Development of colorectal cancer stem cell targeted therapy targeting autophagy and lysosomal dysfunction
Project/Area Number |
16K08621
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Pathological medical chemistry
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Research Institution | Osaka University |
Principal Investigator |
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
Keywords | 大腸癌 / 癌幹細胞 / リソソーム / ドラッグリポジショニング / 癌肝細胞 / がん幹細胞 / ドラッグ・リポジショニング / オートファジー / リプロファイリング / 擬似生体モデル |
Outline of Final Research Achievements |
Endo-lysosomal activity was enhanced in the colorectal cancer stem cell (CSC) population, and sphere formation ability from single cells, tumorigenicity and anticancer drug resistance were highly retained. Chemical screening was performed to identify mefloquine as a endo-lysosome maturation inhibitor. Treatment of colorectal cancer cells with mefloquine efficiently eliminated CSC population. Mefloquine showed an synergistic antitumor effect with oxaliplatin and irinotecan, and that the tumor engrafted in mice almost completely disappeared by mefloquine treatment. Microarray analysis and protein binding analysis showed that mefloquine targets the lysosomal pathway regulator, RAB 5/7. Pathway analysis showed that mefloquine impair the mitochondrial metabolism and induce mitochondria induced cell apoptosis.
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Academic Significance and Societal Importance of the Research Achievements |
大腸癌幹細胞の維持機構にリソソーム活性が密接に関与しており、RAB 5/7を標的とすることでリソソーム活性を特徴的に阻害する化合物であるメフロキンを同定した。抗マラリア薬メフロキンの大腸癌へのリポジショニングは、リソソーム経路を阻害することで癌幹細胞を治療標的とする従来にない薬理作用により、癌幹細胞ヒエラルキーを包括的に標的とする革新的な治療法になると期待される。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells.2019
Author(s)
Takeda M, Koseki J, Takahashi H, Miyoshi N, Nishida N, Nishimura J, Hata T, Matsuda C, Mizushima T, Yamamoto H, Ishii H, Doki Y, Mori M, Haraguchi N.
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Journal Title
Cancer Research
Volume: 印刷中
Related Report
Peer Reviewed / Open Access
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