Matrine is a novel inhibitor of the TMEM16A chloride channel with antilung adenocarcinoma effects

Abstract

Calcium‐activated chloride channels (CaCCs) are ion channels with key roles in physiological processes. They are abnormally expressed in various cancers, including esophageal squamous cell cancer, head and neck squamous cell carcinoma, colorectal cancer, and gastrointestinal stromal tumors. The CaCC component TMEM16A/ANO1 was recently shown to be overexpressed in lung adenocarcinoma cells and may serve as a tumorigenic protein. 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. These findings provide new insight for the development of novel treatments for lung adenocarcinoma.

Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma

“…The three amino acid residues K384, R515, and R535 were located at the entrance of the TMEM16A protein near the pore outside in the cell membrane. The binding sites of a variety of TMEM16A inhibitors were compared, and we found that there are many inhibitors binding with TMEM16A in this region, including CaCC inh -A01, arctigenin, and matrine (Guo et al, 2019a;Guo et al, 2020b;Shi et al, 2020). Moreover, the binding sites of many inhibitors to TMEM16A included two same amino acid residues R515 and R535.…”

Effect of Compound Kushen Injection, a Natural Compound Mixture, and Its Identified Chemical Components on Migration and Invasion of Colon, Brain, and Breast Cancer Cell Lines

“…For example, oxymatrine impaired angiogenesis in mouse breast cancer in vitro and in vivo , by altering NF-κB pathway and VEGF signaling (34). Matrine inhibited migration and proliferation of mouse lung adenocarcinoma in vitro and slowed xenograft growth in vivo , by reducing expression of a calcium-dependent chloride channel shown to be upregulated in multiple cancer types (35, 36). Consistent with these findings, we found matrine added to the CKI minor fraction further impaired cancer cell migration (Figure 2C); however, in contrast, addition of oxymatrine to the CKI minor fraction did not affect the control of migration in any of the cell lines we tested.…”

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

“…Cl – channel inhibition Shikonin 6.5 [ 201 ] Preclinical Inhibition of CaCCs and Ca 2+ -activated basolateral K + channel Natural flavonoids (1 – Luteolin, 2 – Galangin, 3 – Quercetin and 4 – Fisetin) 4.5–15 [ 210 ] Preclinical Modulation of several ion channels. Inhibition of TMEM16A Matrine 27.94 [ 211 ] Preclinical Inhibition of TMEM16A Dehydroandrographolide ~20 [ 212 ] Preclinical Inhibition of TMEM16A. Anticancer activity Avermectins 0.15–1.32 [ 213 ] Preclinical Anthelmintic agents.…”