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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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General Research Article

Sanguinarine Represses the Growth and Metastasis of Non-small Cell Lung Cancer by Facilitating Ferroptosis

Author(s): Rongzhong Xu, Jianchun Wu, Yingbin Luo, Yuli Wang, Jianhui Tian, Wenjing Teng, Bo Zhang, Zhihong Fang* and Yan Li*

Volume 28, Issue 9, 2022

Published on: 28 March, 2022

Page: [760 - 768] Pages: 9

DOI: 10.2174/1381612828666220217124542

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Abstract

Objective: Ethnopharmacological relevance: Sanguinarine (SAG), a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn. (Bloodroot), possesses a potential anticancer activity. Lung carcinoma is the chief cause of malignancy-related mortality in China. Non-small cell lung carcinoma (NSCLC) is the main subtype of lung carcinoma and accounts for about eighty-five percent of this disease. Current treatment in controlling and curing NSCLC remains deficient.

Aim: The role and underlying mechanism of SAG in repressing the growth and metastasis of NSCLC were explored.

Materials and Methods: The role of SAG in regulating the proliferation and invasion of NSCLC cells was evaluated in vitro and in a xenograft model. After treatment with SAG, Fe2+ concentration, reactive oxygen species (ROS) levels, malondialdehyde (MDA), and glutathione (GSH) content in NSCLC cells were assessed to evaluate the effect of SAG on facilitating ferroptosis.

Results: SAG exhibited a dose- and time-dependent cytotoxicity in A549 and H3122 cells. SAG treatment effectively repressed the growth and metastasis of NSCLC in a xenograft model. We, for the first time, verified that SAG triggered ferroptosis of NSCLC cells, as evidenced by increased Fe2+ concentration, ROS level, and MDA content, and decreased GSH content. Mechanistically, SAG decreased the protein stability of glutathione peroxide 4 (GPX4) through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. GPX4 overexpression restored the proliferation and invasion of NSCLC cells treated with SAG through inhibiting ferroptosis.

Conclusion: SAG inhibits the growth and metastasis of NSCLC by regulating STUB1/GPX4-dependent ferroptosis.

Keywords: Non-small cell lung carcinoma, Sanguinarine, ferroptosis, STUB1, GPX4, dorsal flanks.

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