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

• Project/Area Number: 16K21387
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Otorhinolaryngology; Applied pharmacology
• Research Institution: Tokyo 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: ¥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。

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [Presentation] Amino Acid-Starbing Culture Condition Enhances Gefitinib-Induced Cytotoxicity via Necroptosis-like Cell Death in EGFR-Expressing Cancer Cells (2017)
  • Author(s): 齊藤 雄
  • Organizer: 第179回 東京医科大学医学会総会
• [Presentation] Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition (2016)
  • 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
• [Remarks] 分子標的探索センター
  • URL: http://www.tokyo-med.ac.jp/target/