Phytomedicine : international journal of phytotherapy and phytopharmacology · 2022
Andrographolide promoted ferroptosis to repress the development of non-small cell lung cancer through activation of the mitochondrial dysfunction.
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Jiaqi Li, Siqing Huang, Qin Wang, di Zhou, Bei Zhao, Jialin Yao
Аннотация
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.
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.