Development of combinational therapy of non-thermal plasma and carbon nanotubes

• Project/Area Number: 16K15257
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Toyokuni Shinya 名古屋大学, 医学系研究科, 教授 (90252460)
• Research Collaborator: KIKKAWA Fumitaka ; KAJIYAMA Hiroaki ; HORI Masaru ; TANAKA Hiromasa
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 低温プラズマ / カーボンナノチューブ / フェロトーシス / ナノマテリアル / 中皮腫 / フェリチン / 医療応用 / 鉄 / キレート / オートファジー

Outline of Final Research Achievements

We obtained fundamental data for the use of combinational therapy of non-thermal plasma (NTP) and carbon nanotubes. We identified hemoglobin, histones and transferrin as specifically adsorbed proteins on carbon nanotube surface with mass spectrometry. Biological effects of NTP exposure were recognized as oxidative stress with biochemical, FACS and immunostaining studies, which was promoted with preincubation with ferric ammonium citrate and repressed by preincubation with redox-inactive iron chelator, desferal. NTP exposure to mesothelioma cells caused an increase in intracellular catalytic Fe(II), lipid peroxidation with increased ferritin/decreased transferrin receptor, which was accompanied by promoted endocytosis and autophagy (ferritinophagy). These data suggest that NTP can cause ferroptosis in mesothelioma cells. As in vitro experiments we also observed that NTP exposure can directly destroy the ferritin core protein and reduce Fe(III) to Fe(II).

Research Products

• [Int'l Joint Research] University of Sydney(Australia)
• [Journal Article] Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin. (2018)
  • Author(s): Furuta T, Shi L, Toyokuni S.
  • Journal Title: Pathol Int. Volume: - Issue: 7 Pages: 442-443
  • DOI: 10.1111/pin.12665
  • NAID: 120006529635
  • Peer Reviewed
• [Journal Article] Non-Thermal Plasma Induces a Stress Response in Mesothelioma Cells Resulting in Increased Endocytosis, Lysosome Biogenesis and Autophagy. (2017)
  • Author(s): Shi. L., Ito, F., Wang, Y., Okazaki, Y., Tanaka, H., Mizuno, M., Hori. M., Hirayama, T., Nagasawa, H., Richardson, Des R, Toyokuni, S.
  • Journal Title: Free Radic. Biol. Med. Volume: 108 Pages: 904-917
  • DOI: 10.1016/j.freeradbiomed.2017.04.368
  • NAID: 120006343682
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. (2017)
  • Author(s): Chew SH, Okazaki Y, Akatsuka S, Wang S, Jiang L, Ohara Y, Ito F, Saya H, Sekido Y, Toyokuni S.
  • Journal Title: Free Radic Biol Med. Volume: 106 Pages: 91-99
  • DOI: 10.1016/j.freeradbiomed.2017.02.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. (2017)
  • Author(s): Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD.
  • Journal Title: Cell. Volume: 171 Issue: 2 Pages: 273-285
  • DOI: 10.1016/j.cell.2017.09.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. (2017)
  • Author(s): Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S.
  • Journal Title: Free Radic Biol Med. Volume: 108 Pages: 610-616
  • DOI: 10.1016/j.freeradbiomed.2017.04.024
  • NAID: 120006343681
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. (2017)
  • Author(s): Nakamura K, Peng Y, Utsumi F, Tanaka H, Mizuno M, Toyokuni S, Hori M, Kikkawa F, Kajiyama H
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-017-05620-6
  • Peer Reviewed / Open Access
• [Journal Article] Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. (2016)
  • Author(s): Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S.
  • Journal Title: Cancer Sci Volume: 107(3) Issue: 3 Pages: 250-257
  • DOI: 10.1111/cas.12865
  • Peer Reviewed / Open Access
• [Journal Article] Contrasting intra- and extra-cellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. (2016)
  • Author(s): F. Ito, T. Nishiyama, L. Shi, M. Mori, T. Hirayama, H. Nagasawa, H. Yasui, S. Toyokuni
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 476 Issue: 4 Pages: 600-606
  • DOI: 10.1016/j.bbrc.2016.06.003
  • Peer Reviewed
• [Presentation] Cancer as iron addiction with ferroptosis-resistance. (2018)
  • Author(s): Toyokuni S.
  • Organizer: Gordon Research Conference: Oxygen Radicals
  • Int'l Joint Research / Invited
• [Presentation] 特別講演：がんの起源をフェロトーシスとレドックス制御から考える (2018)
  • Author(s): 豊國 伸哉
  • Organizer: 平成29年度文部科学省私立大学研究ブランディング事業 研究成果報告会・シンポジウム
  • Invited
• [Presentation] The effect of aqueous plasma therapy targeting for occult peritonela metastasis of ovarian cancer. (2017)
  • Author(s): Kajiyama H, Utsumi F, Nakamura K, Yang P, Tanaka H, Toyokuni S, Hori M and Kikkawa F.
  • Organizer: The 1st International Conference on Plasma Medical Science Innovation.
  • Place of Presentation: 名古屋大学、愛知県名古屋市
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] Plenary Lecture: Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward biological applications. (2017)
  • Author(s): Toyokuni S.
  • Organizer: XVth Annual Meeting of SFRR-India 2017: Advanced oxidative stress research for health benefits and well-beings
  • Place of Presentation: Mumbai, India
  • Year and Date: 2017-01-09
  • Int'l Joint Research / Invited
• [Presentation] Session VI: Ferroptosis and cancer. Role of iron in carcinogenesis and tumor biology. (2017)
  • Author(s): Toyokuni S.
  • Organizer: Cold Spring Harbor Symposium: Ferroptosis: A Critical Review.
  • Int'l Joint Research / Invited
• [Presentation] Chemical reaction in non-thermal plasma from the viewpoint of exidative stress toward medical applications. (2017)
  • Author(s): Toyokuni S, Shi L and Okazaki Y.
  • Organizer: The 8th Biennial Meeting of the Society for Free Radical Research Asia; the 14th Conference of the Asian Society of Mitochondrial Research & Medicine; Chinese Mit 2017
  • Int'l Joint Research / Invited
• [Presentation] Chemical reaction in non-thermal plasma from the viewpoint of oxidative stress toward medical applications. (2017)
  • Author(s): Toyokuni S.
  • Organizer: 7th Sungkyunkwan University-Nagoya University Joint Symposium 2017
  • Int'l Joint Research / Invited
• [Presentation] Role of ferroptosis in carcinogenesis and cancer therapy. (2017)
  • Author(s): Toyokuni S.
  • Organizer: 8th Joint meeting of the Society for Free Radical Research Australasia and Japan
  • Int'l Joint Research / Invited
• [Presentation] 悪性中皮腫細胞への低温プラズマ照射による鉄の代謝 (2017)
  • Author(s): 丹下 恵里花、石 蕾、豊國 伸哉
  • Organizer: 第106回日本病理学会総会
• [Presentation] プラズマ活性培養液処理した細胞内酸化窒素活性種(RONS)の解析 (2017)
  • Author(s): 石川健治、田中宏昌、橋爪博司、竹田圭吾、太田貴之、伊藤昌文、中村香江、梶山広明、吉川史隆、豊國伸哉、水野正明、堀 勝
  • Organizer: 第70回日本酸化ストレス学会学術集会
• [Presentation] 低温プラズマ技術の医療・生物応用 (2017)
  • Author(s): 豊國 伸哉
  • Organizer: 第14回日本病理学会カンファレンス
  • Invited
• [Presentation] 低温プラズマの生物学的作用 (2017)
  • Author(s): 豊國 伸哉
  • Organizer: 第8回JAAS東京Live Forum
  • Invited
• [Presentation] Chemical reaction mechanism in non-thermal plasma from the viewppoit of oxidative stress toward clinical cancer applications. (2016)
  • Author(s): Toyokuni S, Shi L, Ito F, Okazaki Y, Toyokuni S.
  • Organizer: SfRBM/SFRRI 2016; SFRRI’s 18th Biennial Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] Plenary lecture 1: Insights into chemical reaction mechanism in plasma medicine from the viewpoint of oxidative stress. (2016)
  • Author(s): Toyokuni S.
  • Organizer: 6th International Conference on Plasma Medicine.
  • Place of Presentation: Bratislava, Slovakia
  • Year and Date: 2016-09-04
  • Int'l Joint Research / Invited
• [Remarks] 生体反応病理学・分子
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/basic-med/pathology/pathology1/
• [Remarks] 生体反応病理学・分子病理診断学
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/basic-med/pathology/pathology1/