TY - JOUR
T1 - Limonoids with Wnt signal inhibitory activity isolated from the fruits of Azadirachta excelsa
AU - Fuentes, Rolly G.
AU - Toume, Kazufumi
AU - Arai, Midori A.
AU - Sadhu, Samir K.
AU - Ahmed, Firoj
AU - Ishibashi, Masami
N1 - Funding Information:
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (Grant Numbers, 23102008, 26305001 and 25870128). We are grateful to Prof. J. Nathans (John Hopkins University School of Medicine) for providing us with STF/293 cells and Prof. R.T. Moon (University of Washington) for the SuperFOPflash plasmid.
Publisher Copyright:
© 2015 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
PY - 2015/3
Y1 - 2015/3
N2 - The Wnt signal regulates various biological processes, and its aberrant activation is associated with the development of diseases. Thus, inhibiting the Wnt signal provides a promising strategy to treat these diseases. Our cell-based luciferase assay system, which targets the Wnt signal (TOP assay), revealed that Azadirachta excelsa inhibited the Wnt signal. The activity-guided isolation of the MeOH fruit extract of A. excelsa provided one new (1) and seven known (2-8) limonoids. Their structures were elucidated based on their spectroscopic data, and their NMR data were compared with those in the literature. Compounds 3-6 potently inhibited the Wnt signal with IC50 values of 127 nM, 300 nM, 252 nM, and 121 nM, respectively. Compound 4 exhibited selective cytotoxicity against AGS and HCT116. Western blot analysis showed that 4 did not affect the level or localization of β-catenin, but downregulated the level of c-myc. Our results suggested that 4 may have inhibited the Wnt signal by affecting the components downstream of β-catenin.
AB - The Wnt signal regulates various biological processes, and its aberrant activation is associated with the development of diseases. Thus, inhibiting the Wnt signal provides a promising strategy to treat these diseases. Our cell-based luciferase assay system, which targets the Wnt signal (TOP assay), revealed that Azadirachta excelsa inhibited the Wnt signal. The activity-guided isolation of the MeOH fruit extract of A. excelsa provided one new (1) and seven known (2-8) limonoids. Their structures were elucidated based on their spectroscopic data, and their NMR data were compared with those in the literature. Compounds 3-6 potently inhibited the Wnt signal with IC50 values of 127 nM, 300 nM, 252 nM, and 121 nM, respectively. Compound 4 exhibited selective cytotoxicity against AGS and HCT116. Western blot analysis showed that 4 did not affect the level or localization of β-catenin, but downregulated the level of c-myc. Our results suggested that 4 may have inhibited the Wnt signal by affecting the components downstream of β-catenin.
KW - Adenomatous polyposis coli
KW - Colorectal cancer
KW - Limonoids
KW - β-Catenin
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U2 - 10.1016/j.phytol.2015.01.015
DO - 10.1016/j.phytol.2015.01.015
M3 - Article
AN - SCOPUS:84922270864
SN - 1874-3900
VL - 11
SP - 280
EP - 285
JO - Phytochemistry Letters
JF - Phytochemistry Letters
ER -
