Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling
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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
Yan Li, e-mail: [email protected]
Xiao-Dong Luo, e-mail: [email protected]
Keywords: Bisleuconothine A, inhibitor, Wnt signaling, colorectal cancer cells
Received: August 26, 2015 Accepted: January 23, 2016 Published: February 04, 2016
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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