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

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.