Key Laboratory for Research on Active Ingredients in Natural Medicine of Jiangxi Province, Yichun University, Yichun, China; Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Pharmacol Res. 2020 Jun;156:104763. doi: 10.1016/j.phrs.2020.104763. Epub 2020 Mar 19.
Transmembrane member 16A (TMEM16A) encoded Ca-activated Cl channels were found to be involved in tumorigenesis. Previous studies suggest the effect of TMEM16A gene amplification on tumorigenic proliferation is exerted through its channel function. TMEM16A-specific and potent small molecule inhibitors have been proposed to potentially be useful for the treatment of cancer. Thus, we screened six analogues of avermectin for their inhibitory activities on TMEM16A mediated currents. A whole-cell patch technique was used to record the currents. The IC and E values for TMEM16A inhibition of five tested avermectins (avermectin B, ivermectin, doramectin, selamectin, and moxidectin) were 0.15-1.32 μM and 65-87 %, respectively. In addition, these avermectins significantly inhibited endogenous TMEM16A mediated currents and thus, the proliferation, migration, inducing apoptosis of LA795 cancer cells. Eprinomectin (4"-(acetylamino)-4"-deoxy-avermectin B) and two other important macrolides (erythromycin and azithromycin), which have minimal or no TMEM16A inhibitory effects, were used as negative control drugs. These drugs were found to have limited effects on the proliferation, migration, and apoptosis of LA795 cells. Finally, avermectin B and ivermectin dramatically inhibited the growth of xenograft tumors in mice. These data demonstrate that avermectins are novel TMEM16A inhibitors and are potentially useful in specific cancer therapies. These findings also provide a new opportunity to develop TMEM16A modulators.
跨膜成员 16A（TMEM16A）编码的 Ca 激活 Cl 通道被发现参与肿瘤发生。先前的研究表明，TMEM16A 基因扩增对肿瘤发生增殖的影响是通过其通道功能发挥的。已经提出 TMEM16A 特异性和有效的小分子抑制剂可能对癌症的治疗有用。因此，我们筛选了六种阿维菌素类似物，以研究它们对 TMEM16A 介导电流的抑制活性。使用全细胞贴附技术记录电流。五种测试的阿维菌素（阿维菌素 B、伊维菌素、多拉菌素、塞拉菌素和莫昔克丁）对 TMEM16A 的抑制 IC 和 E 值分别为 0.15-1.32 μM 和 65-87%。此外，这些阿维菌素显著抑制内源性 TMEM16A 介导的电流，从而抑制 LA795 癌细胞的增殖、迁移和诱导凋亡。埃普里诺菌素（4"-(乙酰氨基)-4"-脱氧阿维菌素 B）和另外两种重要的大环内酯类抗生素（红霉素和阿奇霉素），它们对 TMEM16A 几乎没有抑制作用，被用作阴性对照药物。这些药物对 LA795 细胞的增殖、迁移和凋亡的影响有限。最后，阿维菌素 B 和伊维菌素显著抑制了小鼠异种移植肿瘤的生长。这些数据表明阿维菌素是新型的 TMEM16A 抑制剂，在特定的癌症治疗中可能有用。这些发现也为开发 TMEM16A 调节剂提供了新的机会。
