Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects
Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects
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天然黄酮类化合物抑制 TMEM16A 钙激活氯离子通道有助于黄酮类化合物的抗癌作用：天然黄酮类化合物抑制 TMEM16A Cl- 通道
DOI：
10.1111/bph.13841
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发表时间：
2017-07-01
影响因子：
7.3
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Zhang, Xuan;Li, Honglin;Zhang, Wei
背景和技术天然类黄酮普遍存在于膳食植物和蔬菜中，并已被提出具有抗病毒、抗氧化、心血管保护和抗癌作用。跨膜成员16 A（TMEM 16 A）编码的Ca ~（2+）激活的Cl ~-通道在许多器官和组织中发挥着多种生理作用。TMEM 16 A的过表达也被认为与癌症进展相关。因此，抑制TMEM 16 A电流可能是癌症治疗的潜在靶点。本研究中，我们筛选了广谱的黄酮类化合物对TMEM 16 A电流的抑制活性，实验方法采用全细胞膜片钳技术记录电流。在100 μ M的浓度下，20种化合物中有10种对TMEM 16 A电流产生显著抑制（> 50%）。四种最有效的化合物-毛地黄黄酮、高良姜素、槲皮素和非瑟酮-的IC 50值范围为4.5至15 μ M。为了研究这些发现的生理相关性，我们还研究了这些黄酮类化合物对LA 795癌细胞中内源性TMEM 16 A电流以及细胞增殖和迁移的影响。在类黄酮测试，我们检测到TMEM 16 A电流抑制和细胞增殖或减少migration.CONCLUSIONS和IMPLICATIONS本研究表明，类黄酮抑制TMEM 16 A电流，并表明类黄酮可以通过这种机制具有抗癌作用之间的高度显着的相关性。
BACKGROUND AND PURPOSENatural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective and anticancer effects. Transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl- channels play a variety of physiological roles in many organs and tissues. Overexpression of TMEM16A is also believed to be associated with cancer progression. Therefore, inhibition of TMEM16A current may be a potential target for cancer therapy. In this study, we screened a broad spectrum of flavonoids for their inhibitory activities on TMEM16A currents.EXPERIMENTAL APPROACHA whole-cell patch technique was used to record the currents. The BrdU assay and transwell technique were used to investigate cell proliferation and migration.KEY RESULTSAt a concentration of 100 mu M, 10 of 20 compounds caused significant (> 50%) inhibition of TMEM16A currents. The four most potent compounds-luteolin, galangin, quercetin and fisetin-had IC50 values ranging from 4.5 to 15 mu M). To examine the physiological relevance of these findings, we also studied the effects of these flavonoids on endogenous TMEM16A currents in addition to cell proliferation and migration in LA795 cancer cells. Among the flavonoids tested, we detected a highly significant correlation between TMEM16A current inhibition and cell proliferation or reduction of migration.CONCLUSIONS AND IMPLICATIONSThis study demonstrates that flavonoids inhibit TMEM16A currents and suggests that flavonoids could have anticancer effects via this mechanism.