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Establishment of novel "amino acid starvation induction therapy" using macrolide antibiotics for head and neck cancer

Research Project

Project/Area Number 16K21387
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Otorhinolaryngology
Applied pharmacology
Research InstitutionTokyo Medical University

Principal Investigator

Hirasawa Kazuhiro  東京医科大学, 医学部, 助教 (90772161)

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)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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 / 頭頸部腫瘍 / アポトーシス / ネクロプトーシス / がん / マクロライド抗生剤 / 分子標的薬 / マクロライド系抗菌薬 / アミノ酸トランスポーター / EGFR TKI / 薬物治療学 / 分子標的治療
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.

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。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2018 2017 2016 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (5 results) Remarks (1 results)

  • [Journal Article] 嗄声を契機に発見された若年胸部大動脈瘤切迫破裂例2018

    • Author(s)
      平澤一浩, 高田大輔, 西山信宏, 塚原清彰
    • Journal Title

      耳鼻咽喉科臨床

      Volume: 111 Pages: 351-355

    • NAID

      130006729783

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis.2018

    • Author(s)
      Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
    • Journal Title

      Int J Oncol.

      Volume: 52 Pages: 1165-1177

    • DOI

      10.3892/ijo.2018.4282

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Macrolide antibiotics exhibit cytotoxiceffect under amino acid-depleted culture condition by blocking autophagy flux in head and neck squamous cell carcinoma cell lines.2016

    • Author(s)
      Hirasawa K, Moriya S, Miyahara K, Kazama H, Hirota A, Takemura J, Abe A, Inazu M, Hiramoto M, Tsukahara K, Miyazawa K.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 12 Pages: 1848-1858

    • DOI

      10.1371/journal.pone.0164529

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines.2016

    • Author(s)
      Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K,Moriya S, Abe A, Hiramoto M, Ishikawa T, Miyazawa K.
    • Journal Title

      Int J Oncol.

      Volume: 49 Issue: 5 Pages: 1848-1858

    • DOI

      10.3892/ijo.2016.3673

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] プロトンポンプ阻害薬とマクロライド系抗生剤との併用による殺細胞効果の増強2018

    • Author(s)
      武田淳雄
    • Organizer
      第182回 東京医科大学医学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 嗄声を契機に発見された若年胸部大動脈瘤切迫破裂例2018

    • Author(s)
      平澤一浩
    • Organizer
      第80回耳鼻咽喉科臨床学会・学術講演会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アミノ酸飢餓条件下におけるEGFR発現癌細胞に対するゲフィチニブのネクロプトーシス様細胞死を介した殺細胞増強効果2017

    • Author(s)
      齊藤 雄
    • Organizer
      第76回日本癌学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Amino Acid-Starbing Culture Condition Enhances Gefitinib-Induced Cytotoxicity via Necroptosis-like Cell Death in EGFR-Expressing Cancer Cells2017

    • Author(s)
      齊藤 雄
    • Organizer
      第179回 東京医科大学医学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition2016

    • Author(s)
      Kazuhiro Hirasawa、Shota Moriya、Kana Miyahara、Hiromi Kazama、Ayako Hirota、Jun Yoshida、Akihisa Abe、Masato Inazu、Masaki Hiramoto、Kiyoaki Tsukahara、Keisuke Miyazawa
    • Organizer
      日本癌学会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Remarks] 分子標的探索センター

    • URL

      http://www.tokyo-med.ac.jp/target/

    • Related Report
      2018 Annual Research Report 2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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