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2018 Fiscal Year Final Research Report

Development of colon cancer stem cell target therapy by inhibiting autolysosome activity

Research Project

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Project/Area Number 17K16541
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Digestive surgery
Research InstitutionOsaka University

Principal Investigator

Takeda Mitsunobu  大阪大学, 医学部附属病院, 医員 (90768962)

Research Collaborator Haraguchi Naotsugu  
Takahashi Hidekazu  
Miyoshi Norikatsu  
Hata Taishi  
Matsuda Chu  
Mizushima Tsunekazu  
Yamamoto Hirofumi  
Doki Yuichiro  
Mori Masaki  
Project Period (FY) 2017-04-01 – 2019-03-31
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
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.

Free Research Field

大腸癌幹細胞

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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Published: 2020-03-30  

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