Development of a novel therapy for cancer cachexia targeting the purine metabolism in the central nervous system

• Project/Area Number: 18K15037
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: National Agriculture and Food Research Organization (2019); National Cancer Center Japan (2018)
• Principal Investigator: Uzu Miaki 国立研究開発法人農業・食品産業技術総合研究機構, 生物機能利用研究部門, 研究員 (20802896)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: がん悪液質 / プリンヌクレオチド代謝 / アストロサイト / 炎症 / コラーゲンビトリゲル膜 / グリア / プリン代謝 / 薬物治療

Outline of Final Research Achievements

<Research Achievement during the 1st year> Cancer cachexia model was prepared by subcutaneous injection of 85As2 cells (a gastric cancer cell line) into BALB/cAJcl-nu/nu nude mice. The model mice started to present cachexic symptoms such as a decrease of body weight and food intake 2 weeks after 85As2 inoculation. Therefore, the alteration in the central nervous system was investigated at that time point. It was revealed that the purine nucleotide metabolism and the expression of astrocytic marker was increased in the forebrain of the model mice.
<Research Achievement during the 2nd year> A blood-brain barrier model composed of astrocytes and brain microvascular endothelial cells was fabricated utilizing a collagen vitrigel membrane. The model showed high responsiveness to inflammatory stimuli, suggesting that this model is useful for the investigation of the role of astrocytes in the pathogenesis of cancer cachexia.

Academic Significance and Societal Importance of the Research Achievements

本研究は、未だに有効な治療法の確立されていないがん悪液質において、中枢神経系のプリンヌクレオチド代謝やアストロサイトの活性制御が新規治療法となり得ることを明らかにした。また、本研究において新たに構築した血液脳関門モデルはがん悪液質の迅速なスクリーニングを可能とすることが期待される。以上より、本研究はがん緩和医療の発展に貢献し得ると考えられる。

Research Products

• [Journal Article] The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis. (2020)
  • Author(s): 103.Miyano, K., Eto, M., Hitomi, S., Matsumoto, T., Hasegawa, S., Hirano, A., Nagabuchi, K., Asai, N., Uzu, M., Nonaka, M., Omiya, Y., Kaneko, A., Ono, K., Fujii, H., Higami, Y., Kono, T., Uezono, Y.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 625-625
  • DOI: 10.1038/s41598-019-57192-2
  • Peer Reviewed / Open Access
• [Journal Article] A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain (2019)
  • Author(s): Uzu Miaki、Nonaka Miki、Miyano Kanako、Sato Hiromi、Kurebayashi Nagomi、Yanagihara Kazuyoshi、Sakurai Takashi、Hisaka Akihiro、Uezono Yasuhito
  • Journal Title: Journal of Pharmacological Sciences Volume: 140 Issue: 1 Pages: 109-112
  • DOI: 10.1016/j.jphs.2019.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Possible biased analgesic of hydromorphone through the G protein-over β-arrestin-mediated pathway: cAMP, CellKey?, and receptor internalization analyses (2019)
  • Author(s): Manabe Sei、Miyano Kanako、Fujii Yuriko、Ohshima Kaori、Yoshida Yuki、Nonaka Miki、Uzu Miaki、Matsuoka Yoshikazu、Sato Tetsufumi、Uezono Yasuhito、Morimatsu Hiroshi
  • Journal Title: Journal of Pharmacological Sciences Volume: 140 Issue: 2 Pages: 171-177
  • DOI: 10.1016/j.jphs.2019.06.005
  • Peer Reviewed / Open Access
• [Journal Article] Trichostatin A modulates cellular metabolism in renal cell carcinoma to enhance sunitinib sensitivity (2019)
  • Author(s): Sato Hiromi、Uzu Miaki、Kashiba Tatsuro、Fujiwara Takuya、Hatakeyama Hiroto、Ueno Koichi、Hisaka Akihiro
  • Journal Title: European Journal of Pharmacology Volume: 847 Pages: 143-157
  • DOI: 10.1016/j.ejphar.2019.01.040
• [Journal Article] Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System. (2018)
  • Author(s): Uzu M, Sin WC, Shimizu A, Sato H.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 4 Pages: 1159-1173
  • DOI: 10.3390/ijms19041159
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of synaptic inputs in magnocellular neurones in a rat model of cancer cachexia (2018)
  • Author(s): Yokoyama Toru、Terawaki Kiyoshi、Minami Kouichiro、Miyano Kanako、Nonaka Miki、Uzu Miaki、Kashiwase Yohei、Yanagihara Kazuyoshi、Ueta Yoichi、Uezono Yasuhito
  • Journal Title: Journal of Neuroendocrinology Volume: 30 Issue: 9
  • DOI: 10.1111/jne.12630
  • Peer Reviewed
• [Journal Article] Multifunctional Actions of Ninjinyoeito, a Japanese Kampo Medicine: Accumulated Scientific Evidence Based on Experiments With Cells and Animal Models, and Clinical Studies (2018)
  • Author(s): Miyano Kanako、Nonaka Miki、Uzu Miaki、Ohshima Kaori、Uezono Yasuhito
  • Journal Title: Frontiers in Nutrition Volume: 5 Pages: 93-93
  • DOI: 10.3389/fnut.2018.00093
  • Peer Reviewed / Open Access
• [Journal Article] Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats (2018)
  • Author(s): Terawaki Kiyoshi、Kashiwase Yohei、Uzu Miaki、Nonaka Miki、Sawada Yumi、Miyano Kanako、Higami Yoshikazu、Yanagihara Kazuyoshi、Yamamoto Masahiro、Uezono Yasuhito
  • Journal Title: Oncotarget Volume: 9 Issue: 78 Pages: 34748-34764
  • DOI: 10.18632/oncotarget.26190
  • Peer Reviewed / Open Access
• [Presentation] Development of tissue-specific histamine-responsive vascular endothelial models using a collagen vitrigel membrane (2020)
  • Author(s): 宇津美秋
  • Organizer: 第93回日本薬理学会年会
• [Presentation] コラーゲンビトリゲル膜を利用したヒト血液脳関門培養モデルの開発 (2020)
  • Author(s): 宇津美秋
  • Organizer: 日本薬学会第140年会
• [Presentation] コラーゲンビトリゲル膜チャンバー内で培養したヒト血管内皮細胞のバリア機能の解析：炎症血管内皮モデルの開発を目指して (2019)
  • Author(s): 宇津美秋
  • Organizer: 日本組織培養学会第92回大会
• [Presentation] コラーゲンビトリゲル膜を利用したヒスタミン応答性血管内皮モデルの開発 (2019)
  • Author(s): 宇津美秋
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2019
• [Presentation] 炎症誘発物質による血管透過性変化の予測に有用な「コラーゲンビトリゲル膜上に構築した血管内皮培養モデル」 (2019)
  • Author(s): 宇津美秋
  • Organizer: 日本動物実験代替法学会第32回大会
• [Presentation] Development of tissue-specific vascular endothelial models using a collagen vitrigel membrane and their histamine responsiveness (2019)
  • Author(s): 宇津美秋
  • Organizer: 日本薬物動態学会第34回年会つくば
• [Presentation] Voluntary wheel running may improve cardiac dysfunction in experimental mouse model of cancer-induced cachexia (2019)
  • Author(s): Ueno S, Nonaka M, Kakigi R, Uzu M, Kurebayashi N, Murayama T, Terawaki K, Sakurai T, Uezono Y.
  • Organizer: 第92回日本薬理学会年会
• [Presentation] A novel strategy for treatment of cancer cachexia targeting the altered purine metabolism in the brain (2019)
  • Author(s): Uzu M, Nonaka M, Miyano K, Sato H, Kurebayashi N, Murayama T, Sakurai T, Hisaka A, Uezono Y.
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 各種医療麻薬の鎮痛効果におけるオピオイド二量体受容体の役割～μ、κおよび新規作製μ/κ二量体受容体安定発現細胞を用いた比較解析～ (2018)
  • Author(s): 大島佳織, 宮野加奈子, 石橋尚人, 大道容子, 藤井百合子, 真鍋星, 宇津美秋, 野中美希, 宮野加奈子, 藤井秀明, 吉澤一巳, 上園保仁.
  • Organizer: 第12回日本緩和医療薬学会年会
• [Presentation] 漢方薬半夏瀉心湯が抗がん剤のがん細胞増殖抑制作用に及ぼす影響の解析 (2018)
  • Author(s): 永淵かおり, 平野絢音, 江藤萌子, 宮野加奈子, 大宮雄司, 宇津美秋, 野中美希, 樋上賀一, 藤井秀明, 上園保仁.
  • Organizer: 第12回日本緩和医療薬学会年会
• [Presentation] Therapeutic effects of ghrelin and des-acyl ghrelin on anthracycline doxorubicin-induced cardiac toxicity (2018)
  • Author(s): Nonaka M, Kurebayashi N, Murayama T, Sugihara M, Hosoda H, Kishida S, Uzu M, Kangawa K, Sakurai T, Uezono Y.
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] Novel strategy for treatment of cancer cachexia based on metabolic alteration in central nervous system in a mouse model (2018)
  • Author(s): Uzu M, Nonaka M, Miyano K, Sato H, Kurebayashi N, Murayama T, Sakurai T, Hisaka A, Uezono Y.
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] Characterization of the properties of four opioid analgesics approved in Japan with cells stably expressing μORs using the CellKey and GloSensor cAMP assay systems (2018)
  • Author(s): Manabe S, Miyano K, Ogino T, Oshima K, Uzu M, Nonaka M, Matsuoka Y, Sato T, Morimatsu H, Uezono Y.
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] Communication between astrocyte and metastasized cancer cell focused on changes of cellular metabolism (2018)
  • Author(s): Sato H, Shimizu A, Uzu M, Ueno K, Hisaka A.
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] 中枢性プリン代謝変化を標的とした新規がん悪液質治療薬開発 (2018)
  • Author(s): 宇津美秋, 野中美希, 宮野加奈子, 佐藤洋美, 呉林なごみ, 村山尚, 櫻井隆, 樋坂章博, 上園保仁.
  • Organizer: 第4回 次世代を担う若手のためのレギュラトリーサイエンスフォーラム
• [Presentation] A novel strategy for treatment of cancer cachexia targeting for alteration of the purine metabolism in the brain (2018)
  • Author(s): Uzu M, Nonaka M, Miyano K, Sato H, Uezono Y.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Human stomach cancer cell line 85As2 induced cancer cachexia associated with cardiac dysfunction (2018)
  • Author(s): Nonaka M, Uzu M, Terawaki K, Miyano K, Uezono Y.
  • Organizer: 第77回日本癌学会学術総会
• [Patent(Industrial Property Rights)] 血液組織関門インビトロモデル、及び薬物の血液組織関門移行性 評価方法 (2019)
  • Inventor(s): 竹澤俊明、宇津美秋
  • Industrial Property Rights Holder: 農業・食品産業技術総合研究機構
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-190832
  • Filing Date: 2019