title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Edna
authors.initials: E
authors.lastname: Ooko
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Mohamed E M
authors.initials: ME
authors.lastname: Saeed
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Onat
authors.initials: O
authors.lastname: Kadioglu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Sarvi
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Merve
authors.initials: M
authors.lastname: Colak
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Kaoutar
authors.initials: K
authors.lastname: Elmasaoudi
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Rabab
authors.initials: R
authors.lastname: Janah
authors.affiliation: Biomedical Sciences Institute Abel Salazar, University of Porto, Portugal, and Heidelberg School of Chinese Medicine, Heidelberg, Germany.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Greten
authors.affiliation: Biomedical Sciences Institute Abel Salazar, University of Porto, Portugal, and Heidelberg School of Chinese Medicine, Heidelberg, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry*; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D010655:Phenylenediamines / Q000494:pharmacology
chemical_list: D037621:Artemisinins; D003514:Cyclohexylamines; D010655:Phenylenediamines; C573944:ferrostatin-1; C105118:artemisitene; D000077332:Artesunate; D000077549:Artemether; D007501:Iron; D003676:Deferoxamine; C055141:artemotil
keywords: Cancer; Cell death; Iron; Microarray; Pharmacogenomics