Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

doi:10.1007/s13659-015-0056-4

应用天然产物 ›› 2015, Vol. 5 ›› Issue (2): 91-97.DOI: 10.1007/s13659-015-0056-4

Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

Zhen-Nan Ye^1,2, Mu-Yuan Yu^1,2, Ling-Mei Kong^1,2, Wei-Hua Wang^1,2, Yuan-Feng Yang^1,2, Jie-Qing Liu¹, Ming-Hua Qiu¹, Yan Li¹

1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China

收稿日期:2015-02-04 修回日期:2015-03-22 出版日期:2015-04-24 发布日期:2018-02-11
基金资助:
This work was supported financially by the hundreds top talents program from Chinese Academy of Sciences, the NSFC(Nos. 81173076, 81403050), and the projects of science and technology of Yunnan Province(2009C1120, 2013FA047).

Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

Zhen-Nan Ye^1,2, Mu-Yuan Yu^1,2, Ling-Mei Kong^1,2, Wei-Hua Wang^1,2, Yuan-Feng Yang^1,2, Jie-Qing Liu¹, Ming-Hua Qiu¹, Yan Li¹

1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China

Received:2015-02-04 Revised:2015-03-22 Online:2015-04-24 Published:2018-02-11
Supported by:
This work was supported financially by the hundreds top talents program from Chinese Academy of Sciences, the NSFC(Nos. 81173076, 81403050), and the projects of science and technology of Yunnan Province(2009C1120, 2013FA047).

摘要/Abstract

摘要： Medulloblastoma(MB) is a form of malignant brain tumor that predominantly arises in infants and children, of which approximately 25% is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1. Therefore, Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer. In our present study, we undertook a screening for antagonists of Wnt signaling from 600 natural compounds, and identified Ginkgetin, a biflavone isolated from Cephalotaxus fortunei var. alpina. Ginkgetin inhibited Wnt pathway with an IC₅₀ value around 5.92 μM and structure-activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group. Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells. Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G₂/M phase arrest in Daoy cells. Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes, including Axin2, cyclinD1 and survivin in MB cells. The phosphorylation level of β-catenin also decreased in a time-and concentration-dependent manner. Collectively, our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling, and as such warrants further exploration as a promising antimedulloblastoma candidate.

关键词: Wnt signaling, Medulloblastoma, Inhibitor, Biflavone, Ginkgetin

Abstract: Medulloblastoma(MB) is a form of malignant brain tumor that predominantly arises in infants and children, of which approximately 25% is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1. Therefore, Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer. In our present study, we undertook a screening for antagonists of Wnt signaling from 600 natural compounds, and identified Ginkgetin, a biflavone isolated from Cephalotaxus fortunei var. alpina. Ginkgetin inhibited Wnt pathway with an IC₅₀ value around 5.92 μM and structure-activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group. Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells. Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G₂/M phase arrest in Daoy cells. Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes, including Axin2, cyclinD1 and survivin in MB cells. The phosphorylation level of β-catenin also decreased in a time-and concentration-dependent manner. Collectively, our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling, and as such warrants further exploration as a promising antimedulloblastoma candidate.

Key words: Wnt signaling, Medulloblastoma, Inhibitor, Biflavone, Ginkgetin

Zhen-Nan Ye, Mu-Yuan Yu, Ling-Mei Kong, Wei-Hua Wang, Yuan-Feng Yang, Jie-Qing Liu, Ming-Hua Qiu, Yan Li. Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma[J]. 应用天然产物, 2015, 5(2): 91-97.

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Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

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