Inhibition of transmembrane member 16A calcium‐activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects

Zhang, Xuan; Li, Honglin; Zhang, Huiran; Liu, Yani; Huo, Lifang; Jia, Zhanfeng; Xue, Yucong; Sun, Xiaorun; Zhang, Wei

doi:10.1111/bph.13841

Cited by 51 publications

(24 citation statements)

References 40 publications

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“…Several studies have confirmed that T16Ainh-A01 and CaCCinh-A01 exert their inhibitory effects in a dose-dependent manner [18,19,27,28]. T16Ainh-A01 (10 µM) strongly inhibits TMEM16A-mediated iodide influx and completely blocks CaCC conductance in salivary gland cells.…”

Section: Discussionmentioning

confidence: 92%

Effects of the Calcium-Activated Chloride Channel Inhibitors T16Ainh-A01 and CaCCinh-A01 on Cardiac Fibroblast Function

Tian

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Calcium-activated chloride channels (CaCCs) regulate numerous physiological processes including cell proliferation, migration, and extracellular matrix secretion. T16Ainh-A01 and CaCCinh-A01 are selective inhibitors of CaCCs. But it is unknown whether these two compounds have functional effects on cardiac fibroblasts (CFs). Methods: Primary CFs were obtained by enzymatic dissociation of cardiomyocytes from neonatal rat hearts. Intracellular Ca²⁺ ([Ca²⁺]_i) and Cl^- ([Cl^-]_i) were measured using the fluorescent calcium indicators (Fluo-4 AM) and N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide respectively. The expression of anoctamin-1 (ANO1) and α-smooth muscle actin (α-SMA) was detected by quantitative RT-PCR, immunofluorescence, and western blotting. A hydroxyproline assay was used to examine collagen secretion. Cell proliferation, cell cycle distribution, and cell migration were assessed by Cell Counting Kit-8, flow cytometry, and Transwell assays, respectively. Results: ANO1 was preferentially expressed on the nuclear membrane and partially within intracellular compartments around the nucleus. T16Ainh-A01 and CaCCinh-A01 displayed different inhibitory effects on [Cl^-]_i in CFs. T16Ainh-A01 considerably decreased [Cl^-]_i in the nucleus, whereas CaCCinh-A01 reduced [Cl^-]_i in intracellular compartments around the nucleus, and both inhibitors exhibited a minimal effect on [Ca²⁺]_i in CFs. ANO1 and α-SMA expression levels were significantly repressed by CaCCinh-A01. T16Ainh-A01 showed a marked inhibitory effect on the mRNA levels of ANO1 and α-SMA, but had a negligible effect on ANO1 at the protein level. T16Ainh-A01 and CaCCinh-A01 led to the significant repression of cell proliferation, cell migration, and collagen secretion in CFs. Conclusion: Our findings indicate that T16Ainh-A01 and CaCCinh-A01 have the potential to inhibit the proliferation and collagen secretion of CFs and may serve as novel anti-fibrotic therapeutic drugs in the future.

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Section: Discussionmentioning

confidence: 92%

Effects of the Calcium-Activated Chloride Channel Inhibitors T16Ainh-A01 and CaCCinh-A01 on Cardiac Fibroblast Function

Tian

Wang

et al. 2018

Cell Physiol Biochem

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“…Inhibitors of TMEM16A also comprise chemically synthesized compounds and the components from natural products. Some natural products have been identified as inhibitors of TMEM16A, including tannic acid and related gallotannins (Namkung, Thiagarajah, Phuan, & Verkman, ), the major component of clove oil, eugenol (4‐allyl‐2‐methoxyphenol; Yao et al, ), shikonin (Jiang, Yu, Yang, & Ma, ), dehydroandrographolide (DP) (Sui et al, ), and flavonoid compounds (luteolin, galangin, quercetin, and fisetin; X. Zhang et al, ). These compounds were found to have the ability to resist diarrhea or inhibit proliferation, migration, and invasion of cancer cells.…”

Section: Tmem16a Modulators (Summarized In Table )mentioning

confidence: 99%

“…dehydroandrographolide (DP)(Sui et al, 2015), and flavonoid compounds(luteolin, galangin, quercetin, and fisetin;X. Zhang et al, 2017).…”

mentioning

confidence: 99%

Recent advances in TMEM16A: Structure, function, and disease

Guo

Wang

et al. 2018

Journal Cellular Physiology

103

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TMEM16A (also known as anoctamin 1, ANO1) is the molecular basis of the calcium‐activated chloride channels, with ten transmembrane segments. Recently, atomic structures of the transmembrane domains of mouse TMEM16A (mTMEM16A) were determined by single‐particle electron cryomicroscopy. This gives us a solid ground to discuss the electrophysiological properties and functions of TMEM16A. TMEM16A is reported to be dually regulated by Ca2+ and voltage. In addition, the dysfunction of TMEM16A has been found to be involved in many diseases including cystic fibrosis, various cancers, hypertension, and gastrointestinal motility disorders. TMEM16A is overexpressed in many cancers, including gastrointestinal stromal tumors, gastric cancer, head and neck squamous cell carcinoma (HNSCC), colon cancer, pancreatic ductal adenocarcinoma, and esophageal cancer. Furthermore, overexpression of TMEM16A is related to the occurrence, proliferation, and migration of tumor cells. To date, several studies have shown that many natural compounds and synthetic compounds have regulatory effects on TMEM16A. These small molecule compounds might be novel drugs for the treatment of diseases caused by TMEM16A dysfunction in the future. In addition, recent studies have shown that TMEM16A plays different roles in different diseases through different signal transduction pathways. This review discusses the topology, electrophysiological properties, modulators and functions of TMEM16A in mediates nociception, gastrointestinal dysfunction, hypertension, and cancer and focuses on multiple regulatory mechanisms regarding TMEM16A.

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“…Some TMEM16A inhibitors have been identified. One class belongs to natural product TMEM16A inhibitors, including tannic acid, and related gallotannins, 8 eugenol (4-allyl-2-methoxyphenol), 9 shikonin, 10 dehydroandrographolide (DP), 11 flavonoid compounds (luteolin, galangin, quercetin, and fisetin), 12 and matrine. 13 The other class is consists of chemically synthesized TMEM16A inhibitors, including niflumicacid (NFA), 14 CaCC inh -A01, 15 T16A inh -A01, 16 MONNA (N-((4-methoxy)-2-naphthyl)-5nitroanthranilic acid), 17 9-phenanthrol, 18 substituted 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs).…”

Section: Introductionmentioning

confidence: 99%

Activation of TMEM16A by natural product canthaxanthin promotes gastrointestinal contraction

Shi

Guo

et al. 2020

FASEB j.

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Transmembrane 16A (TMEM16A), also known as anoctamin 1, is the molecular basis of the calcium‐activated chloride channels. TMEM16A is present in interstitial cells of Cajal, which are the pacemaker cells that control smooth muscle contraction. TMEM16A is implicated in gastrointestinal disorders. Activation of TMEM16A is believed to promote the gastrointestinal muscle contraction. Here, we report a highly efficient, nontoxic, and selective activator of TMEM16A, canthaxanthin (CX). The study using molecular docking and site‐directed mutation revealed that CX‐specific binging site in TMEM16A is K769. CX was also found to promote the contraction of smooth muscle cells in gastrointestinal tract through activation of TMEM16A channels, which provides an excellent basis for development of CX as a chemical tool and potential therapeutic for gastrointestinal dysfunction.

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Inhibition of transmembrane member 16A calcium‐activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects

Abstract: This study demonstrates that flavonoids inhibit TMEM16A currents and suggests that flavonoids could have anticancer effects via this mechanism.

Cited by 51 publications

References 40 publications

Effects of the Calcium-Activated Chloride Channel Inhibitors T16Ainh-A01 and CaCCinh-A01 on Cardiac Fibroblast Function

Effects of the Calcium-Activated Chloride Channel Inhibitors T16Ainh-A01 and CaCCinh-A01 on Cardiac Fibroblast Function

Recent advances in TMEM16A: Structure, function, and disease

Activation of TMEM16A by natural product canthaxanthin promotes gastrointestinal contraction

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