Three sesquiterpene lactones suppress lung adenocarcinoma by blocking TMEM16A-mediated Ca2+-activated Cl− channels
Ruilian Xiu1,2,#, Jie Jia1,2,#, Qing Zhang3, Fengjiao Liu1,2, Yaxin Jia1,2, Yuanyuan Zhang1,2, Beibei Song4, Xiaodan Liu4, Jingwei Chen5, Dongyang Huang6, Fan Zhang7, Juanjuan Ma2, Honglin Li8,*, Xuan Zhang1,6,7,*, and Yunyun Geng1,2,*
1Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, 2Hebei International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese Medicine, Shijiazhuang 050091, 3College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, 4The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, 5Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, 6Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, 7Hebei Higher Education Applied Technology Research Center of TCM Development and Industrialization, Hebei University of Chinese Medicine, Shijiazhuang 050200, 8Department of Pharmacy, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, China
Author contributions: R.X.: Investigation, Formal analysis, Data curation, Visualization, Writing original draft, preparation. J.J.: Investigation, Visualization. Q.Z.: Investigation, Data curation, Visualization. F.L.: Investigation. Y.J.: Investigation. Y.Z.: Investigation. B.S.: Formal analysis. X.L.: Validation. J.C.: Validation. D.H.: Validation. F.Z.: Reviewing and editing. J.M.: Reviewing and editing. H.L.: Writing, Reviewing and editing. X.Z.: Conceptualization, Visualization, Writing, review and editing. Y.G.: Conceptualization, Visualization, Writing - review and editing.
Received: May 6, 2023; Revised: August 28, 2023; Accepted: September 3, 2023
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Transmembrane protein TMEM16A, which encodes calcium-activated chloride channel has been implicated in tumorigenesis. Overexpression of TMEM16A is associated with poor prognosis and low overall survival in multiple cancers including lung adenocarcinoma, making it a promising biomarker and therapeutic target. In this study, three structure-related sesquiterpene lactones (mecheliolide, costunolide and dehydrocostus lactone) were extracted from the traditional Chinese medicine Aucklandiae Radix and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on the proliferation and migration of lung adenocarcinoma cells were examined. Whole-cell patch clamp experiments showed that these sesquiterpene lactones potently inhibited recombinant TMEM16A currents in a concentration-dependent manner. The half-maximal concentration (IC50) values for three tested sesquiterpene lactones were 29.9 ± 1.1 μM, 19.7 ± 0.4 μM, and 24.5 ± 2.1 μM, while the maximal effect (Emax) values were 100.0% ± 2.8%, 85.8% ± 0.9%, and 88.3% ± 4.6%, respectively. These sesquiterpene lactones also significantly inhibited the endogenous TMEM16A currents and proliferation, and migration of LA795 lung cancer cells. These results demonstrate that mecheliolide, costunolide and dehydrocostus lactone are novel TMEM16A inhibitors and potential candidates for lung adenocarcinoma therapy.
Keywords: Adenocarcinoma of lung, Costunolide, Dehydrocostus lactone, Mecheliolide, TMEM16A