Benzophenanthridine alkaloids suppress lung adenocarcinoma by blocking TMEM16A Ca2+-activated Cl- channels.

An increasing amount of evidence suggests that transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl- channels play a crucial role in regulating tumorigenesis. Therefore, specific and potent TMEM16A inhibitors have been proposed to potentially be useful for the treatment of cancer. During drug screening, we found that benzophenanthridine alkaloids (sanguinarine, sanguinarium chloride, sanguinarine nitrate, ethoxysanguinarine, chelerythrine, and dihydrosanguinarine) potently inhibited the recombinant TMEM16A current. The IC50 and Emax values for TMEM16A inhibition of six tested benzophenanthridine alkaloids were 5.6-12.3 μM and 77-91%, respectively. These benzophenanthridine alkaloids also significantly inhibited the endogenous TMEM16A currents and proliferation, migration, and induced apoptosis in LA795 lung adenocarcinoma cells. These data demonstrate that benzophenanthridine alkaloids are novel TMEM16A inhibitors and are potentially useful in specific cancer therapies. These findings also provide new insight for the development of TMEM16A inhibitors.