栄養飢餓耐性を解除する天然抗がん剤の探索および細胞内代謝物解析による作用機序解明

2018 Fiscal Year Research-status Report

• Project/Area Number: 16K08319
• Research Institution: University of Toyama
• Principal Investigator: Suresh Awale 富山大学, 和漢医薬学総合研究所, 准教授 (00377243)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: pancreatic cancer / PANC-1 / metabolomics / NMR / antiausterity strategy / biomarker / drug discovery

Outline of Annual Research Achievements

このプロジェクトは、抗緊縮戦略を採用することによって新規抗癌剤を発見し、タンパク質およびメタボローム解析を通じて作用機序を解明することを目的とした。2018年度には、このプロジェクトに関連する5つの研究論文が査読付き国際ジャーナルに掲載されました。 薬用植物Bosenbergia pandurata、Uvaria dac、Chamaecyparis obtusa、Ancistrocladus種、Calotropis gigantea、プロポリス、Citrus hystrix、Derris scandens、Anneslea fragrans、Callistemon citrinusから得られた活性成分の抗癌活性を広範囲に調べた。 活性成分の作用機序も調べた。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

選択された新規抗癌剤の作用機序の調査は完了した。特に、５，８－結合ナフチルイソキノリンアルカロイドである新規化合物であるAncistrolikokine E3が、癌細胞の栄養飢餓耐性を排除する有望な抗癌剤として発見された。Ancistrolikokine E3は、Akt / mTOR / Autophagy Signaling Pathwayを阻害し、膵臓癌細胞死を引き起こすことがわかった。この発見はACS化学社会による重要な発見として選ばれ、世界中の何千という報道機関にプレスリリースされました。約130の国際ニュースメディアがこの発見を強調した。現在、さらに3つの論文の執筆が進行中で、2019年内に投稿する予定である。

Strategy for Future Research Activity

薬用植物Derris scandens、Anneslea fragrans、Callistemon citrinusから新規抗癌剤の発見研究を継続する。ヒト膵臓癌細胞の代謝に対する新規抗癌剤の活性検討を継続する。2019年内には、評判の良いジャーナルに3つ以上の論文を投稿する。

Research Products

• [Journal Article] Ancistrolikokine E3, a 5,8-Coupled Naphthylisoquinoline Alkaloid, Eliminates the Tolerance of Cancer Cells to Nutrition Starvation by Inhibition of the Akt/mTOR/Autophagy Signaling Pathway. (2018)
  • Author(s): Awale S., Dibwe D. F., Balachandran C., Fayez S. Li J., Feineis D., Lombe B.K. Bringmann G.
  • Journal Title: Journal of Natural Products Volume: 81 Pages: 2282-2291
  • DOI: 10.1021/acs.jnatprod.8b00733
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemical constituents of Thai Citrus hystrix and their antiausterity activity against the PANC-1 human pancreatic cancer cell line. (2018)
  • Author(s): Sun S., Phrutivorapongkul A., Dibwe D. F., Balachandran C., Awale S.
  • Journal Title: Journal of Natural Products Volume: 81 Pages: 1877-1883
  • DOI: 10.1021/acs.jnatprod.8b00405
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ancistrobrevines E-J and related naphthylisoquinoline alkaloids from the West African liana Ancistrocladus abbreviatus with inhibitory activities against Plasmodium falciparum and PANC-1 human pancreatic cancer cells (2018)
  • Author(s): Fayez S. Li J., Feineis D., Assi L.K., Kaiser M., Brun R., Awale S., Bringmann G.
  • Journal Title: Fitoterapia Volume: 131 Pages: 245-259
  • DOI: 10.1016/j.fitote.2018.11.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ancistroyafungines A-D, 5,8′- and 5,1′-coupled naphthylisoquinoline alkaloids from a Congolese Ancistrocladus species, with antiausterity activities against human PANC-1 pancreatic cancer cells (2018)
  • Author(s): Muyisa S., Lombe B.K., Feineis D., Dibwe D.F., Maharaj V., Awale S., Bringmann G.
  • Journal Title: Fitoterapia Volume: 130 Pages: 6-16
  • DOI: 10.1016/j.fitote.2018.07.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A New Compound from the Rhizomes of Boesenbergia pandurata (2018)
  • Author(s): Do T.N.V., Nguyen H.X., Le T.H., Ngo T.M.T., Dang P.H., Phung N.H., Vo N.T., Nguyen D.M., Le N.H.T., Le T.T., Nguyen M.T.T, Awale S., Nguyen N.T.
  • Journal Title: Nat. Prod. Commun Volume: 13 Pages: 739-740
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Constituents of Callistemon citrinus and Their Antiausterity Activities against Human Pancreatic Cancer Cell Line (2019)
  • Author(s): Ahmed M. Tawila, Ashraf M. Omar, Dia Fita Dibwe, Suresh Awale.
  • Organizer: 日本薬学会第139年会, 2019年3月20日～ 23日
• [Presentation] Chemical Constituents from Anneslea fragrans and Their Antiausterity Activity against the PANC-1 Human Pancreatic Cancer Cell Line. (2019)
  • Author(s): Ashraf M. Omar, Dia Fita Dibwe, Ahmed M. Tawila, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: 日本薬学会第139年会, 2019年3月20日～ 23日
• [Presentation] Discovery of potential antiausterity agents from Thai Piper ribesoides (2019)
  • Author(s): Wasinee Su-Authai, Dya Fita Dibwe, Ashraf M. Omar, Orawan Monthakantirat, Supawadee Daodee, Yaowared Chulikhit, Suresh Awale
  • Organizer: 日本薬学会第139年会, 2019年3月20日～ 23日
• [Presentation] Ancistrolikokine E3, a new naphthylisoquinoline alkaloid with potent activity against pancreatic cancer cells. (2018)
  • Author(s): S. Fayez, D. Feineis, B. K. Lombe, D. F. Dibwe, C. Balachandran, S. Awale, G. Bringmann.
  • Organizer: Chemie-Symposium der Studierenden Mainfrankens 2018 Dec.6; Wuerzburg, Germany.
  • Int'l Joint Research
• [Presentation] Synthesis of novel coumarin derivatives directed toward anti-pancreatic cancer agent based on anti-austerity strategy. (2018)
  • Author(s): Takahiro Okada, Satoyuki Takahara, Takuya Okada, Suresh Awale, Dya Fita Dibwe, Satoshi Endo, Naoki Toyooka.
  • Organizer: 36th Medicinal Chemistry Symposium MCS2018, 2018年9月28日～30日
• [Presentation] Discovery of anti-austerity agents from Derris scandens. (2018)
  • Author(s): Dya Fita Dibwe, Haruka Fujino, Mio Aoike, Nusrin Pongterdsak, Ampai Phrutivorapongkul, Suresh Awale.
  • Organizer: 日本生薬学会第65回年会, 2018年9月17日～18日
• [Presentation] Inspired by Nature: Synthesis of Plumbagin Derivatives as Potential Anti-austerity Agents. (2018)
  • Author(s): Suresh Awale, Dya Fita Dibwe, Naoki Toyooka.
  • Organizer: Toyama Academic Gala, 2018年9月14日
• [Presentation] Discovery of anti-austerity agents from Derris scandens. (2018)
  • Author(s): Dya Fita Dibwe, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: Toyama Academic Gala, 2018年9月14日
• [Presentation] Chemical Constituents of Thai Citrus hystrix and Their Antiausterity Activity against Human Pancreatic Cancer Cell Lines (2018)
  • Author(s): Sijia Sun, Dya Fita Dibwe, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network (3rd TAA-Pharm Symposium); 2018 Sept. 10-12; Toyama.
  • Int'l Joint Research
• [Presentation] Constituents of Anneslea fragrans and Their Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Line. (2018)
  • Author(s): Ashraf M. Omar, Ahmed M. Tawila, Dibwe Dya Fita, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network (3rd TAA-Pharm Symposium); 2018 Sept. 10-12; Toyama.
  • Int'l Joint Research
• [Presentation] Constituents of Callistemon citrinus and Their Antiausterity Activities against Human Pancreatic Cancer Cell Lines (2018)
  • Author(s): Ahmed M. Tawila, Ashraf M. Omar, Dibwe Dya Fita, Suresh Awale
  • Organizer: The Third International Symposium on Toyama-Asia-Africa Pharmaceutical Network (3rd TAA-Pharm Symposium); 2018 Sept. 10-12; Toyama.
  • Int'l Joint Research
• [Presentation] Anticancer Drug Discovery: Strategy and Leads from Medicinal Plants (2018)
  • Author(s): Suresh Awale
  • Organizer: Toyama-Basel Joint Symposium 2018; 2018 Aug. 23-24; Toyama.
  • Int'l Joint Research / Invited
• [Presentation] Prenylated isoflavones from Thai Derris scandens and their antiausterity activity. (2018)
  • Author(s): Dya FIta Dibwe, Haruka Fujino, Mio Aoike, Nusrin Pongterdsak, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: Toyama-Basel Joint Symposium 2018; 2018 Aug. 23-24; Toyama.
  • Int'l Joint Research
• [Presentation] Discovery of potential antiausterity agents from Thai Citrus hystrix (2018)
  • Author(s): Sijia Sun, Dya Fita Dibwe, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: Toyama-Basel Joint Symposium 2018; 2018 Aug. 23-24; Toyama.
  • Int'l Joint Research
• [Presentation] Chemical Constituents from Anneslea fragrans and their antiausterity activity against the PANC-1 human pancreatic cancer cell line. (2018)
  • Author(s): Ashraf M. Omar, Ahmed M. Tawila, Dya Fita Dibwe, Ampai Phrutivorapongkul, Suresh Awale
  • Organizer: Toyama-Basel Joint Symposium 2018; 2018 Aug. 23-24; Toyama.
  • Int'l Joint Research