2018 Fiscal Year Final Research Report
Establishment of novel "amino acid starvation induction therapy" using macrolide antibiotics for head and neck cancer
| Project/Area Number |
16K21387
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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 |
Otorhinolaryngology
Applied pharmacology
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Research Collaborator |
MIYAZAWA Keisuke 東京医科大学, 医学部, 主任教授 (50209897)
MORIYA Shota 東京医科大学, 医学部, 助教 (30634935)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 頭頸部癌 / マクロライド抗菌薬 / オートファジー / アミノ酸 / 小胞体ストレス / EGFR-TKI |
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| Outline of Final Research Achievements |
We have reported that macrolide antibiotics such as azithromycin (AZM) and clarithromycin (CAM) have an inhibitory effect of autophagy flux. We found that AZM and CAM exhibited the prominent cytotoxic effect in head and neck cancer cell lines under amino acid-depleted culture conditions, while they showed no cytotoxicity in complete culture medium. This cytotoxic effect was mediated through induction of pro-apoptotic transcription factor CHOP. Under amino acid-depleted condition, autophagy was pronouced for compensating intracellular amino acid pool. Thus, blocking autophagy with AZM and CAM resulted in CHOP-medicated apopotosis induction in cancer cells under starving condition.
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| Free Research Field |
頭頸部癌
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| Academic Significance and Societal Importance of the Research Achievements |
癌細胞は増殖が旺盛でアミノ酸の需要が高く、アミノ酸の取り込みやオートファジーの亢進によりその高い需要を満たしている。オートファジーは蛋白合成のためのアミノ酸プールを維持するのに重要で、特にアミノ酸飢餓状態では必須機構である。
近年、癌特異的アミノ酸トランスポーターの研究が進んでいる。トランスポーター阻害剤とマクロライド抗菌薬を併用し、高いアミノ酸需要を満たさせず細胞死を誘導する新規治療法の可能性が示唆された。
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