Three sesquiterpene lactones suppress lung adenocarcinoma by blocking TMEM16A-mediated Ca2+-activated Cl− channels

Ruilian Xiu; Jie Jia; Qing Zhang; Fengjiao Liu; Yaxin Jia; Yuanyuan Zhang; Beibei Song; Xiaodan Liu; Jingwei Chen; Dongyang Huang; Fan Zhang; Juanjuan Ma; Honglin Li; Xuan Zhang; Yunyun Geng

doi:10.4196/kjpp.2023.27.6.521

Indexed in SCIE, Scopus, PubMed & PMC

pISSN 1226-4512 eISSN 2093-3827

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Original Article

Korean J Physiol Pharmacol 2023; 27(6): 521-531

Published online November 1, 2023 https://doi.org/10.4196/kjpp.2023.27.6.521

Three sesquiterpene lactones suppress lung adenocarcinoma by blocking TMEM16A-mediated Ca²⁺-activated Cl⁻ channels

Ruilian Xiu^1,2,#, Jie Jia^1,2,#, Qing Zhang³, Fengjiao Liu^1,2, Yaxin Jia^1,2, Yuanyuan Zhang^1,2, Beibei Song⁴, Xiaodan Liu⁴, Jingwei Chen⁵, Dongyang Huang⁶, Fan Zhang⁷, Juanjuan Ma², Honglin Li^8,*, Xuan Zhang^1,6,7,*, and Yunyun Geng^1,2,*

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

Correspondence to:Honglin Li
E-mail: lihl05@sina.com
Xuan Zhang
E-mail: xuan_zhangt@hotmail.com
Yunyun Geng
E-mail: gengyunyun2015@126.com

^#These authors contributed equally to this work.

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

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

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 (E_max) 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