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

Ye ZN, Yu MY, Kong LM, Wang WH, Yang YF, Liu JQ, Qiu MH, Li Y - Nat Prod Bioprospect (2015)

Bottom Line: 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 anti-medulloblastoma candidate.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.

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 anti-medulloblastoma candidate.

No MeSH data available.


Related in: MedlinePlus

Ginkgetin inhibited the growth of Daoy and D283 cell lines, and induced G2/M cell cycle arrest in Daoy cells. a Effects of Ginkgetin on cell viability. Daoy and D283 cells were treated with Ginkgetin for 48 h. Cell viability was detected by MTS assay and represented with relative viability versus control. b Calculated IC50 values of the cytotoxicity of Ginkgetin (mean ± SD, n = 3). c Ginkgetin induced G2/M arrest in Daoy cells. Cells were incubated with Ginkgetin at indicated concentrations for 24 h. Then the cells were stained with PI (propidium iodide) and analyzed by flow cytometry. Counts of G2/M phase cells increased remarkably under Ginkgetin treatment in a dose-dependent manner. d Quantification of flow cytometry analysis of cell cycle (mean ± SD, n = 3)
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Fig2: Ginkgetin inhibited the growth of Daoy and D283 cell lines, and induced G2/M cell cycle arrest in Daoy cells. a Effects of Ginkgetin on cell viability. Daoy and D283 cells were treated with Ginkgetin for 48 h. Cell viability was detected by MTS assay and represented with relative viability versus control. b Calculated IC50 values of the cytotoxicity of Ginkgetin (mean ± SD, n = 3). c Ginkgetin induced G2/M arrest in Daoy cells. Cells were incubated with Ginkgetin at indicated concentrations for 24 h. Then the cells were stained with PI (propidium iodide) and analyzed by flow cytometry. Counts of G2/M phase cells increased remarkably under Ginkgetin treatment in a dose-dependent manner. d Quantification of flow cytometry analysis of cell cycle (mean ± SD, n = 3)

Mentions: As is known, the aberrant activation of Wnt pathway is correlated with sporadic MB [32], and literature data suggested β-catenin and other Wnt pathway components are over-activated in Daoy [33] and D283 [20, 34] cells. Thus the cytotoxicity of Ginkgetin was tested towards the two MB cell lines. Cells were exposed to the compound at concentrations up to 20 μM and the calculated IC50 values were 14.65 ± 0.07 and 15.81 ± 0.57 μM, towards Daoy and D283 cells respectively (Fig. 2a, b).Fig. 2


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

Ye ZN, Yu MY, Kong LM, Wang WH, Yang YF, Liu JQ, Qiu MH, Li Y - Nat Prod Bioprospect (2015)

Ginkgetin inhibited the growth of Daoy and D283 cell lines, and induced G2/M cell cycle arrest in Daoy cells. a Effects of Ginkgetin on cell viability. Daoy and D283 cells were treated with Ginkgetin for 48 h. Cell viability was detected by MTS assay and represented with relative viability versus control. b Calculated IC50 values of the cytotoxicity of Ginkgetin (mean ± SD, n = 3). c Ginkgetin induced G2/M arrest in Daoy cells. Cells were incubated with Ginkgetin at indicated concentrations for 24 h. Then the cells were stained with PI (propidium iodide) and analyzed by flow cytometry. Counts of G2/M phase cells increased remarkably under Ginkgetin treatment in a dose-dependent manner. d Quantification of flow cytometry analysis of cell cycle (mean ± SD, n = 3)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Ginkgetin inhibited the growth of Daoy and D283 cell lines, and induced G2/M cell cycle arrest in Daoy cells. a Effects of Ginkgetin on cell viability. Daoy and D283 cells were treated with Ginkgetin for 48 h. Cell viability was detected by MTS assay and represented with relative viability versus control. b Calculated IC50 values of the cytotoxicity of Ginkgetin (mean ± SD, n = 3). c Ginkgetin induced G2/M arrest in Daoy cells. Cells were incubated with Ginkgetin at indicated concentrations for 24 h. Then the cells were stained with PI (propidium iodide) and analyzed by flow cytometry. Counts of G2/M phase cells increased remarkably under Ginkgetin treatment in a dose-dependent manner. d Quantification of flow cytometry analysis of cell cycle (mean ± SD, n = 3)
Mentions: As is known, the aberrant activation of Wnt pathway is correlated with sporadic MB [32], and literature data suggested β-catenin and other Wnt pathway components are over-activated in Daoy [33] and D283 [20, 34] cells. Thus the cytotoxicity of Ginkgetin was tested towards the two MB cell lines. Cells were exposed to the compound at concentrations up to 20 μM and the calculated IC50 values were 14.65 ± 0.07 and 15.81 ± 0.57 μM, towards Daoy and D283 cells respectively (Fig. 2a, b).Fig. 2

Bottom Line: 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 anti-medulloblastoma candidate.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.

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 anti-medulloblastoma candidate.

No MeSH data available.


Related in: MedlinePlus