The DOI matches its Crossref record; 53 of the 54 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Monks, A. P., Scudiero, D. A., Skehan, P., Shoemaker, R. H., Paull, K. D., Vistica, D. T., Hose, C. D., Langley, J. W., Cronise, P., Vaigro-Wolff, A., et al. (1991) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/83.11.757 · Cited by 3,305
Alley, M. C., Scudiero, D. A., Monks, A. P., Hursey, M. L., Czerwiński, M., Fine, D. L., Abbott, B. J., Mayo, J. G., Shoemaker, R. H., & Boyd, M. R. (1988) · PubMed · Cited by 3,082
The role of iron and reactive oxygen species in cell death
Dixon, S. J., & Stockwell, B. R. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1416 · Cited by 2,381
Dixon, S. J., Patel, D. N., Welsch, M., Skouta, R., Lee, E. D., Hayano, M., Thomas, A. G., Gleason, C. E., Tatonetti, N. P., Slusher, B. S., et al. (2014) · eLife · doi:10.7554/elife.02523 · Cited by 2,088
A gene expression database for the molecular pharmacology of cancer
Scherf, U., Ross, D. T., Waltham, M. C., Smith, L. H., Lee, J. K., Tanabe, L. K., Kohn, K. W., Reinhold, W. C., Myers, T. G., Andrews, D. T., et al. (2000) · Nature Genetics · doi:10.1038/73439 · Cited by 1,450
The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine
Tu, Y. (2011) · Nature Medicine · doi:10.1038/nm.2471 · Cited by 1,397
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146
Reinhold, W. C., Sunshine, M., Liu, H., Varma, S., Kohn, K. W., Morris, J., Doroshow, J., & Pommier, Y. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1370 · Cited by 887
Apoptosis and cancer: the genesis of a research field
Cotter, T. G. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2663 · Cited by 783
Daniels‐Wells, T. R., Delgado, T., Rodríguez, J. A., Helguera, G. F., & Penichet, M. L. (2006) · Clinical Immunology · doi:10.1016/j.clim.2006.06.010 · Cited by 646
Iron‐dependent cell death of hepatocellular carcinoma cells exposed to sorafenib
Louandre, C., Ezzoukhry, Z., Godin, C., Barbare, J., Mazière, J., Chauffert, B., & Galmiche, A. (2013) · International Journal of Cancer · doi:10.1002/ijc.28159 · Cited by 602
The anti-malarial artesunate is also active against cancer
Efferth, T., Dunstan, H. M., Sauerbrey, A., Miyachi, H., & Chitambar, C. R. (2001) · International Journal of Oncology · doi:10.3892/ijo.18.4.767 · Cited by 567
Self-citationMolecular Modes of Action of Artesunate in Tumor Cell Lines
Efferth, T., Sauerbrey, A., Olbrich, A., Gebhart, E., Rauch, P., Weber, H. O., Hengstler, J. G., Halatsch, M., Volm, M., Tew, K. D., et al. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.2.382 · Cited by 431
Self-citationHerbal Medicine as Inducers of Apoptosis in Cancer Treatment
Safarzadeh, E., Shotorbani, S. S., & Baradaran, B. (2014) · PubMed · doi:10.5681/apb.2014.062 · Cited by 383
Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron
Efferth, T., Benakis, A., Romero, M. R., Tomicic, M., Rauh, R., Steinbach, D., Häfer, R., Stamminger, T., Oesch, F., Kaina, B., et al. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.06.023 · Cited by 266
Self-citationArtesunate Induces ROS-Mediated Apoptosis in Doxorubicin-Resistant T Leukemia Cells
Efferth, T., Giaisi, M., Merling, A., Krammer, P. H., & Li‐Weber, M. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000693 · Cited by 256
Self-citationAmundson, S. A., Do, K. T., Vinikoor, L. C., Lee, R. A., Koch-Paiz, C. A., Ahn, J.-Y., Reimers, M., Chen, Y., Scudiero, D. A., Weinstein, J. N., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2120 · Cited by 253
Jain, M. V., Paczulla, A., Klonisch, T. C., Dimgba, F. N., Rao, S. B., Roberg, K. B., Schweizer, F., Lengerke, C., Davoodpour, P., Palicharla, V. R., et al. (2013) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12001 · Cited by 247
Hamacher‐Brady, A., Stein, H., Turschner, S., Toegel, I., Mora-Rodríguez, R. A., Jennewein, N., Efferth, T., Eils, R., & Brady, N. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.210047 · Cited by 233
Self-citationDell’Eva, R., Pfeffer, U., Venè, R., Anfosso, L., Forlani, A., Albini, A., & Efferth, T. (2004) · Biochemical Pharmacology · doi:10.1016/j.bcp.2004.08.021 · Cited by 231
Self-citationSelective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin
Lai, H. C., & Singh, N. P. (1995) · Cancer Letters · doi:10.1016/0304-3835(94)03716-v · Cited by 186
Artesunate in the treatment of metastatic uveal melanoma - first experiences
Berger, T. G., Dieckmann, D., Efferth, T., Schultz, E. S., Funk, J.-O., Baur, A. S., & Schuler, G. (2005) · Oncology Reports · doi:10.3892/or.14.6.1599 · Cited by 176
Self-citationDu, J., Zhang, H., Ma, Z.-J., & Ji, K. (2009) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-009-1095-5 · Cited by 159
Efferth, T., Olbrich, A., & Bauer, R. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01221-2 · Cited by 129
Self-citationLi, L., Zhang, H., Yuan, S., Tian, Z., Wang, L., & Sun, Z. (2007) · International Journal of Cancer · doi:10.1002/ijc.22804 · Cited by 119
Wosikowski, K., Schuurhuis, D. H., Johnson, K., Bates, S. E., Paull, K. D., Myers, T. G., & Weinstein, J. N. (1997) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/89.20.1505 · Cited by 119
Zu-yi, Z. (2008) · Journal of Chinese Integrative Medicine · doi:10.3736/jcim20080206 · Cited by 118
Efferth, T., & Oesch, F. (2004) · Biochemical Pharmacology · doi:10.1016/j.bcp.2004.03.003 · Cited by 115
Self-citationKelter, G., Steinbach, D., Konkimalla, V. B., Tahara, T., Taketani, S., Fiebig, H., & Efferth, T. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000798 · Cited by 112
Self-citationJansen, F. H., Adoubi, I., Comoe, K., Cnodder, T. D., Jansen, N., Tschulakow, A., & Efferth, T. (2011) · PubMed · Cited by 112
Self-citationDetection of apoptosis in KG-1a leukemic cells treated with investigational drugs.
Efferth, T., Rüċker, G., Falkenberg, M. B., Manns, D., Olbrich, A., Fabry, U., & Osieka, R. (1996) · PubMed · Cited by 105
Self-citationWang, Z., Hu, W., Zhang, J., Wu, X., & Zhou, H. (2012) · FEBS Open Bio · doi:10.1016/j.fob.2012.05.002 · Cited by 95
Kuete, V., Ngameni, B., Wiench, B., Krusche, B., Horwedel, C., Ngadjui, B. T., & Efferth, T. (2011) · Planta Medica · doi:10.1055/s-0031-1280023 · Cited by 91
Self-citationHaynes, R. K., Cheu, K., N’Da, D. D., Coghi, P. S., & Monti, D. (2014) · Infectious Disorders - Drug Targets · doi:10.2174/1871526513666131129155708 · Cited by 88
Role of antioxidant genes for the activity of artesunate against tumor cells
Efferth, T., Briehl, M. M., & Tome, M. E. (2003) · International Journal of Oncology · doi:10.3892/ijo.23.4.1231 · Cited by 87
Self-citationYang, D. C., Wang, F., Elliott, R. L., & Head, J. F. (2001) · PubMed · Cited by 87
Evans, A. R., Bates, V., Troy, H., Hewitt, S. M., Holbeck, S. L., Chung, Y., Phillips, R. M., Stubbs, M., Griffiths, J. R., & Airley, R. E. (2007) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-007-0480-1 · Cited by 82
Shterman, N., Kupfer, B., & Moroz, C. (2008) · Pathobiology · doi:10.1159/000163611 · Cited by 81
Case report of a laryngeal squamous cell carcinoma treated with artesunate
Singh, N., & Verma, K. (2002) · Archive of oncology · doi:10.2298/aoo0204279s · Cited by 79
Horwedel, C., Tsogoeva, S. B., Wei, S., & Efferth, T. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100404t · Cited by 73
Self-citationMa, H., Yao, Q., Zhang, A., Lin, S. H., Wang, X., Wu, L., Sun, J., & Chen, Z. (2011) · Molecules · doi:10.3390/molecules161210556 · Cited by 62
Apoptosis and resistance to daunorubicin in human leukemic cells
Efferth, T., Fabry, U., & Osieka, R. (1997) · Leukemia · doi:10.1038/sj.leu.2400669 · Cited by 58
Self-citationArtesunate induces necrotic cell death in schwannoma cells
Button, R. W., Lin, F., Ercolano, E., Vincent, J. H., Hu, B., Hanemann, C. O., & Luo, S. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.434 · Cited by 57
Safety and efficacy field study of artesunate for dogs with non-resectable tumours.
Rutteman, G. R., Erich, S. A., Mol, J. A., Spee, B., Grinwis, G. C. M., Fleckenstein, L. L., London, C. A., & Efferth, T. (2013) · PubMed · Cited by 48
Self-citationLin, W., & Tongyi, S. (2014) · Tumor Biology · doi:10.1007/s13277-014-2064-0 · Cited by 41
Fagan, V., Bonham, S., Carty, M. P., Méndez, P. S., Eriksson, L. A., & Aldabbagh, F. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2012.03.063 · Cited by 35
The Use of DNA Microarrays to Investigate the Pharmacogenomics of Drug Response in Living Systems
Villeneuve, D. J., & Parissenti, A. M. (2004) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026043387610 · Cited by 33
Luzina, E. L., & Popov, A. V. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.03.026 · Cited by 33
Treatment of Iron-Loaded Veterinary Sarcoma by Artemisia annua
Breuer, E., & Efferth, T. (2014) · Natural Products and Bioprospecting · doi:10.1007/s13659-014-0013-7 · Cited by 33
Self-citationRedundancyMiner: De-replication of redundant GO categories in microarray and proteomics analysis
Zeebèrg, B. R., Liu, H., Kahn, A., Ehler, M., Rajapakse, V. N., Bonner, R. F., Brown, J. D., Brooks, B. P., Larionov, V., Reinhold, W. C., et al. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-52 · Cited by 25
Uçar, T., & Gürer, İ. E. (2003) · British Journal of Neurosurgery · doi:10.1080/02688690310001627759 · Cited by 7
Autophagy by Natural Products in Cancer Cells
Efferth, T. (2012) · Biochemistry & Analytical Biochemistry · doi:10.4172/2161-1009.1000e128 · Cited by 6
Self-citation
Research works printed but not linked: 2
- Krishna, 2014, A randomized, double-blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer, EBioMedicine, 2014, 1
- Whitney, 1995, Transferrin receptor expression in nonsmall cell lung cancer, Histopathol. Clin. Correl. Cancer, 76, 20
Cited by
Sorted by citations
Ferroptosis: process and function
Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.158 · Cited by 3,727
Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088
Broadening horizons: the role of ferroptosis in cancer
Chen, X., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-00462-0 · Cited by 2,967
Targeting Ferroptosis to Iron Out Cancer
Hassannia, B., Vandenabeele, P., & Berghe, T. V. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.04.002 · Cited by 2,498
Ferroptosis: machinery and regulation
Chen, X., Li, J., Kang, R., Klionsky, D. J., & Tang, D. (2021) · Autophagy · doi:10.1080/15548627.2020.1810918 · Cited by 2,099
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
