Inhibition of ANO1/TMEM16A Chloride Channel by Idebenone and Its Cytotoxicity to Cancer Cell Lines

• Published in: PloS one Vol. 10; no. 7; p. e0133656
• Main Authors: Seo, Yohan, Park, Jinhong, Kim, Minseo, Lee, Ho K., Kim, Jin-Hee, Jeong, Jin-Hyun, Namkung, Wan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.07.2015; Public Library of Science (PLoS)
• Subjects: Alzheimer's disease; Alzheimers disease; Animals; Anoctamin-1; Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Apoptosis; Biological Products - pharmacology; Breast cancer; Calcium; Calcium (intracellular); Calcium chloride; Calcium Signaling; Calcium signalling; Cancer; Cell Line, Tumor; Cell migration; Cell Proliferation; Chloride channels (calcium-gated); Chloride Channels - antagonists & inhibitors; Chloride Channels - metabolism; Coenzyme Q10; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cytotoxicity; Enzymes; Esophagus; Gene expression; Humans; Inhibition; Inhibitors; Intracellular signalling; Kinases; Metabolism; Metastasis; Miconazole; Miconazole - pharmacology; Naphthoquinones - pharmacology; Natural products; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Pancreatic cancer; Penicillin; Pharmaceutical sciences; Pharmacy; Plumbagin; Prostate cancer; Rats; Rats, Inbred F344; Screening; Signal transduction; Smooth muscle; Toxicity; Tumor cell lines; Tumors; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0133656

The expression levels of anoctamin 1 (ANO1, TMEM16A), a calcium-activated chloride channel (CaCC), are significantly increased in several tumors, and inhibition of ANO1 is known to reduce cell proliferation and migration. Here, we performed cell-based screening of a collection of natural products and drug-like compounds to identify inhibitors of ANO1. As a result of the screening, idebenone, miconazole and plumbagin were identified as novel ANO1 inhibitors. Electrophysiological studies showed that idebenone, a synthetic analog of coenzyme Q10, completely blocked ANO1 activity in FRT cells expressing ANO1 without any effect on intracellular calcium signaling and CFTR, a cAMP-regulated chloride channel. The CaCC activities in PC-3 and CFPAC-1 cells expressing abundant endogenous ANO1 were strongly blocked by idebenone. Idebenone inhibited cell proliferation and induced apoptosis in PC-3 and CFPAC-1 cells, but not in A549 cells, which do not express ANO1. These data suggest that idebenone, a novel ANO1 inhibitor, has potential for use in cancer therapy.