Determination of Common Targets of Metal Complexes that Induce Programmed Cell Death of Cancer Cells and Development of New Anticancer Drugs
| Project/Area Number |
20K05712
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 37010:Bio-related chemistry
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
Aoki Shin 東京理科大学, 薬学部生命創薬科学科, 教授 (00222472)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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| Keywords | イリジウム錯体－ペプチドハイブリッド / プログロム細胞死 / パラトーシス / 発光 / 小胞体 / ミトコンドリア / カルシウム / プログラム細胞死 / プログロム化細胞死 / がん / 金属錯体 |
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| Outline of Research at the Start |
プログラムされた細胞死（Programmed Cell Death, PCD）は、固体の生命維持のために遺伝子によって制御された細胞死であり、発生時の形態形成や恒常性維持、がん、自己免疫疾患、ウィルス感染症等と密接に関わっている。従来、細胞死はapoptosisやnecrosisの他、necroptosis、autophagic cell death、paraptosisなど多様なPCD様式が明らかになり、それらを利用するがん治療に期待が寄せられている。そこで本研究は、PCDの一種であるparaptosisの分子機構を明らかにし、その知見をもとに新規抗がん剤の開発を行う。
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| Outline of Final Research Achievements |
We previously reported on that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) functionalized with a cationic KKKGG peptide unit on the 2-phenylpyridine ligand of Ir complex induces paraptosis, a relatively newly found programmed cell death (PCD), in cancer cells via the direct transport of calcium (Ca2+) from the endoplasmic reticulum (ER) to mitochondria. The results in this work suggest that the induction of paraptosis by IPH is associated with membrane fusion between mitochondria and the ER, subsequent Ca2+ influx from the ER to mitochondria, and the decrease in mitochondrial membrane potential. On the other hand, celastrol, a naturally-occurring triterpenoid, induces paraptosis, while not via ER-mitochondria membrane fusion. We conclude that the paraptosis induced by IPH (referred to as paraptosis II) proceeds via different signaling pathway from that of the previously-known paraptosis induced by celastrol (referred to as paraptosis I).
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| Academic Significance and Societal Importance of the Research Achievements |
プログラム細胞死（PCD）は、組織や器官の形成などに重要な役割を果たしており、代表的なPCDであるapoptosisの他、necroptosis、paraptosis、autophagyなどが報告されている。現在、がん細胞のapoptosisを誘導する抗がん剤が使われているが、耐性が生じ抗がん作用が減弱するなどの問題があるため、異なるPCDの誘起薬剤の開発が求められている。本研究は、従来報告されていたparaptosis (paraptosis I)に類似しているものの、異なるメカニズムで進行するparaptosis (paraptosis II)を発見し、新規抗がん剤設計の指針を示した。
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Report
(4 results)
Research Products
(142 results)
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[Journal Article] Design, Synthesis of Spirooxiindole-Pyrrolidines Embedded with Indole and Pyridine Heterocycles by Multicomponent Reaction: Anticancer and In Silico Studies2022
Author(s)
S. Mayakrishnan, D. Kathirvelan, Y. Arun, K. Saranraj, C. Balachandran, S. Aoki, S. Mayakrishnan, D. Kathirvelan, Y. Arun, K. Saranraj, C. Balachandran, S. Aoki, P. Yuvaraj, N. U. Maheswari
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Journal Title
New Journal of Chemistry
Volume: 46
Issue: 21
Pages: 10089-10106
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Effect of N-Benzyl Group in Indole Scaffold of Thiosemicarbazones on the Biological Activity of Their Pd(II) Complexes: DFT, Biomolecular Interaction, in Silico Docking, ADME and Cytotoxicity Studies2022
Author(s)
Nithya Balakrishnan, Jebiti Haribabu, Rahime Eshaghimalekshah, Srividya Swaminathan, Chandrasekar Balachandran, Nattamai S.P. Bhuvanesh, Shin Aoki, Ramasamy Karvembu,
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Journal Title
Inorganica Chimica Acta
Volume: 534
Issue: 5
DOI
Related Report
Peer Reviewed
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[Journal Article] Mefloquine, a Potent anti-Severe Acute Respiratory Syndrome- related Coronavirus 2 (SARS-CoV-2) drug as an entry inhibitor in vitro2021
Author(s)
Kaho Shionoya, Masako Yamasaki, View ORCID ProfileShoya Iwanami, Yusuke Ito, Shuetsu Fukushi, Hirofumi Ohashi, Wakana Saso, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Shingo Iwami, Yoshimasa Takahashi, Tadaki Suzuki, Masamichi Muramatsu, Makoto Takeda, Takaji Wakita, Koichi Watashi
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Journal Title
Frontiers in Microbiology
Volume: 1
Pages: 1-1
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Isohamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome2021
Author(s)
Yuichi Nishiyama, Akinori Morita, Shogo Tatsuta, Misaki Kanamaru, Masahiro Sakaue, Kenta Ueda, Manami Shono, Rie Fujita, Bing Wang, Yoshio Hosoi, Shin Aoki and Takeshi Sugai
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Journal Title
Genes
Volume: 12
Issue: 12
Pages: 8523-8544
DOI
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[Journal Article] Synthesis, Anticancer and Molecular Docking Studies of New Class of Benzoisoxazolyl-piperidinyl-1,2,3-triazoles2020
Author(s)
G. Muniyappan, S. Kathavarayan, C. Balachandran, E. Kalliyappan, S. M. Mahalingam, A. Ajees A. Salam, S. Aoki, N.Arumugam, A. I. Almansour, R. S. Kumar
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Journal Title
The Journal of King Saud University-Science,
Volume: 32
Issue: 8
Pages: 3286-3292
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Mefloquine Has a Potent Antiviral Activity against Severe Acute Respiratory Syndrome Related Coronavirus 22021
Author(s)
Kaho Shionoya, Masako Yamasaki, Shoya Iwanami, Yusuke Ito, Shuetsu Fukushi, Hirofumi Ohashi, Wakana Saso, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Shingo Iwami, Yoshimasa Takahashi, Tadaki Suzuki, Masamichi Muramatsu, Makoto Takeda, Takaji Wakita and Koichi Watashi
Organizer
第68回日本ウイルス学会学術学会
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