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

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

Korean J Physiol Pharmacol. 2023 Nov 1;27(6):521-531. doi: 10.4196/kjpp.2023.27.6.521.

Authors

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 Li⁸, Xuan Zhang^{1

6

7}, Yunyun Geng^{1

2}

Affiliations

¹ Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
² Hebei International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese Medicine, Shijiazhuang 050091, China.
³ College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
⁴ The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
⁵ Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
⁶ Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China.
⁷ Hebei Higher Education Applied Technology Research Center of TCM Development and Industrialization, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
⁸ Department of Pharmacy, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, China.

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.

Grants and funding

FUNDING This work was supported by Natural Science Foundation of Hebei Province (H2021206380 to H.L., C2020423052 to Y.G., C2020206027 to F.Z.), by National college students innovation and entrepreneurship training program (202314432005 to Q.Z.), by National Natural Science Foundation of China (32071104 to X.Z., 32171018 to F.Z.), by Scientific research project of colleges and universities of Hebei Province (ZD2021075 to D.H.), by Key R&D plan of Hebei Province (22374801D to Y.G.), by the Construction Program of new research and development platform and institution, Hebei Province Innovation Ability Promotion Plan (20567624H to J.C.), by Traditional Chinese Medicine Scientific Research foundation in Hebei Administration of Traditional Chinese Medicine (2020005 to J.M.).