Referenced in: none

Automatically associated channels: ClC3 , ClC4

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

Authors: Junshan Liu, Dongmei Zhang, Yuan Li, Weimin Chen, Zhixiong Ruan, Lijuan Deng, Liwei Wang, Haiyan Tian, Anita Yiu, Chunlin Fan, Hai Luo, Shanwen Liu, Ying Wang, Gaokeng Xiao, Lixin Chen, Wencai Ye

Journal, date & volume: J. Med. Chem., 2013 Jul 25 , 56, 5734-43

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23799775

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.