Idebenone Inhibits Cell Proliferation by Blocking of ANO1/ TMEM16A Chloride Channel in Adenocarcinoma Cells

Ca2+-activated Clˉ channels (CaCCs) play a pivotal role in a number of physiological processes including regulation of cell proliferation, differentiation and apoptosis. The expression levels of anoctamin 1 (ANO1, TMEM16A), a CaCC, are significantly increased in several tumors such as prostate adenocarcinomas and head and neck squamous cell carcinomas. Recent studies revealed that inhibition of ANO1 significantly reduced cell proliferation, cell migration, tumorigenesis and cancer progression. Here, we performed cell-based screening of a collection of drugs and drug-like compounds to identify inhibitors of ANO1. We found that idebenone, a synthetic analog of coenzyme Q10, is a potent inhibitor of ANO1. Electrophysiological studies showed that idebenone completely blocked ANO1 activity in ANO1 expressing FRT cells and significantly inhibited current of CaCC in PC-3 cells expressing abundant endogenous ANO1. Idebenone strongly inhibited cell migration in PC-3 cells, and it did not affect the intracellular Ca2+ concentration. We investigated the effect of idebenone on the cell proliferation and apoptosis in adenocarcinoma cell lines. Idebenone significantly reduced cell proliferation and induced apoptosis in PC-3, CFPAC-1, HT-29, T-84 and Calu-3 cells having CaCCs activities. These data suggest that idebenone, an ANO1/CaCC inhibitor, has potential for use in cancer therapy.