title: Inhibition of ANO1/TMEM16A Chloride Channel by Idebenone and Its Cytotoxicity to Cancer Cell Lines.
abstract: 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.
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 406-840, Korea.
authors.forename: Minseo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Ho K
authors.initials: HK
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 406-840, Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 406-840, Korea.
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 120-749, Korea; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 406-840, Korea.
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001688:Biological Products / Q000494:pharmacology*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D008825:Miconazole / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D000970:Antineoplastic Agents; D000975:Antioxidants; D001688:Biological Products; D018118:Chloride Channels; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014451:Ubiquinone; D008825:Miconazole; C036619:idebenone; C014758:plumbagin