Discovery of Bufadienolides as a Novel Class of ClC-3 Chloride Channel Activators with Antitumor Activities
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：July 25, 2013
- 年：2013
- 卷：56
- 期：14
- 页码：5734-5743
- 全文大小：521K
- 年卷期：v.56,no.14(July 25, 2013)
- ISSN：1520-4804
文摘
ClC-3 chloride (Cl鈥?/sup>) 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鈥?/sup> channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15尾-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl鈥?/sup> channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl鈥?/sup> channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl鈥?/sup> 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鈥?/sup> channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides.