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Research Papers:

Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling

Ling-Mei Kong, Tao Feng, Yuan-Yuan Wang, Xing-Yao Li, Zhen-Nan Ye, Tao An, Chen Qing, Xiao-Dong Luo and Yan Li _

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Oncotarget. 2016; 7:10203-10214. https://doi.org/10.18632/oncotarget.7190

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Abstract

Ling-Mei Kong1,2, Tao Feng1, Yuan-Yuan Wang3, Xing-Yao Li1,4, Zhen-Nan Ye1,2, Tao An1,2, Chen Qing5, Xiao-Dong Luo1, Yan Li1

1State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

2University of the Chinese Academy of Sciences, Beijing 100049, China

3Harbin Institute of Technology (Weihai), Weihai 264209, China

4Present address: Georgia Regents University Health Sciences Campus, Augusta, Georgia 30912, USA

5Kunming Medical University, Kunming 650500, China

Correspondence to:

Yan Li, e-mail: liyanb@mail.kib.ac.cn

Xiao-Dong Luo, e-mail: xdluo@mail.kib.ac.cn

Keywords: Bisleuconothine A, inhibitor, Wnt signaling, colorectal cancer cells

Received: August 26, 2015     Accepted: January 23, 2016     Published: February 04, 2016

ABSTRACT

Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer and small molecule antagonists of Wnt/β-catenin signaling are attractive candidates for developing effective therapeutics. In the present study, we identified Bisleuconothine A, a bisindole alkaloid with an eburnane-aspidosperma type skeleton, as a novel and selective Wnt signaling inhibitor by using a cell-based luciferase assay system. Our study found that Bisleuconothine A down-regulated the endogenous Wnt target gene expression through promoting phosphorylation of β-catenin and the subsequent inhibition of its nuclear translocation in HCT116 and SW480 colorectal cancer cells. In vitro, Bisleuconothine A inhibited cell proliferation through induction of apoptosis by increasing the cleavage of caspases in HCT116 and SW480 colorectal cancer cells. Moreover, in vivo, Bisleuconothine A dramatically suppressed tumor growth in HCT116 Xenograft. And further analysis showed that Bisleuconothine A suppressed the Wnt target gene expression in HCT116 Xenograft, which was associated with up-regulation of β-catenin phosphorylation and subsequent Wnt signaling inhibition. Taken together, our study indicated that bisindole alkaloids could be included as a new chemotype of small-molecule Wnt signaling inhibitors, and have great potential to be further developed for anti-tumor agents.


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