Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis
Open accessAbstract
Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2-antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2-ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. CONDENSED ABSTRACT: Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2-antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2-ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells.
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Upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy.
“The resultant upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy [47,161,165,178,179,180,181,182,183,184].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [184]
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- Authors
- Roh, J.-L., Kim, E. H., Jang, H., & Shin, D.
- Affiliations
- Asan Medical Center (KR)
- Corresponding author
- Roh, Jong-Lyel
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 11
- Pages
- 254-262
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC5198738
- OpenAlex
- W2561420332
- Cited by
- 662
- References
- 46
- Citations by year
- 2026: 48 · 2025: 87 · 2024: 108 · 2023: 100 · 2022: 107 · 2021: 93 · 2020: 67 · 2019: 30 · 2018: 15 · 2017: 6
- FWCI
- 15.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ministry of Health and Welfare
- Korea Health Industry Development Institute
- Ministry of Science, ICT and Future Planning (HI15C2920)
- National Research Foundation of Korea
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- artesunate, ferroptosis, head and neck cancer, cisplatin resistance, Nrf2, Keap1, antioxidant response element, trigonelline, glutathione, reactive oxygen species, drug repurposing, ferrostatin-1, tumor xenografts
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Artesunate, Alkaloids, Animals, Antimalarials, Antineoplastic Agents, Chromans, Cisplatin, Cyclohexylamines, Head and Neck Neoplasms, Humans, Iron, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Nude, Phenylenediamines, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, Reactive Oxygen Species, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Artemisinins, NF-E2-Related Factor 2, Mice, Heme Oxygenase-1, Drug Repositioning
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