Hyperoside suppresses hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis

• Published in: Phytomedicine (Stuttgart) 2020-02, Vol.67, p.153138-153138, Article 153138
• Main Authors: Chen, Dan, Wu, Ya-Xian, Qiu, Yu-bao, Wan, Bin-bin, Liu, Gang, Chen, Jun-liang, Lu, Mu-dan, Pang, Qing-feng
• Format: Article
• Language: English
• Subjects: A549; A549 Cells; AMP-Activated Protein Kinases - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Heme oxygenase-1; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - metabolism; Humans; Hypoxia; Iron - metabolism; Phosphorylation - drug effects; Protoporphyrins - pharmacology; Quercetin - administration & dosage; Quercetin - analogs & derivatives; Quercetin - pharmacology; Survival; Tumor Hypoxia - drug effects
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2019.153138

Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors. Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes. Therefore, Hy may be attractive compound applicable to hypoxia-related diseases. This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism. A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot. We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia. Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis. [Display omitted]