Molecular mechanism of therapy-induced senescence caused by replicative stress
| Project/Area Number |
17H03598
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
飯森 真人 九州大学, 薬学研究院, 准教授 (20546460)
釣本 敏樹 九州大学, 理学研究院, 教授 (30163885)
沖 英次 九州大学, 大学病院, 講師 (70380392)
佐伯 浩司 群馬大学, 大学院医学系研究科, 教授 (80325448)
三浦 大典 九州大学, 農学研究院, 特任准教授 (40532627)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
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| Keywords | 抗がん剤 / DNA複製ストレス / 治療誘導性細胞老化 / がん化学療法 / 複製ストレス / 細胞老化 / M期スキップ |
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| Outline of Final Research Achievements |
Therapy-induced senescence is now recognized as an important mechanism that elucidates irreversible cell cycle arrest induced by chemotherapeutic drugs. In this research project, we found that trifluridine, a cytotoxic component of chemotherapeutic drug FTD/TPI, efficiently induced cellular senescence in the cell culture condition and DNA replication stress induced by trifluridine was the trigger. In tumor cells, trifluridine, as a fluorinated thymidine analog, was incorporated into genomic DNA during DNA replication process. At that process, trifluridine decreased the efficiency of DNA replication. As a result, single-strand DNA was exposed in the nucleus, p53 was activated, and cellular senescence was induced. In the tumor cells with p53 deficiency, apoptosis was induced as a result of abnormal sister chromatid separation.
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| Academic Significance and Societal Importance of the Research Achievements |
FTD/TPIは進行大腸癌・胃癌に対する抗がん剤として世界で広く治療に用いられている。本研究成果は、FTD/TPIの抗腫瘍効果を担うFTDの作用メカニズムの理解に必須の知見である。さらに、悪性度を増したヒト腫瘍で多く見られ、抗がん剤耐性に繋がるとされるp53欠損を持つがん細胞であってもFTDが抗腫瘍効果を発揮するという結果は、このメカニズムに基づく抗がん剤治療がp53変異に関わらず有効であることを示唆しており、今後の抗がん剤開発を考える上でも意義は大きい。
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Report
(4 results)
Research Products
(21 results)
