozawa E, Nagasawa A, Okabe-Kado J, Nakamaki T, Tomoyasu S, Kimura F, Motoyoshi K, Honma Y, and Kasukabe T
- Subjects
- Adult, Aged, Aged, 80 and over, Bone Marrow pathology, Carrier Proteins analysis, Case-Control Studies, Cytogenetic Analysis, Female, Humans, Leukemia, Myeloid, Acute classification, Leukemia, Myeloid, Acute enzymology, Male, Membrane Proteins analysis, Middle Aged, Prognosis, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis, Carrier Proteins genetics, Leukemia, Myeloid, Acute diagnosis, Membrane Proteins genetics, Phospholipid Transfer Proteins
- Abstract
We previously found that expression of the Mm-1 cell-derived transplantability-associated gene 1b (MmTRA1b)/phospholipid scramblase 1 gene was markedly induced during the granulocytic differentiation of human myeloid leukemia cells. To evaluate the role of MmTRA1b expression in human myeloid leukemia, we investigated the relative levels of MmTRA1b transcripts in 81 patients with acute myelogenous leukemia (AML) by the reverse transcriptase polymerase chain reaction. The expression of MmTRA1b in AML-M1, -M5a and -M5b was significantly lower than that in normal bone marrow cells. The levels of MmTRA1b expression in AML-M2 and -M4 varied among patients. Higher MmTRA1b mRNA levels were associated with significantly longer overall survival in AML, especially in AML-M4 patients, independent of chromosomal aberrations such as t(8;21) and inv(16). The present results suggest that the MmTRA1b mRNA level is a new prognostic factor for AML, especially the AML-M4 subtype.
- Published
- 2004
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38. Expression of nm23-H1 is associated with poor prognosis in peripheral T-cell lymphoma.
- Author
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Niitsu N, Nakamine H, Okamoto M, Akamatsu H, Honma Y, Higashihara M, Okabe-Kado J, and Hirano M
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Granzymes, Humans, Immunohistochemistry methods, Lymphatic Metastasis, Lymphoma, T-Cell mortality, Male, Membrane Proteins analysis, Middle Aged, Multivariate Analysis, NM23 Nucleoside Diphosphate Kinases, Poly(A)-Binding Proteins, Prognosis, RNA-Binding Proteins analysis, Serine Endopeptidases analysis, Survival Rate, T-Cell Intracellular Antigen-1, Biomarkers, Tumor analysis, Lymphoma, T-Cell chemistry, Monomeric GTP-Binding Proteins analysis, Nucleoside-Diphosphate Kinase, Proteins, Transcription Factors analysis
- Abstract
We have reported previously that the serum nm23-H1 level is a prognostic factor for non-Hodgkin's lymphoma. In this study, we examined nm23-H1 expression in T- and natural killer (NK)-cell lymphoma in order to evaluate whether lymphoma cells produce the protein. The clinical significance of the cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B and nm23-H1 expression were also examined. Expression of nm23-H1, TIA-1, or granzyme B was examined by immunohistochemistry in 137 previously untreated lymphoma patients. The relationship between the results and clinical outcome was examined in 81 patients with angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, or peripheral T-cell lymphoma, unspecified. The neoplastic cells of some lymphomas produced nm23-H1 and the expression rates of nm-23-H1, TIA-1 and granzyme B were 36.5%, 78.8% and 32.8% respectively. The nm23-H1-positive or TIA-1-positive groups had significantly shorter overall and disease-free survivals. Multivariate analysis confirmed nm23-H1 expression to be an independent prognostic factor. The nm23-H1 protein can be an important prognostic factor in the lymphomas studied here. New treatments that target nm23 overexpression could be developed as a result of nm23-HI production by lymphoma cells.
- Published
- 2003
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39. Induction of apoptosis by combined treatment with differentiation-inducing agents and interferon-alpha in human lung cancer cells.
- Author
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Yamamoto-Yamaguchi Y, Okabe-Kado J, Kasukabe T, and Honma Y
- Subjects
- Acetamides pharmacology, Butyrates pharmacology, Caspase 3, Caspase Inhibitors, Caspases biosynthesis, Caspases, Initiator, Cell Differentiation drug effects, Cytochrome c Group metabolism, DNA-Binding Proteins biosynthesis, Dimethyl Sulfoxide administration & dosage, Enzyme Induction drug effects, Humans, Interferon Regulatory Factor-1, Interferon-alpha administration & dosage, Lung Neoplasms enzymology, Phosphoproteins biosynthesis, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Lung Neoplasms drug therapy, Lung Neoplasms pathology
- Abstract
Background: Differentiation-inducing agents for myeloid leukemic cells, such as dimethyl sulfoxide (DMSO), Na-butyrate and hexamethylene-bis-acetamide (HMBA), barely induce irreversible differentiation or growth inhibition in solid tumors when used alone. However, we previously reported that combined treatment with differentiation-inducing agents and interferon (IFN)-alpha effectively suppressed the growth of human lung cancer cell lines in vitro and in vivo. We show here that combined treatment-induced cell death is caused by apoptosis., Materials and Methods: Induction of apoptosis was examined by expression of several apoptotic markers., Results: Combined treatment-induced cell death is caused by apoptosis, which is characterized by the induction of apoptotic morphological changes and the activation of caspase-3-like protease. The expression of Apo2.7, an early apoptotic change, is also induced by this combined treatment, and is suppressed by the addition of Z-Asp-CH2-DCB, a pan caspase inhibitor. The signal transduction pathway of IFN-alpha is rapidly observed in lung cancer cells, although it does not induce significant growth inhibition when used alone. We analyzed the effect of IFN-alpha on the apoptotic pathway and found that IFN-alpha but not DMSO induces the expression of caspase-4. The combination of IFN-alpha and DMSO did not cause further increase in the expression of caspase-4. In many cases of the induction of apoptosis, cytochrome c is released from mitochondria, which induces the formation of large caspase-activating complexes. Caspase-3-like-activities induced by the combination of DMSO or Na-butyrate with IFN-alpha were analyzed by gel filtration and detected equally in fractions with molecular weights of 200-300 kDa, suggesting that caspase-3 is activated in large complexes in lung cancer cells. However, Na-butyrate and HMBA, when used alone, induced the release of cytochrome c and enhanced the loss of mitochondrial membrane potential, whereas DMSO had no effect., Conclusion: These results suggest that the combination of differentiation-inducing agents with IFN-alpha effectively induces apoptosis in lung cancer cells whereas the mechanism of such induction varies depending on the differentiation-inducing agent used.
- Published
- 2003
40. Physiological and pathological relevance of extracellular NM23/NDP kinases.
- Author
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Okabe-Kado J and Kasukabe T
- Subjects
- Animals, Biomarkers, Tumor analysis, Cell Division, Cell Line, Tumor metabolism, Cell Survival, Humans, NM23 Nucleoside Diphosphate Kinases, Neoplasms blood, Neoplasms pathology, Predictive Value of Tests, Biomarkers, Tumor metabolism, Extracellular Fluid metabolism, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Neoplasms diagnosis, Neoplasms metabolism, Nucleoside-Diphosphate Kinase, Proteins metabolism
- Abstract
The NM23 gene is overexpressed in many hematological malignancies and other neoplasms. Some tumor cell lines that overexpress NM23 secrete this protein into extracellular environment. In this study, we found that the serum concentration of NM23-H1 protein was significantly higher in patients with various hematological malignancies. The serum level of NM23-H1 protein was clinically useful as a prognostic factor in malignant lymphoma and acute myelogeneous leukemia (AML). The level of NM23-H1 protein in all of the normal serum samples examined was lower than 10 ng/mL, while those in the tumors varied from about 0 to 1000 ng/mL. Exogenously added NM23-H1 protein did not affect the growth or survival of various leukemia and lymphoma cell lines. However, NM23-H1 protein inhibited the survival of adherent normal peripheral blood mononuclear cells (PBMNC) at 100-1000 ng/mL, and slightly stimulated the survival of nonadherent PBMNC. These results suggest that the effect of NM23-H1 protein on normal PBMNC may be associated with a poor prognosis in hematological malignancies.
- Published
- 2003
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41. Expression of cell surface NM23 proteins of human leukemia cell lines of various cellular lineage and differentiation stages.
- Author
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Okabe-Kado J, Kasukabe T, and Honma Y
- Subjects
- Biomarkers, Tumor metabolism, Cell Differentiation, Cell Lineage, Erythrocytes pathology, Flow Cytometry, Humans, Lymphocytes pathology, Myeloid Cells pathology, NM23 Nucleoside Diphosphate Kinases, Neoplasm Proteins metabolism, Tumor Cells, Cultured, Leukemia metabolism, Leukemia pathology, Monomeric GTP-Binding Proteins metabolism, Nucleoside-Diphosphate Kinase, Transcription Factors metabolism
- Abstract
Cell surface expression of NM23 protein is only observed on tumor cell lines, but not on normal cells. To examine what types of tumor cell line express the cell surface NM23 protein, we measured the cell surface NM23-H1 and NM23-H2 proteins of leukemia line cells on various cellular lineage and differentiation stages. The NM23-H1 was expressed on myeloid leukemia lines but not lymphoid lines, while NM23-H2 was only expressed on erythroleukemia lines. The complement-dependent cytolysis confirmed the expression of these proteins on the surface. Surface NM23-H1 and NM23-H2 proteins were decreased during in vitro erythroid and granulocyte differentiation. These results show that the surface expression of NM23 proteins is related to cellular lineage and differentiation stage of leukemia line cells.
- Published
- 2002
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42. Role of MmTRA1b/phospholipid scramblase1 gene expression in the induction of differentiation of human myeloid leukemia cells into granulocytes.
- Author
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Nakamaki T, Okabe-Kado J, Yamamoto-Yamaguchi Y, Hino Ki, Tomoyasu S, Honma Y, and Kasukabe T
- Subjects
- Ca(2+) Mg(2+)-ATPase genetics, Calcitriol pharmacology, Cell Differentiation drug effects, HL-60 Cells, Humans, Leukemia, Myeloid pathology, Macrophages cytology, Monocytes cytology, RNA, Messenger genetics, Transcription, Genetic, Tumor Cells, Cultured, U937 Cells, Carrier Proteins genetics, Cell Differentiation genetics, Gene Expression Regulation, Neoplastic, Granulocytes physiology, Leukemia, Myeloid genetics, Membrane Proteins genetics, Phospholipid Transfer Proteins
- Abstract
Objective: We previously cloned a human normal counterpart (MmTRA1b/phospholipid scramblase 1) of the mouse leukemogenesis-associated gene MmTRA1a. MmTRA1b gene expression was increased during differentiation of human monoblastic leukemia U937 cells using some differentiation inducers but not 1alpha,25-dihydroxyvitamin D(3) (a typical monocytic differentiation inducer). To further elucidate the role of human MmTRA1b gene expression in the differentiation of myelogenous leukemia cells, we measured MmTRA1b gene expression in several myeloid leukemia cell lines and primary leukemia cells., Materials and Methods: The expression of MmTRA1b mRNA was determined by semiquantitative reverse transcriptase polymerase chain reaction., Results: Expression of the MmTRA1b gene was markedly induced during granulocytic differentiation of promyelocytic leukemia NB4 and HT93 cells induced by all-trans retinoic acid (ATRA). The level of MmTRA1b mRNA was significantly increased during differentiation toward granulocytes, but not monocytes/macrophages, in bipotential myeloid leukemia HL-60 cells. The level of MmTRA1 mRNA was not increased during erythroid differentiation induced by hemin in erythroid leukemia K562 and HEL cells or during megakaryocytic differentiation induced by 12-O-tetradecanoylphorbol-13-acetate in K562 cells. Expression of the MmTRA1b gene also was not induced when apoptosis of NB4 cells was induced by antileukemic drugs. ATRA-induced differentiation of antisense MmTRA1b-transfected NB4 cells was significantly suppressed. On the other hand, ATRA induced the differentiation of MmTRA1b-transfected NB4 cells more efficiently than that of mock-transfected cells. MmTRA1b mRNA also was clearly induced in ATRA-treated primary acute promyelocytic leukemia cells during granulocytic differentiation., Conclusion: MmTRA1b mRNA was specifically induced during granulocytic differentiation of acute promyelocytic leukemia cells and was associated with induction of their differentiation.
- Published
- 2002
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43. Serum nm23-H1 protein as a prognostic factor in hematological malignancies.
- Author
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Okabe-Kado J
- Subjects
- Antigens, Viral metabolism, Enzyme-Linked Immunosorbent Assay, Epstein-Barr Virus Nuclear Antigens, Humans, Leukemia, Myeloid, Acute mortality, Lymphoma, Non-Hodgkin mortality, Monomeric GTP-Binding Proteins analysis, Monomeric GTP-Binding Proteins genetics, NM23 Nucleoside Diphosphate Kinases, Prognosis, Telomere, Transcription Factors analysis, Transcription Factors genetics, Leukemia, Myeloid, Acute blood, Lymphoma, Non-Hodgkin blood, Monomeric GTP-Binding Proteins blood, Nucleoside-Diphosphate Kinase, Transcription Factors blood
- Abstract
A nondifferentiating mouse myeloid leukemia cell line produces differentiation-inhibiting factors. One of these factors was purified as a homologue of nm23. The nm23 gene was isolated as a metastasis-suppressor gene that exhibits low expression in high-level metastatic cancer cells. The nm23 gene was overexpressed in acute myelogenous leukemia (AML) cells and a higher level of nm23-H1 expression was correlated with a poor prognosis in AML. Multivariate analysis of putative prognostic factors revealed that elevated nm23-H1 mRNA levels significantly contributed to the prognosis of patients with AML. The overexpression of nm23-H1 was also observed in various hematological neoplasms. To use nm23 overexpression to determine the prognosis for lymphoma, we established an enzyme-linked immunosorbent assay (ELISA) technique to determine the serum level of nm23-H1 protein. This assay is far simpler than that used to determine nm23 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). Using this system, we measured nm23-H1 protein levels in many hematological malignancies. Serum nm23-HI levels were significantly higher in patients with all of the hematological neoplasms tested (AML, chronic myelogenous leukemia, acute lymphoblastic leukemia, (ALL) myelodysplastic syndrome (MDS) and malignant lymphomas) than in normal controls. An elevated serum nm23-H1 protein concentration predicted a poor outcome for AML and non-Hodgkin's lymphoma. Especially in diffuse large B-cell lymphoma (DLBCL), seram nm23-H1 protein levels were an important prognostic factor in planning an appropriate treatment strategy for DLBCL. The serum nm23-H I protein levels probably depend on the total mass of malignant cells overexpressing nm23-H1.
- Published
- 2002
- Full Text
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44. Serum nm23-H1 protein as a prognostic factor in aggressive non-Hodgkin lymphoma.
- Author
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Niitsu N, Okabe-Kado J, Okamoto M, Takagi T, Yoshida T, Aoki S, Hirano M, and Honma Y
- Subjects
- Actuarial Analysis, Adolescent, Adult, Aged, Aged, 80 and over, Antigens, Neoplasm blood, Biomarkers blood, Female, Follow-Up Studies, Freezing, Humans, Hyaluronan Receptors blood, Lymphoma, Non-Hodgkin blood, Male, Middle Aged, NM23 Nucleoside Diphosphate Kinases, Prognosis, Receptors, Interleukin-2 blood, Survival Rate, Lymphoma, Non-Hodgkin diagnosis, Monomeric GTP-Binding Proteins blood, Nucleoside-Diphosphate Kinase, Transcription Factors blood
- Abstract
Advances in chemotherapy have led to a favorable long-term prognosis in approximately 50% of patients with aggressive non-Hodgkin lymphoma (NHL). However, the remaining patients do not enjoy such prolonged survival after standard treatment. New prognostic factors are needed to define this poor-prognosis group and to plan an appropriate treatment strategy. It has been reported that serum nm23-H1 protein may be a new prognostic factor for aggressive NHL. In the present study involving multiple institutions and a large number of patients, the level of nm23-H1 protein was compared among different types of lymphoma; it was lowest for indolent lymphoma, followed by aggressive lymphoma and then highly aggressive lymphoma. In addition, patients with aggressive NHL and higher nm23-H1 levels had worse overall and progression-free survival rates than those with lower nm23-H1 levels. The nm23-H1 level was also compared between patients with diffuse large B-cell lymphoma and patients with peripheral T-cell lymphoma. The results suggest that the level of nm23-H1 could serve as a prognostic factor in both groups. Moreover, the prognosis of lymphoma patients could be ascertained even more precisely by combining soluble interleukin-2 receptor or soluble CD44 and nm23-H1 levels. A multivariate analysis confirmed that the nm23-H1 level is an independent and important prognostic factor in aggressive NHL. Therefore, it may provide useful information for clinicians to determine the appropriate therapy for each type of lymphoma.
- Published
- 2001
- Full Text
- View/download PDF
45. Antileukemic efficacy of 2-deoxycoformycin in monocytic leukemia cells.
- Author
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Niitsu N, Yamamoto-Yamaguchi Y, Kasukabe T, Okabe-Kado J, Umeda M, and Honma Y
- Subjects
- Animals, Antibiotics, Antineoplastic therapeutic use, Antimetabolites pharmacology, Antimetabolites therapeutic use, Cell Survival drug effects, Humans, Leukemia, Monocytic, Acute pathology, Mice, Mice, Nude, Pentostatin therapeutic use, U937 Cells, Vidarabine pharmacology, Vidarabine therapeutic use, Antibiotics, Antineoplastic pharmacology, Leukemia, Monocytic, Acute drug therapy, Pentostatin pharmacology
- Abstract
2'-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2'-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 micromol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-beta-D-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia. (Blood. 2000;96:1512-1516)
- Published
- 2000
46. Plasma levels of the differentiation inhibitory factor nm23-H1 protein and their clinical implications in acute myelogenous leukemia.
- Author
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Niitsu N, Okabe-Kado J, Nakayama M, Wakimoto N, Sakashita A, Maseki N, Motoyoshi K, Umeda M, and Honma Y
- Subjects
- Adult, Aged, Antigens, Neoplasm blood, Female, Humans, Leukemia, Myeloid, Acute physiopathology, Male, Middle Aged, Multivariate Analysis, NM23 Nucleoside Diphosphate Kinases, Prognosis, Biomarkers, Tumor, Leukemia, Myeloid, Acute blood, Monomeric GTP-Binding Proteins blood, Nucleoside-Diphosphate Kinase, Transcription Factors blood
- Abstract
A previous study reported that a nondifferentiating myeloid leukemia cell line produced differentiation-inhibiting factors. One of the factors was purified as a homologue of the nm23 genes. The nm23 genes were overexpressed in acute myelogenous leukemia (AML) cells, and a higher level of nm23 gene expression was correlated with a poor prognosis in AML. The present study determined the plasma levels of nm23-H1 protein by enzyme-linked immunosorbent assay and assessed the association between this level and the clinical outcome in 102 patients with AML. The plasma concentration of nm23-H1 was higher in patients with AML than in normal controls (P =.0001). Plasma nm23-H1 levels were correlated with the product of the intracellular nm23 messenger RNA (mRNA) level and the white blood cell count, but not with the mRNA level alone. Therefore, nm23-H1 plasma levels probably depend on the total mass of leukemic cells overexpressing the nm23-H1 gene. Overall survival was lower in patients with higher plasma nm23-H1 levels than in those with lower levels. Multivariate analysis using the Cox proportional hazard model showed that elevated plasma nm23-H1 levels significantly contributed to the prognosis of AML patients. Furthermore, the plasma nm23-H1 levels were investigated in 70 patients with other hematologic neoplasms, including 6 with acute lymphoblastic leukemia, 13 with chronic myelogenous leukemia, and 12 with myelodysplastic syndrome. Plasma nm23-H1 levels were significantly higher in all of these hematologic neoplasms than in normal controls. Increased plasma levels of nm23-H1 may have prognostic value in these hematologic malignancies as well as in AML.
- Published
- 2000
47. Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity.
- Author
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Niitsu N, Kasukabe T, Yokoyama A, Okabe-Kado J, Yamamoto-Yamaguchi Y, Umeda M, and Honma Y
- Subjects
- Antibiotics, Antineoplastic pharmacology, Biological Transport, Cell Cycle drug effects, Cell Division drug effects, DNA drug effects, DNA metabolism, Drug Resistance, Neoplasm genetics, Drug Synergism, Glycoside Hydrolases drug effects, Glycoside Hydrolases metabolism, Humans, Lung Neoplasms pathology, Lymphoma pathology, Microsomes enzymology, Microsomes metabolism, Oligonucleotides, Antisense pharmacology, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Butyrates pharmacology, Daunorubicin pharmacology, Doxorubicin pharmacology, Microsomes drug effects
- Abstract
Pivalyloxymethyl butyrate (AN9) is an anticancer derivative of butyric acid. In this study, doxorubicin (DXR) and AN9 synergistically inhibited the growth of lymphoma and lung carcinoma cells, whereas there was no synergy between AN9 and antimetabolites. AN9 did not affect the intracellular uptake of DXR. Among anthracyclines and their derivatives, the synergistic effect was prominent in compounds with a daunosamine moiety, suggesting that AN9 may affect the catabolism of these compounds. The degradation of DXR in the extract from AN9-treated cells was much less than that in extract from untreated cells. AN9 did not directly inhibit the enzyme activity but rather suppressed expression of the enzyme. With respect to the expression of drug resistance-related genes, there was no significant difference between untreated and AN9-treated cells. However, AN9 significantly down-regulated the levels NADPH-cytochrome P450 reductase and DT-diaphorase mRNA in the presence of DXR but not the level of xanthine oxidase mRNA. The enhancement of the sensitivity to anthracyclines was closely associated with the suppression of the mRNA expression.
- Published
- 2000
- Full Text
- View/download PDF
48. Prognostic implications of the differentiation inhibitory factor nm23-H1 protein in the plasma of aggressive non-Hodgkin's lymphoma.
- Author
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Niitsu N, Okabe-Kado J, Kasukabe T, Yamamoto-Yamaguchi Y, Umeda M, and Honma Y
- Subjects
- Adult, Cell Differentiation, Female, Humans, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin mortality, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Multivariate Analysis, NM23 Nucleoside Diphosphate Kinases, Prognosis, Survival Rate, Biomarkers, Tumor blood, Lymphoma, Non-Hodgkin blood, Monomeric GTP-Binding Proteins, Nucleoside-Diphosphate Kinase, Transcription Factors blood
- Abstract
The outcome of patients with non-Hodgkin's lymphoma has been improved by current approaches to treatment. Nevertheless, many patients either do not have a complete remission or ultimately relapse. To identify such patients, it is important to be able to predict the outcome. We previously found that the differentiation inhibitory factor/nm23 was correlated with the prognosis of acute myeloid leukemia. To examine the prognostic effect of nm23 on non-Hodgkin's lymphoma, we established an enzyme-linked immunosorbent assay procedure to determine nm23-H1 protein levels in plasma and assessed the association of this protein level with the response to chemotherapy, overall survival, and progression-free survival in patients with aggressive non-Hodgkin's lymphoma. The plasma concentration of nm23-H1 was significantly higher in patients with malignant lymphoma than in normal controls, especially in aggressive non-Hodgkin's lymphoma. The complete remission rate in patients with higher nm23-H1 levels was significantly worse than that in patients with lower nm23-H1 levels. Overall survival and progression-free survival were also lower in patients with higher nm23-H1 levels than in those with lower levels. The 3-year survival rates in patients with low and high nm23-H1 levels were 79.5% and 6. 7% (P =.0001). A multivariate analysis of prognostic factors showed that the plasma nm23-H1 level was independently associated with the survival and progression-free survival. An elevated plasma nm23-H1 concentration predicts a poor outcome of advanced non-Hodgkin's lymphoma. Therefore, nm23-H1 in plasma may be useful for identifying a distinct group of patients at very high risk.
- Published
- 1999
49. Role of CD14 expression in the differentiation-apoptosis switch in human monocytic leukemia cells treated with 1alpha,25-dihydroxyvitamin D3 or dexamethasone in the presence of transforming growth factor beta1.
- Author
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Kanatani Y, Kasukabe T, Okabe-Kado J, Yamamoto-Yamaguchi Y, Nagata N, Motoyoshi K, and Honma Y
- Subjects
- Cell Differentiation, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclins genetics, Humans, Microtubule-Associated Proteins genetics, Proto-Oncogene Proteins c-bcl-2 biosynthesis, U937 Cells, bcl-X Protein, Apoptosis, Calcitriol pharmacology, Cell Cycle Proteins, Dexamethasone pharmacology, Lipopolysaccharide Receptors biosynthesis, Transforming Growth Factor beta pharmacology, Tumor Suppressor Proteins
- Abstract
Transforming growth factor beta (TGF-beta) enhanced the growth-inhibitory activities of dexamethasone (Dex) and 1alpha,25-dihydroxyvitamin D3 (VD3) on human monocytoid leukemia U937 cells. TGF-beta and VD3 synergistically increased the expression of differentiation-associated markers such as the CD11b and CD14 antigens, whereas TGF-beta and Dex did not. On the other hand, TGF-beta and Dex synergistically increased the number of Apo2.7-positive cells, which represents the early stage of apoptosis, whereas TGF-beta and VD3 did not, suggesting that TGF-beta enhanced apoptosis with Dex and enhanced monocytic differentiation with VD3. In the presence of TGF-beta, the retinoblastoma susceptibility gene product, pRb, was synergistically dephosphorylated by Dex as well as VD3. TGF similarly enhanced the expression of the p21Waf1 gene in U937 cells treated with Dex and VD3. TGF-beta dose-dependently increased the expression of Bcl-2 and Bad and decreased the expression of Bcl-X(L) in U937 cells. Dex enhanced the down-regulation of Bcl-X(L) expression in TGF-beta-treated cells, whereas VD3 blocked this down-regulation of Bcl-X(L). However, the down-regulation of Bcl-X(L) by treatment with the antisense oligomer did not affect the apoptosis or differentiation of U937 cells. The apoptosis of CD14-positive cells was suppressed in the VD3 plus TGF-beta-treated cultures. These results suggest that the expression of CD14 is involved in the survival of differentiated cells.
- Published
- 1999
50. Differentiation inhibitory factor Nm23 as a prognostic factor for acute myeloid leukemia.
- Author
-
Okabe-Kado J, Kasukabe T, and Honma Y
- Subjects
- Acute Disease, Amino Acid Sequence, Animals, Antigens, Neoplasm metabolism, Biomarkers, Tumor metabolism, Female, Gene Expression, Hematologic Neoplasms metabolism, Humans, Leukemia, Myeloid mortality, Male, Mice, Middle Aged, Molecular Sequence Data, NM23 Nucleoside Diphosphate Kinases, Prognosis, RNA, Messenger metabolism, Sequence Homology, Amino Acid, Survival Analysis, Leukemia, Myeloid diagnosis, Leukemia, Myeloid metabolism, Monomeric GTP-Binding Proteins, Nucleoside-Diphosphate Kinase, Transcription Factors metabolism
- Abstract
The differentiation inhibitory factor nm23 inhibits the differentiation of murine and human myeloid leukemia cells. The inhibition of differentiation may be associated with the aggressive behavior of leukemia. To clarify the role of nm23 in human myeloid leukemia, we investigated the relative levels of nm23-H1, nm23-H2 and c-myc transcripts in bone marrow and blood samples from 110 patients with acute myeloid leukemia (AML) using the reverse transcriptase polymerase chain reaction. The expression levels of nm23-H1 and nm23-H2 in these AML samples were significantly higher than in normal blood cells, and a higher level of nm23-H1 expression was correlated with poor prognosis for AML patients. Analysis of the correlation between nm23 expression and clinical parameters demonstrated that increased nm23-H1 mRNA levels were associated with resistance to initial chemotherapy and reduced overall survival. Multivariate analysis of putative prognostic factors revealed that elevated nm23-H1 mRNA levels significantly influenced the prognosis of patients with AML, particularly in AML-M5.
- Published
- 1998
- Full Text
- View/download PDF
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