Identification of novel candidate chemical compounds targeting TrkB to induce apoptosis in neuroblastoma
| Project/Area Number |
24592703
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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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| Research Field |
Pediatric surgery
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| Research Institution | Chiba Cancer Center (Research Institute) |
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Principal Investigator |
NAKAMURA Yohko 千葉県がんセンター(研究所), がん予防センター, 主席研究員 (60260254)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWARA Akira 千葉県がんセンター(研究所), その他部局等, 参与 (50117181)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 神経芽腫 / TrkB / 低分子化合物 / BDNF / 細胞死 |
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| Outline of Final Research Achievements |
The neurotrophin receptor TrkB and its ligand BDNF are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF binding domain of TrkB. We have finally identified seven compounds that kill NB cells. The TUNEL assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion and colony formation, possibly suggesting competition at the BDNF binding site of TrkB. The candidate compounds had tumor suppressive activity in xenograft and in vivo toxicity tests using mice. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti-cancer drugs.
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas.2014
Author(s)
Suenaga Y, Islam SM, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibata T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A.
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Journal Title
PLoS Genet
Volume: 10
Issue: 1
Pages: 1-14
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.2013
Author(s)
Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
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Journal Title
J Clin Invest.
Volume: 123
Issue: 7
Pages: 2935-47
DOI
Related Report
Peer Reviewed
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[Journal Article] ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma.2013
Author(s)
Hasan MK, Nafady A, Takatori A, Kishida S, Ohira M, Suenaga Y, Hossain S, Akter J, Ogura A, Nakamura Y, Kadomatsu K, Nakagawara A.
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Journal Title
Sci Rep
Volume: 3
Issue: 1
Pages: 3450-3450
DOI
Related Report
Peer Reviewed
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[Presentation] Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma: in silico screening utilizing a grid computing technology2014
Author(s)
Yohko Nakamura, Akiko Suganami, Mayu Fukuda, MD. Kamrul Hasan, Tomoki Yokochi, Atsushi Takatori, Shunpei Satoh, Tyuji Hoshino, Yutaka Tamura, and Akira Nakagawara
Organizer
ANR2014
Place of Presentation
COLOGNE, GERMANY
Related Report
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