Matrine is a novel inhibitor of the TMEM16A chloride channel with antilung adenocarcinoma effects.Calcium-activated chloride channels (CaCCs) are ion channels with key roles in physiological processes.  In this study, we determined that matrine is a potent TMEM16A inhibitor that exerts anti-lung adenocarcinoma effects.  Patch clamp experiments showed that matrine inhibited TMEM16A current in a concentration-dependent manner with an IC 50 of 27.94 ± 4.78 μM.  Molecular simulation and site-directed mutation experiments demonstrated that the matrine-sensitive sites of the TMEM16A channel involve the amino acids Y355, F411, and F415.  Results of cell viability and wound healing assays showed that matrine significantly inhibited the proliferation and migration of LA795 cells, which exhibit high TMEM16A expression.  In contrast, matrine has only weak inhibitory effect on CCD-19Lu and HeLa cells lacking TMEM16A expression.  Matrine-induced effects on the proliferation and migration of LA795 cells were abrogated upon shRNA-mediated TMEM16A knockdown in LA795 cells.  Finally, in vivo experiments demonstrated that matrine dramatically inhibited the growth of lung adenocarcinoma xenograft tumors in mice but did not affect mouse body weight.  Collectively, these data indicate that matrine is an effective and safe TMEM16A inhibitor and that TMEM16A is the target of matrine anti-lung adenocarcinoma activity. 
Matrine
Matrine is a novel inhibitor of the TMEM16A chloride channel with antilung adenocarcinoma effects.Calcium-activated chloride channels (CaCCs) are ion channels with key roles in physiological processes. 
TMEM16A chloride channel
Patch clamp experiments showed that matrine inhibited TMEM16A current in a concentration-dependent manner with an IC 50 of 27.94 ± 4.78 μM. 
Patch clamp experiments
Molecular simulation and site-directed mutation experiments demonstrated that the matrine-sensitive sites of the TMEM16A channel involve the amino acids Y355, F411, and F415. 
Molecular simulation
Molecular simulation and site-directed mutation experiments demonstrated that the matrine-sensitive sites of the TMEM16A channel involve the amino acids Y355, F411, and F415. 
Site-directed mutation experiments
Results of cell viability and wound healing assays showed that matrine significantly inhibited the proliferation and migration of LA795 cells, which exhibit high TMEM16A expression. 
Wound healing assays
Matrine-induced effects on the proliferation and migration of LA795 cells were abrogated upon shRNA-mediated TMEM16A knockdown in LA795 cells. 
shRNA-mediated TMEM16A knockdown
Finally, in vivo experiments demonstrated that matrine dramatically inhibited the growth of lung adenocarcinoma xenograft tumors in mice but did not affect mouse body weight. 
In vivo experiments