| Project/Area Number |
17K16541
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Digestive surgery
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| Research Institution | Osaka University |
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Principal Investigator |
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| Research Collaborator |
Haraguchi Naotsugu
Takahashi Hidekazu
Miyoshi Norikatsu
Hata Taishi
Matsuda Chu
Mizushima Tsunekazu
Yamamoto Hirofumi
Doki Yuichiro
Mori Masaki
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 癌幹細胞 / リソソーム / オートファジー / 抗マラリア薬 / 大腸癌 / RAB5/7 / メフロキン / ドラックリポジショニング / 癌幹細胞標的化治療 / オートリソソーム / 新規標的化治療 / オートリソソーム活性 |
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| Outline of Final Research Achievements |
Cancer stem cells (CSCs) are deeply involved in resistance to treatment and are the most important target cells in cancer treatment. We focused on autophagy and lysosomal activity of CSCs and colon CSC targeting by drug repositioning.Autophagy and lysosome were labeled by LC3B imaging vector and Lysotracker respectively. Lysotracker+/CD44v9+ cells showed high sphere formation and tumorigenic activities. During the process of screening of antimalarial drugs, anti-lysosomal effect of mefloquine was identified. Mefloquine treatment significantly decreased CD44v9+/ CD133+ cell number. Mefloquine demonstrated the synergic effect on oxaliplatin. In the patient-derived xenografted (PDX) mice, combined treatment of mefloquine with oxaliplatin drastically abrogated the tumorigenic activity of cancer cells.
Repositioning of mefloquine to colon cancer will be a promising strategy for cure of colon cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
日本で使用可能な抗マラリア薬のメフロキンを大腸癌にリボジショニングすることにより、リソソーム経路を阻害することで癌幹細胞を治療標的にすることが可能になれば、抗癌剤に不応・不耐な難治性再発大腸癌においても根治を目指すことが出来る新規治療薬開発につながると考えられる。メフロキンは、抗癌剤と比べて重篤な副作用の発現がなく、イリノテカンやオキサリプラチンに相乗的に働き、K-ras変異に依存せずに高い抗腫瘍効果をもつ。メフロキンの大腸癌への臨床応用は、癌幹細胞を治療標的とする従来にない薬理作用をもつ革新的な治療法になりうる。
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