College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and §Department of Pharmacology, College of Medicine, Jinan University , Guangzhou 510632, People's Republic of China.
J Med Chem. 2013 Jul 25;56(14):5734-43. doi: 10.1021/jm400881m. Epub 2013 Jul 10.
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.
氯离子通道 ClC-3 已被证明参与细胞增殖、细胞周期和细胞迁移过程。在此，我们发现，从蟾蜍毒液中分离出的一系列蟾毒内酯是一类新型的 ClC-3 氯离子通道激活剂，具有抗肿瘤活性。其中，蟾毒灵具有最强的抗肿瘤活性，而 15β-乙酰氧基蟾毒灵则没有抗肿瘤活性，因此选择这两种化合物作为代表性化合物来研究 ClC-3 氯离子通道的作用。研究发现，蟾毒灵能迅速激活 ClC-3 氯离子通道，并通过抑制 PI3K/Akt/mTOR 通路诱导细胞凋亡。氯离子通道阻滞剂（他莫昔芬和 5-硝基-2-(3-苯丙基氨基)苯甲酸，NPPB）或 ClC-3 小干扰 RNA 预处理可减弱 PI3K/Akt/mTOR 通路。综上所述，我们发现激活 ClC-3 氯离子通道，随后抑制 PI3K/Akt/mTOR 信号通路，参与了蟾毒内酯的抗肿瘤活性。
