2018 Fiscal Year Final Research Report
Novel small-molecule sirtuin inhibitors induce cell apoptic death in leukemia cells
| Project/Area Number |
16K09863
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Fukuoka University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
SUZUKI Takayoshi 京都府立医科大学, 医学部, 教授 (90372838)
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| Research Collaborator |
YOSHIMITSU Makoto 鹿児島大学, 医学部, 准教授 (70404530)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | ATL / HTLV-1 / Sirtuin |
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| Outline of Final Research Achievements |
Sirtuin 2 (SIRT2) is a member of the sirtuin family which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Therefore, selective inhibitors of SIRT2 are candidate therapeutic agents for cancer. Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy that has a poor prognosis and develops after long-term infection with human T-cell leukemia virus (HTLV)-1. Sirtuin 1 inhibition has been shown to induce apoptosis and autophagy in HTLV-1-infected cell lines, whereas the effects of SIRT2 inhibition alone have not been elucidated. Our novel small molecule SIRT2-specific inhibitors NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T-cells. NCO-90/141 are highly effective against leukemic cells in caspase-dependent or -independent manners via autophagy, and they may have a novel therapeutic potential for treatment of leukemias including ATL.
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| Free Research Field |
血液腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
HTLV-1は、慢性持続感染後にATLを発症するため、感染・腫瘍・免疫の観点から興味深いモデルである。SIRT2の造血器悪性腫瘍に対する報告は乏しく、その阻害剤に関する報告は無い。本研究では、新規SIRT2阻害剤がアポトーシス及びオートファジーを介してATL患者細胞の細胞生存率を低下させる事を報告した。サーチュインは長寿遺伝子として注目され、その研究は、がん研究のみならず老化関連疾患など幅広い研究に有益であり、高齢者人口が25%を超える高齢化社会への波及効果も高い。また、サーチュインを標的とした新規白血病治療法の研究は、抗がん剤治療が主流であるなかで独創性の高い研究であると考えられる。
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