| Project/Area Number |
10670940
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
NAOE Tomoki Nagoya University, School of Medicine, Associate professor, 医学部, 助教授 (50217634)
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| Co-Investigator(Kenkyū-buntansha) |
KITAMURA Kunio School of Medicine, the Medical Staff, 医学部, 医員
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | leukemia / apoptosis / AsィイD22ィエD2OィイD23ィエD2 / caspase 8 / 白血病 / As_< 2> O_< 3> / caspase-8 / 急性前骨髄性白血病 / 亜ヒ素酸 / レドックス |
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| Research Abstract |
Arsenic trioxide (AsィイD22ィエD2OィイD23ィエD2)-treatment is effective in acute promyelocytic leukemia (APL) patients with t(15;17). Clinically achievable concentrations of AsィイD22ィエD2OィイD23ィエD2 induces apoptosis of NB4, and APl cell line, and some leukemia /cancer cell lines inn vitro. Here, to study the mechanism of AsィイD22ィエD2OィイD23ィエD2-induced apoptosis, we established as AsィイD22ィエD2OィイD23ィエD2-loe sensitive subline, NB4/As. This cell line had a higher concentration of intracellular glutathione (GSH) than NB4 (96 vs. 32 nmol/mg). Reduction of the GSH level by buthionine sulfoxide (BSO) completely restored the sensitivity to AsィイD22ィエD2OィイD23ィエD2. PML-modification and degradation of PMl-RARα were similarly observed on treatment with AsィイD22ィエD2OィイD23ィエD2 in NB4 and NB4 / As, Suggesting their contribution to apoptosis is small. AsィイD22ィエD2OィイD23ィエD2 induced the activation of caspase 3 as well as a loss of mitocondrial transmembrane potential (ΔΨm) in NB4. IN NB4 / As, they were not observed but restored by pretreatment with BSO. Caspase 8 and Bid were activated by the treatment with AsィイD22ィエD2OィイD23ィエD2 in NB4 but not in NB4 / As. In NB4, an inhibitor of caspase 8 blocked not only the activation of caspase 3 and Bid but also the loss of ΔΨm. In both the cell lines, Fas expressed little and agonistic anti-Fas antibody (CH-11) failed to cause apoptosis. These findings suggest that the treatment with AsィイD22ィエD2OィイD23ィエD2 activate caspase 8 in a Fas-ligand independent manner, and that the AsィイD22ィエD2OィイD23ィエD2-resistance in NB4 / As is induced upstream of BSO, AsィイD22ィエD2OィイD23ィエD2might be applied to therapy of leukemias and cancers which are insensitive to low concentrations of AsィイD22ィエD2OィイD23ィエD2.
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