Sugimoto, Yoshikazu

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 化学療法学講座 (Shiba-Kyoritsu)

Position

Professor

Related Websites

External Links

Academic Background 【 Display / hide

  • 1980.03

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

    Japan, University, Graduated

  • 1985.03

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

    Japan, Graduate School, Completed, Doctoral course

 

Research Areas 【 Display / hide

  • Medical pharmacy (Clinical Pharmaceutical Science)

Research Keywords 【 Display / hide

  • ABC transporter

  • molecular targer therapy

  • anticancer drug resistance

  • gene therapy

 

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

display all >>

Papers 【 Display / hide

  • Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway

    Lu X., Yan G., Klauck S.M., Fleischer E., Klinger A., Sugimoto Y., Shan L., Efferth T.

    Biochemical Pharmacology (Biochemical Pharmacology)  193 2021.11

    ISSN  00062952

     View Summary

    After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G2M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.

  • 2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action

    Hegazy M.E.F., Dawood M., Mahmoud N., Elbadawi M., Sugimoto Y., Klauck S.M., Mohamed N., Efferth T.

    Phytomedicine (Phytomedicine)  81 2021.01

    ISSN  09447113

     View Summary

    Background: Sesquiterpene lactones having α-methylene-γ-lactone moiety are promising natural metabolites showing various biological activity. One of the major metabolites isolated from Pulicaria undulata, 2α-hydroxyalantolactone (PU-1), has not been investigated in detail yet. Multidrug resistance (MDR) represents a major obstacle for cancer chemotherapy and the capability of novel natural products to overcoming MDR is of great interest. Purpose: Exploring the molecular modes of action for potent natural product metabolites. Methods: The resazurin reduction assay was employed to evaluate the cytotoxicity of PU-1 on sensitive and their corresponding drug-resistant cell lines (overexpressing P-glycoprotein, BCRP, ABCB5, ΔEGFR, or TP53 knockout). Gene expression profiling was performed by transcriptome-wide mRNA microarray in the human CCRF-CEM leukemic cells after treatment with PU-1. The top significantly up- or down-regulated genes were identified by Chipster program and analyzed using Ingenuity Pathway Analysis (IPA) software. Finally, flow cytometry and Western blotting were performed for cell cycle analyses and apoptosis detection. Results: The sesquiterpene lactone, PU-1, showed potent cytotoxicity towards the drug-sensitive and -resistant cell lines. Transcriptome-wide mRNA expression profiling and pathway analysis pointed to genes involved in DNA damage response and G2/M cell cycle arrest. G2/M arrest was verified by flow cytometry and further confirmed by the upregulation of p21 and downregulation of p-CDC25C expression in Western blotting. Moreover, the suggested DNA damage checkpoint regulation was confirmed by immunofluorescence and Western blotting by upregulation of pS345 Chk1, p-H3 and γ-H2AX. Furthermore, PU-1 inhibited PI3K/AKT pathway, which is involved in signaling DNA damage and G2/M arrest. Cells ultimately induced apoptosis upon PU-1 treatment. Conclusions: PU-1 is a potent natural product inhibiting otherwise drug-resistant human tumor cell growth through DNA damage, G2/M cell cycle arrest and apoptosis.

  • A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells

    Lu X., Yan G., Dawood M., Klauck S.M., Sugimoto Y., Klinger A., Fleischer E., Shan L., Efferth T.

    Biochemical Pharmacology (Biochemical Pharmacology)   2021

    ISSN  00062952

     View Summary

    New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3‐(naphthalen‐2‐ylsulfanyl)‐4‐{[(2Z)‐1,3,3‐trimethyl‐2,3‐dihydro‐1H‐indol‐2‐ylidene]methyl}cyclobut‐3‐ene‐1,2‐dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G2/M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy.

  • Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides

    Morita T., Akiyoshi T., Sato R., Uekusa Y., Katayama K., Yajima K., Imaoka A., Sugimoto Y., Kiuchi F., Ohtani H.

    Journal of Agricultural and Food Chemistry (Journal of Agricultural and Food Chemistry)  68 ( 48 ) 14182 - 14191 2020.12

    ISSN  00218561

     View Summary

    Organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1 are expressed in the small intestine and are involved in drug absorption. We identified narirutin, which is present in grapefruit juice, as a novel OATP inhibitor. The citrus fruit jabara also contains high levels of narirutin; therefore, we investigated the inhibitory potency of jabara juice against OATPs. The inhibitory effects of various related compounds on the transport activity of OATPs were evaluated using OATP-expressing HEK293 cells. The IC50 values of narirutin for OATP1A2- and OATP2B1-mediated transport were 22.6 and 18.2 μM, respectively. Other flavanone derivatives from grapefruit juice also inhibited OATP1A2/OATP2B1-mediated transport (order of inhibitory potency: naringenin > narirutin > naringin). Five percent jabara juice significantly inhibited OATP1A2- and OATP2B1-mediated transport by 67 ± 11 and 81 ± 5.5%, respectively (p < 0.05). Based on their inhibitory potency and levels in grapefruit juice, the inhibition of OATPs by grapefruit juice is attributable to both naringin and narirutin. Citrus × jabara, which contains narirutin, potently inhibits OATP-mediated transport.

  • GZD824 inhibits GCN2 and sensitizes cancer cells to amino acid starvation stress

    Kato Y., Kunimasa K., Takahashi M., Harada A., Nagasawa I., Osawa M., Sugimoto Y., Tomida A.

    Molecular Pharmacology (Molecular Pharmacology)  98 ( 6 ) 669 - 676 2020.12

    ISSN  0026895X

     View Summary

    Eukaryotic initiation factor 2a (eIF2a) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells. Indeed, GZD824 suppressed GCN2 activation, eIF2a phosphorylation, and ATF4 induction during amino acid starvation stress. However, at lower nonsuppressive concentrations, GZD824 paradoxically stimulated eIF2a phosphorylation and ATF4 expression in a GCN2-dependent manner under unstressed conditions. Such dual properties conceivably arose from a direct effect on GCN2, as also observed in a cell-free GCN2 kinase assay and shared by a selective GCN2 inhibitor. Consistent with the GCN2 pathway inhibition, GZD824 sensitized certain cancer cells to amino acid starvation stress similarly to ATF4 knockdown. These results establish GZD824 as a multikinase GCN2 inhibitor and may enhance its utility as a drug under development.

display all >>

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

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

    Introduction and explanation (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

    Introduction and explanation (scientific journal), Single Work

  • 分子標的薬.

    杉本芳一.

    薬局 (南山堂)  61(2)   11 2010.02

    Introduction and explanation (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

    Introduction and explanation (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

    Introduction and explanation (scientific journal), Single Work

display all >>

Presentations 【 Display / hide

  • カチオニック修飾はdextranにBCRP阻害効果を付与する

    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36回年会, 2021.11, Poster (general)

  • WEE1阻害薬耐性細胞におけるAKTの活性化

    奥田賢, 近藤慎吾, 加藤優, 杉本芳一.

    第65回日本薬学会関東支部大会, 2021.09, Oral Presentation(general)

  • Side population細胞に対するepigenetic阻害薬の効果

    春名俊志, 加藤優, 近藤慎吾, 杉本芳一.

    第65回日本薬学会関東支部大会, 2021.09, Oral Presentation(general)

  • エピジェネティック阻害剤によるSP細胞形質の抑制

    加藤優, 近藤慎吾, 杉本芳一.

    第25回日本がん分子標的治療学会学術集会, 2021.05, Oral Presentation(general)

  • FLT3-ITDによるintegrated stress response の誘導

    佐々木大河, 加藤優, 片山和浩, 近藤慎吾, 杉本芳一

    日本薬学会第141回年会, 2021.03, Poster (general)

display all >>

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, 杉本 芳一, 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, 杉本 芳一, 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, 杉本 芳一, 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.

 

Courses Taught 【 Display / hide

  • STUDY OF MAJOR FIELD: (CHEMOTHERAPY)

    2021

  • SEMINAR: (CHEMOTHERAPY)

    2021

  • RESEARCH FOR BACHELOR'S THESIS 1

    2021

  • PHARMACEUTICAL-ENGLISH SEMINAR

    2021

  • PHARMACEUTICAL SCIENCES OF DISEASES

    2021

display all >>