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

Yohan Seo; Jinhong Park; Minseo Kim; Ho K Lee; Jin-Hee Kim; Jin-Hyun Jeong; Wan Namkung

doi:10.1371/journal.pone.0133656

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

PLoS One. 2015 Jul 21;10(7):e0133656. doi: 10.1371/journal.pone.0133656. eCollection 2015.

Authors

Yohan Seo¹, Jinhong Park¹, Minseo Kim², Ho K Lee¹, Jin-Hee Kim², Jin-Hyun Jeong², Wan Namkung³

Affiliations

¹ Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, 120-749, Korea.
² College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 406-840, Korea.
³ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anoctamin-1
Antineoplastic Agents / pharmacology*
Antioxidants / pharmacology*
Apoptosis
Biological Products / pharmacology*
Calcium Signaling
Cell Line, Tumor
Cell Proliferation
Chloride Channels / antagonists & inhibitors
Chloride Channels / metabolism*
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
Humans
Miconazole / pharmacology
Naphthoquinones / pharmacology
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism*
Rats
Rats, Inbred F344
Ubiquinone / analogs & derivatives*
Ubiquinone / pharmacology

Substances

ANO1 protein, human
Anoctamin-1
Antineoplastic Agents
Antioxidants
Biological Products
Chloride Channels
Naphthoquinones
Neoplasm Proteins
Cystic Fibrosis Transmembrane Conductance Regulator
Ubiquinone
Miconazole
idebenone
plumbagin

Grants and funding

This work was funded by Yonsei University Global Specialization Project of 2014, a Grant of the Korea Healthcare technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI08C2149) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [NRF-2012R1A1A1040142].