Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer
Abstract
A principal limitation to the clinical use of cisplatin is the high incidence of chemoresistance to this drug. Combination treatments with other drugs may help to circumvent this problem. Wogonin, one of the major natural flavonoids, is known to reverse multidrug resistance in several types of cancers. We investigated the ability of wogonin to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Two cisplatin-resistant HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effects of wogonin, either alone or in combination with cisplatin, were assessed in HNC cells and normal cells using cell cycle and death assays and by measuring cell viability, reactive oxygen species (ROS) production, and protein expression, and in tumor xenograft mouse models. Wogonin selectively killed HNC cells but spared normal cells. It inhibited nuclear factor erythroid 2-related factor 2 and glutathione S-transferase P in cisplatin-resistant HNC cells, resulting in increased ROS accumulation in HNC cells, an effect that could be blocked by the antioxidant N-acetyl-L-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and activating cell death pathways involving PUMA and PARP. Hence, wogonin significantly sensitized resistant HNC cells to cisplatin both in vitro and in vivo. Wogonin is a promising anticancer candidate that induces ROS accumulation and selective cytotoxicity in HNC cells and can help to overcome cisplatin-resistance in this cancer.
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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 [183]
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- Authors
- Kim, E. H., Jang, H., Shin, D., Baek, S. H., & Roh, J.-L.
- Affiliations
- Asan Medical Center (KR)
- Corresponding author
- Roh, Jong-Lyel
- Venue
- APOPTOSIS
- Published
- 2016-08-20
- Volume
- 21
- Issue
- 11
- Pages
- 1265-1278
- ISSN
- 1360-8185 (ISSN-L)
- 1573-675X
- OpenAlex
- W2514831411
- Cited by
- 77
- References
- 44
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 6 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 5
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- APOPTOSIS (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Basic Science Research Program through the National Research Foundation of Korea (NRF), Ministry of Science, ICT, and Future Planning, Seoul, Republic of Korea (2015R1A2A1A15054540)
- Topics
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- wogonin, cisplatin resistance, head and neck cancer, Nrf2, glutathione S-transferase pi, reactive oxygen species, flavonoids, chemosensitization, PUMA, poly(ADP-ribose) polymerase, N-acetylcysteine, tumor xenografts
- MeSH terms
- Animals, Antineoplastic Agents, Cell Cycle, Cisplatin, Drugs, Chinese Herbal, Glutathione Transferase, Head and Neck Neoplasms, Humans, Male, Mice, Inbred C57BL, Mice, Nude, Apoptosis, Reactive Oxygen Species, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Scutellaria baicalensis, Flavanones, Cell Line, Tumor, NF-E2-Related Factor 2, Mice
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