Inhibitory effect of daidzein on the calcium-activated chloride channel TMEM16A and its anti-lung adenocarcinoma activity

Xuzhao Wang; Anqi Hao; Guoqiang Song; Vorobeva Elena; Yiming Sun; Hailin Zhang; Yong Zhan; Hailong An; Yafei Chen

doi:10.1016/j.ijbiomac.2023.127261

Inhibitory effect of daidzein on the calcium-activated chloride channel TMEM16A and its anti-lung adenocarcinoma activity

Int J Biol Macromol. 2023 Dec 31;253(Pt 6):127261. doi: 10.1016/j.ijbiomac.2023.127261. Epub 2023 Oct 4.

Authors

Xuzhao Wang¹, Anqi Hao², Guoqiang Song², Vorobeva Elena², Yiming Sun², Hailin Zhang³, Yong Zhan⁴, Hailong An⁴, Yafei Chen⁵

Affiliations

¹ Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China.
² Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
³ College of Pharmacy, Hebei Medical University, Shijiazhuang 050017, Hebei, China.
⁴ Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China.
⁵ Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China. Electronic address: chenyafei@hebut.edu.cn.

PMID: 37802433
DOI: 10.1016/j.ijbiomac.2023.127261

Abstract

TMEM16A is highly expressed in a variety of tumor cells and is involved in the growth and metastasis of malignancies. It has been established that down-regulation of TMEM16A expression or functional activity can inhibit tumor cells growth. However, there is a lack of targeted inhibitors with high efficiency and low toxicity. Here, we identified a novel inhibitor daidzein from dozens of natural product molecules. Whole-cell patch clamp data indicated that daidzein inhibits TMEM16A channel in a dose-dependent manner, with IC₅₀ of 1.39 ± 0.59 μM. Western blot result showed that daidzein can also reduce the expression of TMEM16A protein in LA795 cells. These results indicated that the inhibitory effects of daidzein exert on TMEM16A in two ways, both inhibiting TMEM16A current and decreasing its protein expression. In addition, the putative binding sites of daidzein on TMEM16A are G608, G628, and K839 through molecular docking. Moreover, daidzein concentration-dependently reduced cell viability and cell migration, causing G1/S cell cycle arrest in vitro. It was also confirmed that daidzein can effectively inhibit the growth of LA795 lung adenocarcinoma cells implanted nude mice in vivo. In conclusion, daidzein can be used as a lead compound for the development of therapeutic drugs for lung adenocarcinoma.

Keywords: Daidzein; Lung adenocarcinoma; TMEM16A.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Animals
Chloride Channels / metabolism
Lung Neoplasms* / drug therapy
Mice
Mice, Nude
Molecular Docking Simulation

Substances

Chloride Channels
daidzein