Koike, Naoyoshi

写真a

Affiliation

School of Medicine, Joint Research Laboratory for New BNCT treatment (Shinanomachi)

Position

Project Senior Assistant Professor (Non-tenured)/Project Assistant Professor (Non-tenured)/Project Lecturer (Non-tenured)

External Links

Career 【 Display / hide

  • 2005.04
    -
    2007.03

    静岡赤十字病院, 院研修医

  • 2007.04
    -
    2009.03

    慶應義塾大学病院, 放射線科, 専修医

  • 2009.04
    -
    2011.01

    川崎市立川崎病院, 放射線治療科, 医師

  • 2011.02
    -
    2011.03

    独立行政法人東京医療センター, 放射線科, レジデント

  • 2011.04
    -
    2012.03

    独立行政法人東京医療センター, 放射線科, 医員

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Academic Background 【 Display / hide

  • 1999.04
    -
    2005.03

    Keio University, 医学部

    University, Graduated

  • 2013.04
    -
    2017.03

    Keio University, 医学部

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Coursework, 2020.12

Licenses and Qualifications 【 Display / hide

  • 医師免許, 2005

  • 放射線治療専門医, 2011.09

  • がん治療認定医, 2013.04

 

Research Areas 【 Display / hide

  • Life Science / Radiological sciences

Research Keywords 【 Display / hide

  • Cance stem cells

  • hypoxia

  • Brain tumor

 

Papers 【 Display / hide

  • Mean heart dose-based normal tissue complication probability model for pericardial effusion: a study in oesophageal cancer patients

    Fukada J., Fukata K., Koike N., Kota R., Shigematsu N.

    Scientific Reports (Scientific Reports)  11 ( 1 ) 18166 2021.12

    ISSN  2045-2322

     View Summary

    We investigated the normal tissue complication probability (NTCP) of the incidence of pericardial effusion (PCE) based on the mean heart dose (MHD) in patients with oesophageal cancer treated with definitive chemoradiotherapy. The incidences of PCE in any grade (A-PCE) and symptomatic PCE (S-PCE) were evaluated separately. To identify predictors for PCE, several clinical and dose-volume parameters were analysed using a receiver operating characteristic (ROC) curve and multivariate regression analysis. To validate its clinical applicability, the generated NTCP model was compared to the Lyman–Kutcher–Burman (LKB) model. Among 229 eligible patients, A-PCE and S-PCE were observed in 100 (43.7%) and 18 (7.9%) patients, respectively. MHD showed a preferable area under the curve (AUC) value for S-PCE (AUC = 0.821) and A-PCE (AUC = 0.734). MHD was the only significant predictor for A-PCE; MHD and hypertension were selected as significant factors for S-PCE. The estimated NTCP, using the MHD-based model, showed excellent correspondence to the LKB model in A-PCE and S-PCE. The NTCP curve of A-PCE was gentler than that of S-PCE and had no threshold. The MHD-based NTCP model was simple but comparable to the LKB model for both A-PCE and S-PCE. Therefore, the estimated NTCP may provide clinically useful parameters for predicting PCE.

  • Thymoma-associated T-cell immunodeficiency after radiotherapy: A case report

    Nakagawara K., Chubachi S., Azekawa S., Otake S., Saito A., Okada M., Lee K., Masaki K., Koike N., Kamata H., Kawada I., Suzuki S., Ishii M., Fukunaga K.

    Respiratory Medicine Case Reports (Respiratory Medicine Case Reports)  33   101408 2021.01

    ISSN  2213-0071

     View Summary

    Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

  • 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche

    Koike N., Kota R., Naito Y., Hayakawa N., Matsuura T., Hishiki T., Onishi N., Fukada J., Suematsu M., Shigematsu N., Saya H., Sampetrean O.

    Communications Biology (Communications Biology)  3 ( 1 ) 450 2020.12

     View Summary

    © 2020, The Author(s). Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.

  • Antifungal Agent Luliconazole Inhibits the Growth of Mouse Glioma-initiating Cells in Brain Explants.

    Nagashima H, Koike N, Yoshida K, Saya H, Sampetrean O

    The Keio journal of medicine (Keio Journal of Medicine)  69 ( 4 ) 97 - 104 2020.07

    ISSN  0022-9717

     View Summary

    © 2020 by The Keio Journal of Medicine. Imidazole antifungal compounds exert their antipathogenic effects through inhibition of sterol biosyn-thesis. These drugs have also recently been identified as candidate anticancer agents for several solid tumors including glioblastoma. However, their effects on glioma-initiating cells (GICs), i.e., glioma cells with stemlike properties that are able to initiate tumors, remain unclear. Consequently, we examined the effects of the optically active imidazole compound luliconazole on mouse GICs and GIC-based tumors. Luliconazole impaired in a concentration-dependent manner the growth of spheres formed by GICs in vitro. In contrast to the inhibitory effects of ionizing radiation and temozolomide on sphere growth, that of luliconazole was attenuated by the addition of exogenous cholesterol. Exposure to luliconazole of brain slices derived from mice with orthotopic GIC implants for 4 days in culture resulted in a marked increase in the number of tumor cells positive for cleaved caspase-3, but without a similar effect on nor-mal cells. Furthermore, in brain slices, luliconazole inhibited the expansion of GIC-based tumors and the parenchymal infiltration of tumor cells. Our findings therefore indicate that luliconazole effectively targets GICs, thereby providing further support for the antitumorigenic effects of imidazole antifungal compounds.

  • Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy

    Otsuki Y., Yamasaki J., Suina K., Okazaki S., Koike N., Saya H., Nagano O.

    Cancer Science (Cancer Science)  111 ( 1 ) 127 - 136 2020.01

    ISSN  13479032

     View Summary

    © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.

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

Reviews, Commentaries, etc. 【 Display / hide

  • 放射線治療のトランスレーショナルリサーチと臨床へのインパクト 低酸素ニッチ内癌幹細胞の放射線抵抗性の克服戦略(Role of Translational Research in Radiation Oncology Strategies to overcome the radioresistance of cancer stem cells residing in hypoxic niches)

    サンペトラ・オルテア , 小池 直義, 佐谷 秀行

    日本癌学会総会記事 ((一社)日本癌学会)  78回   SST4 - 1 2019.09

    ISSN  0546-0476

Presentations 【 Display / hide

  • 放射線照射後のマウス心臓の形態学的・病理学的検討

    小池 直義

    日本放射線腫瘍学会第32回学術大会, 

    2019.11

    Poster presentation

  • マウス膠芽腫モデルにおける低酸素放射線増感剤ドラニダゾールの効果

    Koike Naoyoshi

    日本放射線腫瘍学会第30回学術大会, 

    2017.11

    Oral presentation (general)

  • グリオーマ幹細胞の放射線抵抗性におけるネスチンの役割の解析

    KOIKE Naoyoshi

    日本放射線腫瘍学会第29回学術大会, 

    2016.11

    Oral presentation (general)

  • 放射線によって誘導されるグリオーマ幹細胞の細胞外小胞の解析

    KOIKE Naoyoshi

    第33回日本脳腫瘍学会学術集会, 

    2015.12

    Poster presentation

  • Cell cycle imaging in irradiated murine glioma stem cells.

    KOIKE Naoyoshi

    International Symposium on Multi-dimensional Fluorescence Live Imaging of Cellular Functions and Molecular Activities, 

    2015.01

    Poster presentation

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

  • 光感受性物質による放射線増強効果を用いた悪性脳腫瘍に対する新規治療の開発

    2021.04
    -
    2024.03

    Keio University, Grant-in-Aid for Scientific Research (C), No Setting

     View Summary

    悪性脳腫瘍の中でも膠芽腫は最も治療困難かつ予後不良な悪性腫瘍で放射線治療が腫瘍の長期制御において重要な役割を担う。しかし高い放射線抵抗性により未だ治療成績は不十分であり放射線抵抗性の解除を目指す新規治療が望まれる。光感受性物質である5-アミノレブリン酸は膠芽腫摘出術時に用いる診断用既存薬であり腫瘍特異的に高い集積能を有する。申請者らはヒト膠芽腫細胞株の放射線感受性解析において5-ALAが放射線増感効果を有することを見出した。本研究は既存薬再開発として脳腫瘍細胞における5-ALAの放射線増感剤としての薬効を証明しその増感機序及び腫瘍増殖抑制機序を解明することにより新規治療法の開発を目的とする。

  • 放射線による心毒性の克服に向けた病態解析と細胞骨格を標的とした新規治療法の検討

    2020.04
    -
    2022.03

    Keio University, Grant-in-Aid for Early-Career Scientists, No Setting

     View Summary

    放射線治療で肺がん、食道がんを含む胸部悪性腫瘍は根治可能な疾患となりつつある。一方で長期生存が達成されることで、新たに顕在化した問題として胸部放射線治療による晩発性の心毒性がある。放射線誘発性の心毒性発症のメカニズムは不明な点が多く、予防法や根本的治療法は確立されていない。そこで、本研究では、照射による心毒性のメカニズムの解明と心毒性の軽減を目指して、筋線維芽細胞を標的とした治療の確立をマウスモデルで試みる。

  • Development of new radiation sensitization therapy by drug repositioning of chloroquine

    2018.04
    -
    2021.03

    Keio University, SHIGEMATSU Naoyuki, Grant-in-Aid for Scientific Research (C), No Setting

     View Summary

    As a treatment method for pancreatic cancer, which is an intractable malignant tumor, we focused on radiation resistance by autophagy and searched for the radiosensitizing effect of chloroquine drug repositioning. Pancreatic cancer cells were used to form spheroids, which were irradiated and administered with chloroquine in both normal medium and undernutrition, but there was no significant change in survival rate or size due to chloroquine, and no radiation sensitizing effect was observed.Moreover, the autophagy inhibitory effect was not clear. However, another study suggested an inhibitory effect on mitochondrial autophagy, mitophagy.

  • ポルフィリン前駆体による悪性脳腫瘍に対する新規放射線増感治療の開発

    2018.04
    -
    2021.03

    Keio University, Grant-in-Aid for Scientific Research (C), No Setting

     View Summary

    悪性グリオーマ摘出術において蛍光診断薬として用いられる5-aminolevulinic acid (5-ALA)は、その代謝物である細胞内のヘム代謝系酵素であるプロトポルフィリンⅨ(PpIX)が腫瘍細胞内に特異的に蓄積能を有することを利用している。5-ALAは診断用薬剤として既に臨床使用されているため、脳腫瘍に対する移行性・集積性は十分な裏付けと実績がある薬剤であり、本研究は「安全性・脳腫瘍集積性が確立された既存薬剤において放射線増感効果を有するものはあるか」という問いに端を発して既存薬再開発として脳腫瘍細胞における5-ALAの放射線増感剤としての薬効を証明し、その機序を解明することにより新規薬剤開発に繋がるような知見の発見を目的とする。
    本年度の研究実積として、5-ALAをヒト悪性グリオーマ培養細胞株U251,LN229, LN428に投与した後に照射を行い、コロニー法により5-ALAの放射線増感効果を検討した。その結果、5-ALA 投与後の照射では、5-ALA投与を行わない照射単独に比べコロニー形成能が抑制されることが示され、In vitro において5-ALAは放射線増感作用をもつことが確認された。しかしながら5-ALAと放射線照射の併用がどのような機序で放射線増感作用に影響を及ぼすかはこれまでに明らかにされておらず、5-ALAの放射線増感剤としてのメカニズムはまだ不明な点が多く残されている。そこで我々は照射と5-ALAの併用による抗腫瘍効果の機序として、細胞周期について検討した。その結果、5-ALAと照射併用では、5-ALA単独、照射単独に比較し、G2/M期に細胞周期が集積する傾向が確認された。この結果は5-ALAは悪性グリオーマ細胞に対して有効な放射線増感剤となりうる可能性が示唆された。
    まず悪性ヒトグリオーマ細胞株U251,LN229, LN428の細胞生存率をコロニー法で検討した。その結果、5Gy単独の照射では生存率60%以上を各細胞株が示したことより、以下の実験では照射線量は5Gyを用いた。
    5-ALAは1mM濃度に調整し細胞生存アッセイ法に使用した。96wellのプレートを用い各wellに5000個の悪性ヒトグリオーマ細胞株U87, U251, LN229を培養し、1 mM の5-ALAで4時間処理後、CCK-8 assayキット (Dojindo, Kumamoto, Japan)を用いて生細胞の測定を行った。その結果、細胞株U87, U251, LN229ともに5-ALAが細胞に与える影響は非常に低かった。
    予備実験によって得られた情報とコロニー法の結果をもとに、5-ALAを1 mM濃度に調整し、ヒトグリオーマ細胞株U87, U251, LN229に4時間作用させた。その後放射線5Gyを照射し37度で培養し、14日培養した後コロニー形成能を検討した。5-ALA投与を行わない照射単独に比べコロニー形成能が抑制された。以上よりIn vitroにおいて5-ALAは悪性ヒトグリオーマ細胞株に対し放射線増感作用を持つことが確認された。
    PI法によりフローサイトメーターで細胞周期を解析した。10cm dishに悪性ヒトグリオーマ細胞株U87, U251, LN229を培養し、5-ALA (1 mM)を投与し4時間後5Gyで照射し24時間後に細胞を固定しサンプルとした。結果、5-ALAと照射併用により、5-ALA単独、照射単独に比較し、G2/M期に細胞周期が集積する傾向を示した。
    10cm dishに悪性ヒトグリオーマ細胞株U87, U251, LN229を培養し、5-ALA(1 mM)を投与し4時間後に5Gy照射し24時間後にAnnexin V-PI染色しフローサイトメーターによるアポトーシスの解析を行う。次に悪性ヒトグリオーマ細胞株に対する照射後TUNEL法を行なう。5-ALAと照射の併用は5-ALA単独投与、照射単独と比較し、アポトーシスを検出する。
    5-ALAの悪性グリオーマ細胞株に対する放射線増感作用の分子メカニズムを解明する目的で、細胞死や生存の重要なシグナル分子であるAKT, PARP, Caspase3の活性化状態を免疫ブロット法で検討する。また、5-ALA添加の有無により、放射線照射後のグリオーマ細胞のDNA損傷の程度の違いを比較する目的で、核内のリン酸化γH2AXの発現量を細胞免疫染色、免疫ブロット法で検討する。
    6週齢のBALB/cnu/nu雌マウスの背部皮下に1x106個/50μlの悪性グリオーマ細胞を移植し皮下腫瘍モデルを作成する。使用する細胞は実験1の結果を参考にして決定する。作成した悪性グリオーマ皮下腫瘍モデルを用いて、無治療群、放射線治療単独群、5-ALA単独投与群、5-ALA+放射線治療群の4群間の腫瘍量の変化を継時的に比較する。悪性グリオーマ皮下移植後5日目に5-ALA投与と放射線治療を実施する。5-ALAはマウスの体重に応じ腹腔投与を行い、放射線治療は5-ALA投与4時間後に麻酔沈静下に実施する。経時的に腫瘍径を測定し、 無治療群の腫瘍量を指標にして屠殺時期を決定し、腫瘍重量を計測する。

  • Identification and analysis of drugs for overcoming hypoxia in glioblastoma

    2018.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Koike Naoyoshi, Grant-in-Aid for Early-Career Scientists , Principal investigator

     View Summary

    The radioresistance of glioblastoma is caused by the hypoxic region in the tumor. The nitroimidazole compounds that accumulates specifically in the hypoxic region were analyzed for overcoming radioresistance. Among nitroimidazole compounds, doranidazole had a radiosensitizing effect in the hypoxic region of glioblastoma and a cell-killing effect by itself. The mechanism of cell death by doranidazole was mitochorial stress. In the allogeneic orthotopic mouse brain tumor model, the combined use of doranidazole and irradiation contributed to prolongation of mouse survival.

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Courses Taught 【 Display / hide

  • 放射線医学「治療」

    2020, Autumn Semester, Lecture, Within own faculty, 1h

  • 放射線医学臨床実習

    2020, Full academic year, Lecture, Within own faculty, 3h

  • 放射線医学臨床実習

    2019, Full academic year, Laboratory work/practical work/exercise, Outside own faculty (within Keio), 3h

  • 放射線医学臨床実習

    2018, Full academic year, Laboratory work/practical work/exercise, Outside own faculty (within Keio), 3h

  • 放射線医学臨床実習

    2017, Full academic year, Laboratory work/practical work/exercise, Outside own faculty (within Keio), 3h

 

Memberships in Academic Societies 【 Display / hide

  • JAPANESE CANCER ASSOCIATION, 

    2018.08
    -
    Present
  • 日本脳腫瘍学会, 

    2015
    -
    Present
  • 日本医学放射線学会, 

    2007
    -
    Present
  • 日本放射線腫瘍学会, 

    2007
    -
    Present