Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells
Abstract
Background Apoptosis and other forms of cell death have been intensively investigated in the past years to explain the mode of action of synthetic anticancer drugs and natural products. Recently, a new form of cell death emerged, which was termed ferroptosis, because it depends on intracellular iron. Here, the role of genes involved in iron metabolism and homeostasis for the cytotoxicity of ten artemisinin derivatives have been systematically investigated.Material and methods Log10IC50 values of 10 artemisinin derivatives (artesunate, artemether, arteether, artenimol, artemisitene, arteanuin B, another monomeric artemisinin derivative and three artemisinin dimer molecules) were correlated to the microarray-based mRNA expression of 30 iron-related genes in 60 cell lines of the National Cancer Institute (NCI, USA) as determined in 218 different microarray hybridization experiments. The effect of desferoxamine and ferrostatin-1 on the cytotoxicity of artenimol of CCRF-CEM cells was determined by resazurin assays. The mRNA expression of TFRC was exemplarily validated by immunohistochemical detection of transferrin receptor protein expression.Results The mRNA expression of 20 genes represented by 59 different cDNA clones significantly correlated to the log10IC50 values for the artemisinins, including genes encoding transferrin (TF), transferrin receptors 1 and 2 (TFRC, TFR2), cerulopasmin (CP), lactoferrin (LTF) and others. The ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine led to a significantly reduced cytotoxicity of artenimol, indicating ferroptosis as cell death mode.Conclusion The numerous iron-related genes, whose expression correlated with the response to artemisinin derivatives speak in factor for the relevance of iron for the cytotoxic activity of these compounds. Treatment with ferroptosis-inducing agents such as artemisinin derivatives represents an attractive strategy for cancer therapy. Pre-therapeutic determination of iron-related genes may indicate tumor sensitivity to artemisinins. Ferroptosis induced by artemisinin-type drugs deserve further investigation for individualized tumor therapy.
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Artemisinin derivatives induce iron-dependent cell death, specifically ferroptosis.
“Of note, artemisinin derivatives have been reported to induce iron-dependent cell death, and specifically ferroptosis”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [84]
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- Authors
- Ooko, E., Saeed, M. E. M., Kadioglu, O., Sarvi, S., Colak, M., Elmasaoudi, K., Janah, R., Greten, H. J., & Efferth, T.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Universidade do Porto (PT)
- Corresponding author
- Efferth, Thomas
- Venue
- Phytomedicine
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 11
- Pages
- 1045-1054
- ISSN
- 0944-7113 (ISSN-L)
- OpenAlex
- W1156477804
- Cited by
- 387
- References
- 54
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 37 · 2023: 48 · 2022: 60 · 2021: 57 · 2020: 46 · 2019: 27 · 2018: 23 · 2017: 14 · 2016: 16 · 2015: 3
- FWCI
- 14.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Phytomedicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- artemisinin derivatives, ferroptosis, iron metabolism, ferrostatin-1, deferoxamine, transferrin receptor, ceruloplasmin, lactoferrin, tumor cell killing, anticancer natural products, CCRF-CEM cells, precision oncology
- MeSH terms
- Artesunate, Artemether, Cyclohexylamines, Deferoxamine, Humans, Iron, Phenylenediamines, Molecular Structure, Gene Expression Regulation, Neoplastic, Cell Death, Apoptosis, Inhibitory Concentration 50, Oligonucleotide Array Sequence Analysis, Artemisinins, Cell Line, Tumor
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