Sugimoto, Yoshikazu

写真a

Affiliation

Faculty of Pharmacy (Mita)

Position

Professor Emeritus

External Links
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Academic Background 【 Display / hide 】

  • 1980.03

    The University of Tokyo, Faculty of Pharmaceutical Science, 薬学科

    University, Graduated

  • 1985.03

    The University of Tokyo, Graduate School of Pharmaceutical Sciences, 生命薬学専攻

    Graduate School, Completed, Doctoral course

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Research Areas 【 Display / hide 】

  • Life Science / Clinical pharmacy (Clinical Pharmaceutical Science)

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Research Keywords 【 Display / hide 】

  • ABC transporter

  • molecular targer therapy

  • anticancer drug resistance

  • gene therapy

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Books 【 Display / hide 】

  • がん化学療法・分子標的治療update.

    杉本芳一., 中外医学社, 東京, 2009.10

    Scope: 59-63

  • がん薬物療法学.

    杉本芳一., 大阪/日本臨床社, 2009.01

    Scope: 349-355

  • がんの分子標的治療.

    '野口耕司, 杉本芳一.', 東京/南山堂, 2008.09

    Scope: 278-290

  • 薬剤師生涯研修ガイド.

    杉本芳一., 東京/学校法人医学アカデミー出版部, 2008.05

    Scope: 223-224

  • 薬学の未来を拓く.

    杉本芳一., 東京/慶應義塾, 2008.04

    Scope: 72-81

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Papers 【 Display / hide 】

  • Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation

    Takahashi M., Okamoto Y., Kato Y., Shirahama H., Tsukahara S., Sugimoto Y., Tomida A.

    Heliyon (Heliyon)  9 ( 4 )  2023.04

    ISSN  24058440

    　View Summary

    Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.

  • Kaposi's sarcoma–associated herpesvirus replication and transcription activator protein activates CD274/PD-L1 gene promoter

    Miyazawa M., Yamamoto Y., Katayama K., Sugimoto Y., Noguchi K.

    Cancer Science (Cancer Science)  114 ( 4 ) 1718 - 1728 2023.04

    ISSN  13479032

    　View Summary

    Kaposi's sarcoma–associated herpesvirus (KSHV) is responsible for the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. The expression of immunosuppressive genes, such as IL-10 and CD274/PD-L1 is observed during KSHV-associated pathogenesis, and the modulation of the host immune system by KSHV contributes to establishing viral persistence in the host. Understanding the mechanism that allows the virus to evade host cell immunity would be helpful in order to develop therapeutic strategies for KSHV malignancy. In this study, we show that KSHV replication and transcriptional activator (K-RTA), an essential activator of the viral lytic cycle, transactivates the CD274/PD-L1 gene promoter. Mechanistically, we demonstrate that the binding of K-RTA to the cellular specificity protein 1 (SP1) is critical for K-RTA–mediated CD274/PD-L1 promoter activation. These findings suggest that K-RTA cooperates with intracellular SP1 to activate the expression of CD274/PD-L1, which helps the virus regulate immune checkpoints to escape and survive.

  • Inhibitory Effect of Dextran Derivatives on Multidrug Resistance-Related Efflux Transporters in Vitro

    Morimoto K., Ishii M., Sugimoto Y., Ogihara T., Tomita M.

    Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin)  45 ( 8 ) 1036 - 1042 2022.08

    ISSN  09186158

    　View Summary

    Dextran is a promising candidate as a nanocarrier of chemotherapeutic drugs due to its biocompatibility, biodegradability, and ability to accumulate in tumors. Furthermore, dextran derivatives interact with P-glycoprotein (P-gp), so we hypothesized that they may be available as tumor-specific drug delivery systems with the ability to reverse multidrug resistance. Here, to test this idea, we investigated whether dextran and its derivatives inhibit breast cancer resistance protein (BCRP), multidrug resistance associated protein 1 (MRP1), and P-gp in vitro. First, we examined their effect on the uptake of specific fluorescent substrates by inside-out Sf-9 membrane vesicles overexpressing BCRP, MRP1, and P-gp. BCRP and MRP1 were significantly inhibited by 2-hydroxypropyl-trimethylammonium-dextran of 4 and 70kDa (Q-D4 and Q-D70) at a concentration near the clinically used concentration of dextran; however, P-gp was not inhibited. A structure–activity study showed that Q-D4, Q-D70, and 40kDa diethylaminoethyl-dextran (DEAE-D40) significantly inhibited BCRP, while 4, 40, and 70kDa dextrans (D4, D40, and D70), dextran sulfate (Sul-D40), and the individual saccharide components of dextran did not. These results suggest that the cationic side chains, but not the saccharides, are important for BCRP inhibition. Finally, cell-based efflux assay was conducted. Q-D4, Q-D70, and DEAE-D40 did not specifically increase the retention of Hoechst33342 in BCRP-overexpressing KB cells. Similarly, Q-D4 and Q-D70 did not affect the intracellular retention of specific fluorescent substrates in MRP1- and P-gp-overexpressing KB cells. The ineffectiveness in cellular systems is presumably due to inability of the dextran derivatives to access transporters located on the cytoplasmic side of the cell membrane.

  • Transcriptomics, molecular docking, and cross-resistance profiling of nobiletin in cancer cells and synergistic interaction with doxorubicin upon SOX5 transfection

    Adham A.N., Abdelfatah S., Naqishbandi A., Sugimoto Y., Fleischer E., Efferth T.

    Phytomedicine (Phytomedicine)  100 2022.06

    ISSN  09447113

    　View Summary

    Background: Nobiletin is a polymethoxylated flavone from citrus fruit peels. Among other bioactivities, it acts antioxidative, anti-inflammatory, neuroprotective, and cardiovascular-protective. Nobiletin exerts profound anticancer activity in vitro and in vivo but the underlying mechanisms are not well understood. Purpose: The aim was to unravel the multiple modes of action against cancer cells by bioinformatic and transcriptomic techniques and their verification by molecular pharmacological methods. Methods: The in silico methods used were COMPARE analysis of transcriptomic data, signaling pathway analysis, transcription factor binding motif analysis in promoter sequences of target genes, and molecular docking. The in vitro methods used were resazurin assay, isobologram analysis, generation of stably SOX5-tranfected cells, and Western blotting. Results: Nobiletin was cytotoxic against a wide range of cell lines from different tumor types, including diverse phenotypes to established anticancer drugs (e.g., P-glycoprotein, ABCB5, p53, EGFR). Cross-resistance profiling with 83 standard anticancer drugs revealed a correlation to antihormonal anticancer drugs, which can be explained by the phytoestrogenic features of nobiletin. Transcriptomic analysis showed that the responsiveness of tumor cells was predictable by their specific mRNA expression profile. Nobiletin bound to the transcription factor SOX5 in silico. SOX5 conferred resistance to the control drug doxorubicin but collateral sensitivity to nobiletin in HEK293 cells transfected with a lentiviral GFP-tagged pLOC–ORF-SOX5 vector. The combination of nobiletin and doxorubicin synergistically killed HEK293-SOX5 cells in isobologram analyses, implying attractive new treatment options. Conclusion: Nobiletin represents an interesting candidate for cancer therapy with broad-spectrum activity and multiple modes of action. The identification of novel targets (i.e., SOX5) may allow its use for targeted tumor therapy in individualized treatment protocols.

  • Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML.

    Yamatani K, Ai T, Saito K, Suzuki K, Hori A, Kinjo S, Ikeo K, Ruvolo V, Zhang W, Mak PY, Kaczkowski B, Harada H, Katayama K, Sugimoto Y, Myslinski J, Hato T, Miida T, Konopleva M, Hayashizaki Y, Carter BZ, Tabe T, Andreeff M.

    Translational Oncology (Translational Oncology)  18   101354 2022.01

    Research paper (scientific journal), Joint Work, Accepted

    　View Summary

    Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics.

    Noguchi K, Katayama K, Sugimoto Y*.

    Pharmacogenomics and Personalized Medicine (Dove medical Press)  7   53-64 2014.02

    Article, review, commentary, editorial, etc. (scientific journal), Joint Work

  • トランスポーターの遺伝子多型.

    杉本芳一.

    がん分子標的治療 (メディカルレビュー社)  9(3)   29-35 2011.07

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

  • 分子標的薬.

    杉本芳一.

    薬局 (南山堂)  61(2)   11 2010.02

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

  • 抗悪性腫瘍薬の薬理学・薬力学・薬理遺伝学ー薬物相互作用.

    杉本芳一.

    日本臨床 (日本臨床社)  67, Suppl 1   349-355 2009.01

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

  • 抗癌剤開発における民族差について.

    杉本芳一.

    臨床評価 (/臨床評価刊行会)  33(2)   393-398 2006.04

    Article, review, commentary, editorial, etc. (scientific journal), Single Work

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Presentations 【 Display / hide 】

  • 上皮間葉転換に伴うglutathione peroxidase 4阻害剤感受性の変動機構の解明.

    加藤優, 近藤慎吾, 杉本芳一.

    第45回日本分子生物学会年会, 

    2022.11
    -
    2022.12
    , 

    Poster presentation

  • 多剤耐性関連輸送体の一括阻害効果を兼備したがん特異的Drug Delivery System開発の試み.

    森本かおり, 石井敬, 杉本芳一, 荻原琢男, 富田幹雄.

    日本薬物動態学会第37回年会, 

    2022.11
    , 

    Poster presentation

  • SYDE1はSW620細胞のP-gp発現を上昇させる.

    武田卓, 近藤慎吾, 片山和浩, 加藤優, 杉本芳一.

    第81回日本癌学会学術総会, 

    2022.09
    -
    2022.10
    , 

    Poster presentation

  • 肺がん細胞におけるPI3K-mTOR経路によるATF4発現制御機構の解析.

    髙橋瑞希, 加藤優, 岡本有加, 杉本芳一, 冨田章弘.

    第81回日本癌学会学術総会, 

    2022.09
    -
    2022.10
    , 

    Poster presentation

  • 脱アセチル化酵素によるKSHV由来の転写調節因子RTA/ORF50の制御とそのリジン残基の関与.

    野口耕司, 杉本芳一.

    第81回日本癌学会学術総会, 

    2022.09
    -
    2022.10
    , 

    Poster presentation

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

  • 複数のがん分子標的治療薬の効果を左右する薬剤耐性・感受性規定因子の統合的研究

    2021.04
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • Analysis of the resistance mechanisms to molecular-targeting anticancer agents

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • Identification of factors regulating the capacity for both self-renewal and pluripotent differentiation of cancer stem cells and application to cancer treatment.

    2015.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Challenging Exploratory Research, Principal investigator

    　View Summary

    SP(+) cells have a property of Hoechst 33342 exclusion and are considered as stem-like cells. SP(+) cells isolated from human colorectal cancer 116/slug-25 cells showed higher expression of drug efflux transporter ABCG2 and histone acetyl transferase HAT1, and lower expression of histone methyltransferase EZH2 than SP(-) cells. Treatment of 116/slug-25 cells with inhibitors of histone acetyltransferases and methyltransferases diminished SP(+) cells. Genes regulating this SP(+) phenotype have been identified from a screening with shRNA library.

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Courses Taught 【 Display / hide 】

  • DOCTORAL LECTURE ON BIOLOGICAL PHARMACY 2

    2025

  • ADVANCED MOLECULAR BIOLOGY OF DISEASE

    2025

  • DOCTORAL LECTURE ON BIOLOGICAL PHARMACY 2

    2024

  • CLINICAL PHARMACOLOGY

    2024

  • ADVANCED MOLECULAR BIOLOGY OF DISEASE

    2024

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