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Novel mechanisms of drug resistance in leukemia and the new molecular target therapeutic strategies.

Research Project

Project/Area Number 16590959
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionJICHI MEDICAL SCHOOL

Principal Investigator

OHMINE Ken  JICHI MEDICAL SCHOOL, Faculty of Medicine, Research Associate, 医学部, 助手 (90316521)

Co-Investigator(Kenkyū-buntansha) NAGAI Tadashi  JICHI MEDICAL SCHOOL, Faculty of Medicine, Assistant Professor, 医学部, 助教授 (40237483)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsCML / Drug resistance / BCR / ABL / imatinib / RhoA / KCL22 / SR / Heme / glutatione / Faenesyltransferase阻害薬 / UCN-01
Research Abstract

The ABL tyrosine kinase inhibitor imatinib mesylate has shown a substantial clinical effect in CML. It is important to determine the potential mechanism of resistance to this compound.
1.We found that RhoA, which plays important roles in signal transduction pathways, is expressed at higher levels in an imatinib-resistant BCR/ABL-positive cell line KCK22/SR, than in the parent cell line KCL22. We cloned new imatinib-resistant cells, K562/SR and KU812/SR. Western blot analysis showed that RhoA was up-regulated in KU812/SR cells.
2.We examined the cytotoxic effect of treatment with a combination of imatinib and Chk1 inhibitor UCN-01. The level of apoptosis of imatinib-resistant BCR/ABL-positive cell lines was not increased by the combination treatment, but G0/G1 accumulation in the cells was increased by the combination treatment. Isoborograms showed that combined treatment of all cells with UCN-01 and imatinib did not result in synergistic inhibition of cell growth. In contrast, some of th … More em showed an antagonistic effect. The results suggest that a cell cycle blockage compound inhibits the imatinib effect.
3.Heme plays an important biomodulating role in various cell systems. We investigated the role of heme in modulation of the sensitivity of leukemia cells to imatinib using human BCR/ABL-positive cells. IC_<50> values of imatinib in KCL22 cells were increased by hemin treatment in a dose-dependent manner. Hemin treatment also suppressed imatinib-mediated induction of apoptosis. Levels of phosphorylated BCR/ABL and phosphorylated ERK1/2 were decreased by imatinib treatment regardless of the presence or absence of hemin, indicating that the hemin-mediated increase in IC_<50> values of imatinib does not involve imatinib-mediated inhibition of BCR/ABL kinase activity. On the other hand, hemin treatment increased the activity of the human γ-GCS light subunit gene promoter and the intracellular glutathione (GSH) concentration. These findings thus indicate that heme plays an essential role in determining the sensitivity of leukemia cells to imatinib and that its effect is mediated, in part, via the GSH modulate pathway. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (14 results)

All 2006 2005 2004 Other

All Journal Article (14 results)

  • [Journal Article] The usefulness of magnetic resonance imaging (MRI) for disseminated trichosporosis of the gastrocnemius muscles.2006

    • Author(s)
      Meguro-Hashimoto A., et al.
    • Journal Title

      J Infect 20(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The usefulness of magnetic resonance imaging (MRI) for disseminated trichosporosis of the gastrocnemius muscles.2006

    • Author(s)
      Meguro-Hashimoto, A., et al.
    • Journal Title

      J Infect. 20 (in print)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777and imatinib treatment in BCR/ABL-positive cell lines.2005

    • Author(s)
      Miyoshi T., et al.
    • Journal Title

      Biochem Pharmacol. 69

      Pages: 1585-94

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Autologous gamete cryopreservation before hemopoietic stem cell transplantation.2005

    • Author(s)
      Nagashima T., et al.
    • Journal Title

      Med Sci Monit CR 9

      Pages: 1-4

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines.2005

    • Author(s)
      Miyoshi, T., et al.
    • Journal Title

      Biochem Pharmacol. 69

      Pages: 1585-1594

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line.2005

    • Author(s)
      Tarumoto, T., et al.
    • Journal Title

      Med Sci Monit. 11(3)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines.2005

    • Author(s)
      Miyosi, T.
    • Journal Title

      Biochemical Pharmacology 69

      Pages: 1585-1594

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Iron deficiency anemia with marked thrombocytosis complicated by central retinal vein occlusion.2005

    • Author(s)
      Nagai, T.
    • Journal Title

      Internal Medicine 44・10

      Pages: 1090-1092

    • NAID

      130000085276

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Autologous gamete cryopreservation before hemopoietic stem cell transplantation : information and decision-making.2005

    • Author(s)
      Nagashima, T
    • Journal Title

      Medical Science Monitor 11

      Pages: 91-94

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in imatinib-resistant cell line.2004

    • Author(s)
      Tarumoto T., et al.
    • Journal Title

      Exp Hematol. 32

      Pages: 375-81

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Pseudomonas sepsis with ecthyma gangrenosum in an acute myeloid leukemia patient.2004

    • Author(s)
      Obara, Y., et al.
    • Journal Title

      Rinsho Ketsueki (in Japanese) 45

      Pages: 1138-1140

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ascorbic acid restores the sensitivity to imatinib through suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line, KCL22/SR.2004

    • Author(s)
      Tarumoto, T
    • Journal Title

      Experimental Hematology 32

      Pages: 357-381

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 壊疽性膿瘡を伴う緑膿菌敗血症を合併した急性骨髄性白血病2004

    • Author(s)
      小原陽子
    • Journal Title

      臨床血液 45

      Pages: 1138-1140

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Relative importance of apoptosis and cell cycle blockage in synergistic effect of combined R115777 and imatinib treatment differs among BCR/ABL-positive cell lines.

    • Author(s)
      Miyoshi, T
    • Journal Title

      Biochemical Pharmacology (in press)

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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