Mashino, Tadahiko

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmaceutical Sciences 医薬品化学講座 (Shiba-Kyoritsu)

Position

Professor

E-mail Address

E-mail address

Career 【 Display / hide

  • 1983.10
    -
    1996.12

    Assistant professor, Tokyo University, Faculty of Pharmaceutical Sciense

  • 1997.01
    -
    2002.03

    Associate professor, Kyoritsu University of Pharmacy

  • 2002.04
    -
    2008.03

    Pprofessor, Kyoritsu University of Pharmacy

  • 2008.04
    -
    Present

    Keio University. Faculty of Pharmacy

Academic Background 【 Display / hide

  • 1979.03

    The University of Tokyo, Faculty of Pharmaceutical Science, Devision of Pharmaceutical Science

    University, Graduated

  • 1983.09

    The University of Tokyo, Graduate School, Division of Pharmaceutical Sciences, Division of Pharmaceutical Sciences

    Graduate School, Withdrawal before completion, Doctoral course

Academic Degrees 【 Display / hide

  • Ph.D, The University of Tokyo, Dissertation, 1985.07

 

Research Areas 【 Display / hide

  • Chemical pharmacy (Chemical Pharmaceutical Science)

  • Drug development chemistry (Drug Development Chemistry)

Research Keywords 【 Display / hide

  • Cytochrome P450

  • Fullerene Derivatives

  • Antioxidant

  • Drug Metabolism

Research Themes 【 Display / hide

  • 抗酸化物質の開発, 

    1999.01
    -
    Present

  • 医薬品を目指したフラーレン誘導体の合成と評価, 

    1997.04
    -
    Present

  • 2. 薬物・環境物質の新規代謝物検索とその生理活性の検討, 

    1995.04
    -
    Present

 

Books 【 Display / hide

  • フラーレン誘導体・内包技術の最前線.

    Ohe T, Mashino T., シーエムシー出版, 東京, 2014.04

    Scope: 237-247

  • Fullerene Nanowhiskers. Preparation and characterization of fullerene derivatives and their nanowhiskers.

    Nakamura S, Miyazawa K, Mashino T., Pan Stanford Publishing, Singapore, 2011.09

    Scope: 53-62

  • 各ナノ粒子・微粒子の毒性評価・安全性試験の動向 フラーレン.

    増野匡彦, 中村成夫., 東京/技術情報協会, 2007.10

    Scope: 383-396

  • ナノカーボンハンドブック(遠藤守信,飯島澄男監修) フラーレンの抗菌薬、抗ウイルス薬等医薬への応用.

    中村成夫, 増野匡彦, 他180名., 東京/エヌ・ティー・エス, 2007.07

    Scope: 668-673

  • フラーレンの医薬への応用.

    増野匡彦., /医学書院, 2006.12

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Papers 【 Display / hide

  • N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties

    Uchihara Y., Ohe T., Mashino T., Kidokoro T., Tago K., Tamura H., Funakoshi-Tago M.

    Pharmacological Reports (Pharmacological Reports)  71 ( 6 ) 1067 - 1078 2019.12

    ISSN  17341140

     View Summary

    © 2019 Institute of Pharmacology, Polish Academy of Sciences Background: Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102. Methods: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC–MS. Results: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC–MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3. Conclusions: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.

  • Synthesis and antitumor activity of novel pyridinium fullerene derivatives

    Yasuno T., Ohe T., Ikeda H., Takahashi K., Nakamura S., Mashino T.

    International Journal of Nanomedicine (International Journal of Nanomedicine)  14   6325 - 6337 2019

    ISSN  11769114

     View Summary

    © 2019 Yasuno et al. Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.

  • Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

    Tomoyuki Ohe, Ryutaro Umezawa, Yumina Kitagawara, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Akiko Abe, Shuichi Sekine, Kousei Ito, Kentaro Okunushi, Hanae Morio, Tomomi Furihata, Naohiko Anzai, and Tadahiko Mashino*

    Bioorg Med Chem Lett 28   3708 - 3711 2018.12

    Research paper (scientific journal), Joint Work, Accepted

  • A 5-hydroxyoxindole derivative attenuates LPS-induced inflammatory responses by activating the p38-Nrf2 signaling axis

    Niino Tomomi, Tago Kenji, Yasuda Daisuke, Takahashi Kyoko, Mashino Tadahiko, Tamura Hiroomi, Funakoshi-Tago Megumi

    Biochemical Pharmacology 155   182 - 197 2018.09

    Research paper (scientific journal), Joint Work, Accepted

  • A major component of vitamin E, α-tocopherol inhibits the anti-tumor activity of crizotinib against cells transformed by EML4-ALK

    Uchihara Y., Kidokoro T., Tago K., Mashino T., Tamura H., Funakoshi-Tago M.

    European Journal of Pharmacology (European Journal of Pharmacology)  825   1 - 9 2018.04

    ISSN  00142999

     View Summary

    © 2018 Elsevier B.V. Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and is of significant therapeutic benefit to patients with non-small cell lung cancer (NSCLC) harboring the EML4-ALK fusion gene. In the present study, we demonstrated that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. α-Tocopherol significantly inhibited crizotinib-induced apoptosis in cells transformed by EML4-ALK. It also effectively attenuated the crizotinib-induced inhibition of EML4-ALK and its downstream molecules, STAT3 and ERK, and suppressed the inhibitory effects of crizotinib on EML4-ALK-mediated transformation in the focus formation assay. On the other hand, other members of the vitamin E family, namely, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, and a water-soluble analog of vitamin E, Trolox had no effects on the anti-tumor activity of crizotinib in cells transformed by EML4-ALK. Collectively, these results revealed the risk of the anti-tumor activity of crizotinib being attenuated when it is administrated in combination with vitamin E supplements containing α-tocopherol as a major component.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • アカデミアにおける Hit-to-Lead の実践 ~Keap1-Nrf2 タンパク間相互作用阻害剤の創製~

    安田大輔,小畠りか,高橋恭子,大江知之,増野匡彦

    薬学雑誌 138 ( 8 ) 1059 - 1065 2018.08

    Introduction and explanation (scientific journal), Joint Work

  • ヒトや野生生物における医薬品、環境化学物質の安全性評価の精度向上にむけて -代謝的活性化、種差、エピジェネティクスの観点から 肝毒性を示す医薬品の代謝活性化機構の解析とそれに基づいた創薬戦略

    大江知之, 高橋恭子, 中村成夫, 増野匡彦

    薬学雑誌 137 ( 3 ) 249 - 255 2017.03

    Introduction and explanation (scientific journal), Joint Work

Presentations 【 Display / hide

  • グルクロン酸抱合経由の代謝活性化を回避する新規ジクロフェナク類縁体の合成と評価

    立石泰寛 、大江知之 、安田大輔 、高橋恭子 、中村成夫 、増野匡彦

    日本薬物動態学会第34回年会 (つくば) , 2019.12, Oral Presentation(general)

  • 新規反応性代謝物検出法の開発ーシステインを基盤とした蛍光標識トラッピング剤の創製とその捕捉能評価ー

    柴崎智香子、髙橋恭子、中村成夫、大江知之、増野匡彦

    第37回メディシナルケミストリーシンポジウム (八王子) , 2019.11, Poster (general)

  • HIV プロテアーゼ阻害活性を有するプロリン型フラーレン誘導体の立体選択的合成

    片岸大紀、高橋恭子、中村成夫、大江知之、増野匡彦

    第63回日本薬学会関東支部大会 (東京), 2019.09, Oral Presentation(general)

  • リモナバンの代謝活性化を回避する構造変換

    除川貴太 、高橋恭子 、中村成夫 、大江知之 、増野匡彦

    第63回日本薬学会関東支部大会 (東京), 2019.09, Oral Presentation(general)

  • 2018年度薬学共用試験報告

    石川さと子、伊藤智夫、中村明弘、増野匡彦、石塚忠男、橋詰 勉、松野純男、前田定秋、小澤孝一郎、出口芳春、三田智文、野田幸裕、岡村昇、田村豊、飯島史朗、宮崎智、矢ノ下良平、奥直人

    日本医学教育学会大会, 2019.07, Oral Presentation(general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 成功確率の高いリード創出を支援する高機能ADMET評価基盤の構築

    2017.04
    -
    2022.03

    日本医療研究開発機構, 創薬等ライフサイエンス研究支援基盤事業, 増野匡彦, Research grant, Principal Investigator

  • 神経細胞死保護作用を有するテトラロン型新規パーキンソン病治療薬の創製

    2017.04
    -
    2019.03

    日本医療研究開発機構, 橋渡し研究戦略的推進プログラム シーズ A, 増野 匡彦, Research grant, Principal Investigator

Intellectual Property Rights, etc. 【 Display / hide

  • パーキンソン病治療薬

    Application No.: 特願2019-014281  2019.01 

    Patent, Joint, National application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: PCT/JP2014/053950  2014.02 

    Announcement No.: WO2014/129513  2014.08 

    Patent, Joint, PCT international application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: 特願2013-030455  2013.02 

    Patent, Joint, National application

  • Anti-Hepatitis C Virus Agents and Anti-HIV Agents.

    Application No.: 444404719087.1  2004.03 

    Registration No.: 1607091  2009.05

    Patent, Joint, PCT international application

  • フラーレンウィスカー及びフラーレンウィスカーの製造方法

    Application No.: 2003-110087  2003.04 

    Registration No.: 4322540  2009.06

    Patent, Joint, National application

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Courses Taught 【 Display / hide

  • ADVANCED MEDICINAL AND ORGANIC CHEMISTRY

    2020

  • BACHELOR'S THESIS

    2020

  • STUDY OF MAJOR FIELD: (BIOORGANIC AND MEDICINAL CHEMISTRY)

    2020

  • SEMINAR: (BIOORGANIC AND MEDICINAL CHEMISTRY)

    2020

  • RESEARCH FOR BACHELOR'S THESIS 1

    2020

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Courses Previously Taught 【 Display / hide

  • INTRODUCTION TO MEDICINAL CHEMISTRY

    Keio University, 2015, Spring Semester, Major subject, Lecture, Within own faculty, 1h, 220people

  • ORGANIC CHEMISTRY LABORATORY COURSE

    Keio University, 2015, Autumn Semester, Major subject, Laboratory work/practical work/exercise, Lecturer outside of Keio, 220people

  • ADVANCED ORGANIC CHEMISTRY LABORATORY COURSE

    Keio University, 2015, Autumn Semester, Major subject, Laboratory work/practical work/exercise, Lecturer outside of Keio, 65people

  • BIOORGANIC AND BIOINORGANIC CHEMISTRY A

    Keio University, 2015, Autumn Semester, Major subject, Lecture, Within own faculty, 1h, 220people

  • ANALYSIS OF REACTION MECHANISMS

    Keio University, 2015, Spring Semester, Lecture, Within own faculty, 1h, 40people

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Educational Activities and Special Notes 【 Display / hide

  • 薬学教育の改善・充実に関する調査研究委員会

    2015.12
    -
    Present

    , Special Affairs

  • 薬学教育モデル・コアカリキュラム改訂案に関する全国説明会

    2013.09
    -
    Present

    , Lecture at Education Method and Practice

  • 薬学生のための実習実験安全ガイド

    2012.12

    , Development of Textbook and Teaching Material

  • 薬学教育モデル・コアカリキュラム改訂に向けて

    2012.09
    -
    Present

    , Lecture at Education Method and Practice

  • 薬学共用試験センターCBT実施委員会委員長

    2011
    -
    Present

    , Special Affairs

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