Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction

Li Jiaqi; Huang Siqing; Wang Qin; Zhou di; Zhao Bei; Yao Jialin

doi:10.1016/j.phymed.2022.154601

Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction

Phytomedicine. 2023 Jan:109:154601. doi: 10.1016/j.phymed.2022.154601. Epub 2022 Dec 11.

Authors

Li Jiaqi¹, Huang Siqing¹, Wang Qin¹, Zhou di¹, Zhao Bei², Yao Jialin³

Affiliations

¹ Department of Oncology, Yue yang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200080, China.
² China Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zhaobei0207@shutcm.edu.cn.
³ Department of Oncology, Yue yang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200080, China. Electronic address: yaojialin@shyueyanghospital.com.

PMID: 36610134
DOI: 10.1016/j.phymed.2022.154601

Abstract

Background: Ferroptosis, a form of regulated cell death by lipid peroxidation, was currently considered as a key factor affecting the occurrence and progression in various cancers. Andrographolide (ADE), a major effective ingredient of Andrographis paniculate, has proven to have a substantial anti-tumor effect on multiple cancer types. However, the function and underlying mechanism of ADE in Non-Small Cell Lung Cancer remain unclear.

Methods: CCK8 assay, colony-formation assay, flow cytometry, scratch test, transwell assay, western blotting, ferroptosis analysis and mitochondria analysis were performed to reveal the role and underlying mechanisms of ADE in NSCLC cell lines (H460 and H1650). In vivo, xenograft model and lung metastatic model were performed to verify the effect of ADE on the growth and metastasis of NSCLC.

Results: In this present study, we demonstrated that treatment with ADE could inhibit cell growth and metastases through eliciting ferroptosis in vitro an in vivo. The IC50 of ADE in H460 and H1650 cells were 33.16 μM and 32.45 μM respectively. In Lewis xenografted animals, i.p. ADE repressed relative tumor growth (p < 0.01) and inhibited metastases (p < 0.01). Notably, the ferroptosis inhibitor Fer-1 abrogated the anti-tumor capacity of ADE. Induction of ferroptosis by ADE was confirmed by elevated levels of reactive oxygen sepsis (ROS), glutathione (GSH), malondialdehyde (MDA), intracellular iron content and lipid ROS reduced glutathione (GSH) accumulation (p < 0.01). Furthermore, ADE inhibited the expression of ferroptosis-related protein GPX4 and SLC7A11. Simultaneously, it also disclosed that ADE enhanced mitochondrial dysfunction, as evidenced by increased mitochondrial ROS release, mitochondrial membrane potential (MMP) depolarization, and decreased mitochondrial ATP. Most interestingly, Mito-TEMPO, a mitochondria-targeted antioxidant, rescued ADE-induced ferroptosis.

Conclusion: Our data validated that ADE treatment could restrain proliferation and metastases of NSCLC cells through induction of ferroptosis via potentiating mitochondrial dysfunction.

Keywords: Andrographolide; Chinese medicine; Ferroptosis; Mitochondrial dysfunction; NSCLC.

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung* / drug therapy
Ferroptosis*
Glutathione
Humans
Lung Neoplasms* / drug therapy
Reactive Oxygen Species

Substances

andrographolide
Reactive Oxygen Species
Glutathione