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Development of new BNCT sensitizer based on molecular chirality recognition of amino acid transporter LAT

Research Project

Project/Area Number 21K19348
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionChiba University

Principal Investigator

ANZAI Naohiko  千葉大学, 大学院医学研究院, 教授 (70276054)

Co-Investigator(Kenkyū-buntansha) 根本 哲宏  千葉大学, 大学院薬学研究院, 教授 (80361450)
松川 岳久  順天堂大学, 医学部, 准教授 (60453586)
Project Period (FY) 2021-07-09 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Keywordsトランスポーター / 分子キラリティ / 分子標的創薬
Outline of Research at the Start

ホウ素中性子捕捉療法(Boron Neutron Capture Therapy,BNCT)は原子炉からの中性子と、組織に取り込まれた中性子との反応が大きい元素であるホウ素との核反応により発生する粒子放射線により、選択的に細胞を殺すという原理に基づく放射線療法で、陽子線、重粒子線などの一般放射線治療では出来ないがん細胞と正常細胞の区別が可能な「正常細胞に非常に優しいがん治療法」である。今回ホウ素化フェニルアラニンBPAの2つの鏡像異性体L体とD体という「分子キラリティ」認識が悪性腫瘍の薬物治療に有効な「選択毒性」に繋がることを着想し、トランスポーターを標的とする新規BNCT増感薬開発を行う。

Outline of Final Research Achievements

This study was based on the idea that chirality recognition of the two enantiomers of boronated phenylalanine could lead to selective toxicity effective against malignant tumors, and aimed to develop a new BNCT sensitizer that targets the transporter. Regarding the in vitro uptake evaluation of asymmetric compounds in human LAT1-expressing tumor-derived cells, we established an intracellular boron measurement system using LAICP-MS and succeeded in identifying trace amounts of boron taken up into the cells. Regarding the increase in selectivity between tumor-type LAT1 and normal-type LAT2, we confirmed the inhibitory effects of the existing LAT1 inhibitor JPH203 and the LAT2 inhibitor KYT0284 in a stable expression experimental system, and reaffirmed the need for continued investigation.

Academic Significance and Societal Importance of the Research Achievements

陽子線、重粒子線などの一般放射線治療では出来ないがん細胞と正常細胞の区別が可能な「正常細胞に非常に優しいがん治療法」であるBNCTは我が国において病院設置型小型加速器が開発されたことにより世界で最初に国内医療機関での普及が大きく見込まれている。この適応拡大のためには腫瘍選択性が高いより有効な新規ホウ素化合物合成は不可欠であり、本研究が今後の創薬開発のための重要な基盤情報となるものと思われる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (13 results)

All 2024 2023 2022 2021

All Journal Article (12 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 9 results) Presentation (1 results)

  • [Journal Article] The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism2024

    • Author(s)
      Saito S, Ando K, Sakamoto S, Xu M, Yamada Y, Rii J, Kanaoka S, Wei J, Zhao X, Pae S, Kanesaka M, Goto Y, Sazuka T, Imamura Y, Reien Y, Hamaguchi-Suzuki N, Saito S, Hirayama Y, Hashimoto H, Kanai Y, Ichikawa T, Anzai N.
    • Journal Title

      Cancer Science

      Volume: 115 Issue: 7 Pages: 2461

    • DOI

      10.1111/cas.16191

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Preconditioning-Induced Facilitation of Lactate Release from Astrocytes Is Essential for Brain Ischemic Tolerance2024

    • Author(s)
      Hirayama Yuri、Le Ha Pham Ngoc、Hashimoto Hirofumi、Ishii Itsuko、Koizumi Schuichi、Anzai Naohiko
    • Journal Title

      eneuro

      Volume: 11 Issue: 4 Pages: ENEURO.0494-23.2024

    • DOI

      10.1523/eneuro.0494-23.2024

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules2024

    • Author(s)
      Hamaguchi-Suzuki Norie、Adachi Naruhiko、Moriya Toshio、Yasuda Satoshi、Kawasaki Masato、Suzuki Kano、Ogasawara Satoshi、Anzai Naohiko、Senda Toshiya、Murata Takeshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 709 Pages: 149855-149855

    • DOI

      10.1016/j.bbrc.2024.149855

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Copy Number Gain in Androgen Receptors Predicts the Poor Prognosis in Japanese Castration-resistant Prostate Cancer2024

    • Author(s)
      SAKAMOTO SHINICHI、ANDO KEISUKE、PAE SANGJON、ZHAO XUE、SAKAI KAZUKO、SATO KODAI、SAITO SHINPEI、YAMADA YASUTAKA、RII JUNRYO、GOTO YUSUKE、SAZUKA TOMOKAZU、IMAMURA YUSUKE、ANZAI NAOHIKO、AKAKURA KOICHIRO、NISHIO KAZUTO、ICHIKAWA TOMOHIKO
    • Journal Title

      Anticancer Research

      Volume: 44 Issue: 2 Pages: 639

    • DOI

      10.21873/anticanres.16853

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity2024

    • Author(s)
      Rii Junryo、Sakamoto Shinichi、Mizokami Atsushi、Xu Minhui、Fujimoto Ayumi、Saito Shinpei、Koike Hidekazu、Tamura Takaaki、Arai Takayuki、Yamada Yasutaka、Goto Yusuke、Sazuka Tomokazu、Imamura Yusuke、Suzuki Kazuhiro、Kanai Yoshikatsu、Anzai Naohiko、Ichikawa Tomohiko
    • Journal Title

      Cancer Science

      Volume: 115 Issue: 3 Pages: 937

    • DOI

      10.1111/cas.16062

    • URL

      https://pure.teikyo.jp/en/publications/afc88fc7-9d3e-4443-bf93-29ebd7a47134

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interaction of buspirone and its major metabolites with human organic cation transporters2023

    • Author(s)
      Jinakote Metee、Jutabha Promsuk、Anzai Naohiko、Ontawong Atcharaporn、Soodvilai Sunhapas、Inchai Jakkapong、Vaddhanaphuti Chutima S.
    • Journal Title

      Fundamental & Clinical Pharmacology

      Volume: 37 Issue: 4 Pages: 833-842

    • DOI

      10.1111/fcp.12883

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Targeting L-type amino acid transporter 1 in urological malignancy: Current status and future perspective2022

    • Author(s)
      Pae Sangjon、Sakamoto Shinichi、Zhao Xue、Saito Shinpei、Tamura Takaaki、Imamura Yusuke、Sazuka Tomokazu、Reien Yoshie、Hirayama Yuri、Hashimoto Hirofumi、Kanai Yoshikatsu、Ichikawa Tomohiko、Anzai Naohiko
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 150 Issue: 4 Pages: 251-258

    • DOI

      10.1016/j.jphs.2022.10.002

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of a novel hepatitis B anti-viral drug E-CFCP in renal organic acid transporters2022

    • Author(s)
      Ishibane Misaki、Hashimoto Hirofumi、Kaneko Meika、Saito Shota、Pae Sangjon、Saito Shinpei、Reien Yoshie、Hirayama Yuri、Higashi-Kuwata Nobuyo、Mitsuya Hiroaki、Anzai Naohiko
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 150 Issue: 4 Pages: 201-203

    • DOI

      10.1016/j.jphs.2022.09.002

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] LAT1-specific inhibitor ameliorates severe autoimmune arthritis in SKG mouse2022

    • Author(s)
      Owada Takayoshi、Kurasawa Kazuhiro、Endou Hitoshi、Fujita Tomoe、Anzai Naohiko、Hayashi Keitaro
    • Journal Title

      International Immunopharmacology

      Volume: 109 Pages: 108817-108817

    • DOI

      10.1016/j.intimp.2022.108817

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways2022

    • Author(s)
      Zhao Xue、Sakamoto Shinichi、Maimaiti Maihulan、Anzai Naohiko、Ichikawa Tomohiko
    • Journal Title

      Cancers

      Volume: 14 Issue: 1 Pages: 229-229

    • DOI

      10.3390/cancers14010229

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] L-type amino acid transporter 1 as a target for inflammatory disease and cancer immunotherapy2022

    • Author(s)
      Hayashi K, Anzai N.
    • Journal Title

      J Pharmacol Sci

      Volume: 148 Issue: 1 Pages: 31-40

    • DOI

      10.1016/j.jphs.2021.09.006

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Significance of <sup>18</sup>F-fluorodeoxyglucose and Glucose Transporter 1 mRNA in Clear Cell Renal Cell Carcinoma2021

    • Author(s)
      BETSUNOH HIRONORI、SAKAMOTO SETSU、KAJI YASUSHI、NUKUI AKINORI、KOBAYASHI MINORU、YASHI MASAHIRO、HAYASHI KEITARO、ANZAI NAOHIKO、KAMAI TAKAO
    • Journal Title

      Anticancer Research

      Volume: 41 Issue: 10 Pages: 5179-5188

    • DOI

      10.21873/anticanres.15336

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] 去勢抵抗性前立腺癌におけるアミノ酸トランスポーターLAT1選択的阻害薬JPH203を用いた抗腫瘍効果の検討2023

    • Author(s)
      齋藤心平、坂本信一、安藤敬佑、裵祥存、齊藤将太、霊園良恵、平山友里、橋本弘史、Xu Minhui、 金井好克、市川智彦、安西尚彦
    • Organizer
      第7回黒潮カンファレンス
    • Related Report
      2023 Annual Research Report

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Published: 2021-07-13   Modified: 2025-01-30  

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