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
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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

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Research Areas 【 Display / hide 】

  • Medical 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 】

  • Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses

    Mahmoud N., Saeed M.E.M., Sugimoto Y., Klinger A., Fleischer E., Efferth T.

    Phytomedicine （Phytomedicine)  77 2020.10

    ISSN  09447113

    　View Summary

    © 2020 Elsevier GmbH Background: Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known. Purpose: We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA. Study design: Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells. Methods: The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting. Results: Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis. Conclusion: CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.

  • Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells

    Takahashi C., Kondo S., Sadaoka K., Ishizuka S., Noguchi K., Kato Y., Sugimoto Y.

    Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications)  530 （ 1 ） 230 - 234 2020.09

    ISSN  0006291X

    　View Summary

    © 2020 Elsevier Inc. JQ1 disrupts the binding of bromodomain and extra-terminal (BET) family of proteins to acetylated histones, modulates the expression of various genes, and inhibits the proliferation of cancer cells. We established two JQ1-resistant sublines from human colorectal cancer HCT116 cells. These resistant cells showed an 8- to 9-fold higher resistance to JQ1, and a 2- to 4-fold higher resistance to various anti-cancer agents, such as doxorubicin, etoposide, mitoxantrone, SN-38, cisplatin, and methotrexate than the parental HCT116 cells. The JQ1-resistant cells expressed higher levels of TRAF2 and NCK-interacting protein kinase (TNIK), cyclin D1 (CCND1), cyclin E1 (CCNE1), and their corresponding mRNAs than the parental cells. TNIK is a regulator of Wnt/β-catenin signaling and is known to transactivate CCND1. Transient transfection of HCT116 cells with a TNIK expression plasmid resulted in the upregulation of cyclin D1, cyclin E1, and their corresponding mRNAs, as well as an increase in CCNE1 promoter activity. Furthermore, luciferase assay revealed that the JQ1-resistant cells showed high CCNE1 promoter activity. These results suggest that TNIK also transactivates CCNE1. Three stable TNIK transfectant clones of HEK293 cells expressed 1.5- to 2-fold higher levels of TNIK, cyclin D1, and cyclin E1 than the parental cells. The 293/TNIK-6 cells, which expressed the highest level of TNIK among the transfectants, showed a 2.3-fold higher resistance to JQ1 than the parental cells. These results suggest the possible involvement of TNIK in cellular resistance to JQ1.

  • pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2

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

    Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics)  35 （ 2 ） 220 - 227 2020.04

    ISSN  13474367

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    © 2019 The Japanese Society for the Study of Xenobiotics Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.

  • STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism

    Kondo S., Kato Y., Minagawa S., Sugimoto Y.

    Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications)  523 （ 3 ） 672 - 677 2020.03

    ISSN  0006291X

    　View Summary

    © 2020 Elsevier Inc. We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.

  • SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells

    Xu S.W., Law B.Y.K., Qu S.L.Q., Hamdoun S., Chen J., Zhang W., Guo J.R., Wu A.G., Mok S.W.F., Zhang D.W., Xia C., Sugimoto Y., Efferth T., Liu L., Wong V.K.W.

    Pharmacological Research （Pharmacological Research)  153 2020.03

    ISSN  10436618

    　View Summary

    © 2020 Elsevier Ltd Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.

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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

    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

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Presentations 【 Display / hide 】

  • SLUG導入HCT116細胞におけるxCTの発現上昇とフェロトーシス抵抗性

    加藤優, 近藤慎吾, 杉本芳一.

    第24回日本がん分子標的治療学会学術集会, 2020.10, Poster (general)

  • GZD824のGCN2-ATF4ストレス応答経路に対する阻害効果

    高橋瑞希, 加藤優, 國政和弘, 杉本芳一, 冨田章弘.

    第24回日本がん分子標的治療学会学術集会, 2020.10, Oral Presentation(general)

  • STAT１が関与する薬剤耐性とその克服

    近藤慎吾, 加藤優, 杉本芳一.

    第79回日本癌学会学術総会, 2020.10, Poster (general)

  • SLUG導入HCT116細胞におけるフェロトーシス感受性規定因子の解明

    加藤優, 近藤慎吾, 杉本芳一.

    第79回日本癌学会学術総会, 2020.10, Poster (general)

  • High and low affinity kinetics of OATP2B1 - Inhibitory potency and pH-dependency of inhibitors -.

    Sato R, Akiyoshi T, Imaoka A, Katayama K, Sugimoto Y, Ohtani H.

    日本薬物動態学会第34回年会, 2019.12, Poster (general)

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

  • 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.

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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

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