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.
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.
Int J Biol Macromol. 2023 Dec 31;253(Pt 6):127261. doi: 10.1016/j.ijbiomac.2023.127261. Epub 2023 Oct 4.
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 IC 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.
TMEM16A 在多种肿瘤细胞中高表达，参与恶性肿瘤的生长和转移。已经证实下调 TMEM16A 的表达或功能活性可以抑制肿瘤细胞的生长。然而，目前缺乏高效低毒的靶向抑制剂。在这里，我们从数十种天然产物分子中鉴定出一种新型抑制剂大豆苷元。全细胞膜片钳数据表明，大豆苷元以剂量依赖的方式抑制 TMEM16A 通道，IC 为 1.39±0.59μM。Western blot 结果表明，大豆苷元也可以降低 LA795 细胞中 TMEM16A 蛋白的表达。这些结果表明，大豆苷元对 TMEM16A 的抑制作用有两种方式，既抑制 TMEM16A 电流，又降低其蛋白表达。此外，通过分子对接，大豆苷元在 TMEM16A 上的可能结合位点为 G608、G628 和 K839。此外，大豆苷元浓度依赖性地降低细胞活力和细胞迁移，导致体外 G1/S 细胞周期停滞。还证实大豆苷元可有效抑制体内植入裸鼠的 LA795 肺腺癌细胞的生长。总之，大豆苷元可作为开发肺腺癌治疗药物的先导化合物。
