Cepharanthine, a novel selective ANO1 inhibitor with potential for lung adenocarcinoma therapy

• Published in: Biochimica et biophysica acta. Molecular cell research 2021-11, Vol.1868 (12), p.119132-119132, Article 119132
• Main Authors: Zhang, Xuan, Zhang, Gaohua, Zhao, Zhijun, Xiu, Ruilian, Jia, Jie, Chen, Pingping, Liu, Yanshuang, Wang, Yuanyuan, Yi, Jianfeng
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - drug therapy; Animals; ANO1; Anoctamin-1 - antagonists & inhibitors; Anoctamin-1 - chemistry; Anoctamin-1 - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Benzylisoquinolines - pharmacology; Benzylisoquinolines - therapeutic use; Binding Sites; CaCCs; Cepharanthine; CHO Cells; Cricetinae; Cricetulus; Humans; Lung adenocarcinoma; Lung Neoplasms - drug therapy; Male; Mice; Mice, Inbred BALB C; Protein Binding; Selective inhibitor
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2021.119132

Anoctamin-1 (ANO1), also known as transmembrane protein 16A (TMEM16A), is identified as a Ca2+-activated Cl− channel that is expressed in many organs and tissues. It is involved in numerous major physiological functions and especially in tumor growth. By screening 530 natural compounds, we identified cepharanthine as a potent blocker of ANO1 channels with an IC50 of 11.2 ± 0.9 μM and Emax of 92.7 ± 1.7%. The Lys384, Arg535, Thr539, and Glu624 in ANO1 are critical for the inhibitory effect of cepharanthine. Similar to its effect on ANO1, cepharanthine inhibits ANO2, the closest analog of TMEM16A. In contrast, up to 30 μM of cepharanthine showed limited inhibitory effects on recombinant ANO6 and bestrophin-1-encoded Ca2+-activated Cl− currents, but it showed no effects on endogenous volume-regulated anion currents (VRAC). Cepharanthine could also potently suppress endogenous ANO1 currents, significantly inhibit cell proliferation and migration, and induce apoptosis in LA795 lung adenocarcinoma cells. Moreover, animal experiments have shown that cepharanthine can dramatically inhibit the growth of xenograft tumors in mice. The high specificity provided by cepharanthine could be an important foundation for future studies of the physiological role of ANO1 channels, and these findings may reveal a new mechanism of its anticancer effect. •Cepharanthine is a potent and selective blocker of ANO1 channels.•The Lys384, Arg535, Thr539, and Glu624 in ANO1 are critical for the inhibitory effect of cepharanthine.•Inhibition of ANO1 by cepharanthine may be related to its in vitro and in vivo anticancer effect.