Cepharanthine, a novel selective ANO1 inhibitor with potential for lung adenocarcinoma therapy
Xuan Zhanga b, Gaohua Zhangb, Zhijun Zhaob, Ruilian Xiub, Jie Jiab, Pingping Chenb, Yanshuang Liuc, Yuanyuan Wangb, Jianfeng Yid e✉
- aKey Laboratory for Research on Active Ingredients in Natural Medicine of Jiangxi Province, Yichun University, Yichun, China.
- bDepartment of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
- cDepartment of Diagnostics, School of Integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- dResearch Center for Differentiation and Development of Traditional Chinese Medicine Basic Theory, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- eKey Laboratory for Research on Active Ingredients in Natural Medicine of Jiangxi Province, Yichun University, Yichun, China.. Electronic address: jianfeng_yi21@163.com
- ✉Corresponding author
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Abstract
Anoctamin-1 (ANO1), also known as transmembrane protein 16A (TMEM16A), is identified as a Ca 2+ -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 IC 50 of 11.2 ± 0.9 μM and E max of 92.7 ± 1.7%. The Lys 384 , Arg 535 , Thr 539 , and Glu 624 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 Ca 2+ -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.