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Discovery of bufadienolides as a novel class of ClC-3 chloride channel activators with antitumor activities.

Authors
  • Liu, Junshan
  • Zhang, Dongmei
  • Li, Yuan
  • Chen, Weimin
  • Ruan, Zhixiong
  • Deng, Lijuan
  • Wang, Liwei
  • Tian, Haiyan
  • Yiu, Anita
  • Fan, Chunlin
  • Luo, Hai
  • Liu, Shanwen
  • Wang, Ying
  • Xiao, Gaokeng
  • Chen, Lixin
  • Ye, Wencai
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jul 25, 2013
Volume
56
Issue
14
Pages
5734–5743
Identifiers
DOI: 10.1021/jm400881m
PMID: 23799775
Source
Medline
License
Unknown

Abstract

ClC-3 chloride (Cl(-)) channel has been shown to be involved in cell proliferation, cell cycle, and cell migration processes. Herein, we found that a series of bufadienolides isolated from toad venom were a novel class of ClC-3 Cl(-) channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15β-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl(-) channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl(-) channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl(-) channel blockers [tamoxifen and 5-nitro-2-(3-phenylpropylamino)benzoic acid, NPPB] or ClC-3 small interfereing RNA. In summary, we discovered that activation of the ClC-3 Cl(-) channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides.

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