Modulation of transferrin receptor expression by dexrazoxane (ICRF-187) via activation of iron regulatory protein.
Dexrazoxane (ICRF-187) has recently been demonstrated to reduce cardiac toxicity induced by chemotherapy with anthracyclines, although the reason for this phenomenon has remained obscure thus far. In order to investigate whether ICRF-187 might exert its effects by modulating iron metabolism, we studied the drug's potential to influence the maintenance of iron homeostasis in two human cell lines. We demonstrate that ICRF-187 enhanced the binding affinity of iron regulatory protein (IRP), the central regulatory factor for posttranscriptional iron regulation, to RNA stem loop structures, called iron responsive elements (IRE), in THP-1 myelomonocytic as well as K562 erythroleukemic cells. Increased IRE/IRP interaction was paralleled by an elevation of transferrin receptor (trf-rec) mRNA levels which, according to the well-established mechanism of posttranscriptional iron regulation, was likely due to stabilisation of trf-rec mRNA by IRP. Subsequently, ICRF-187 treatment of cells increased trf-rec surface expression and enhanced cellular iron uptake. All these events, i.e. IRP activation, stabilisation of trf-rec mRNA and increased surface expression of the protein in response to ICRF-187, follow a dose-response relationship. Increased cellular uptake and sequestration of iron in response to ICRF-187 may contribute to the protective activity of ICRF-187 by reducing the iron-anthracycline complex and iron-catalysed generation of hydroxyl radicals via the Haber-Weiss reaction.
Weiss
G
G
Department of Internal Medicine, University Hospital, Innsbruck, Austria. guenter.weiss@uibk.ac.at
Kastner
S
S
Brock
J
J
Thaler
J
J
Grünewald
K
K
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011929:Razoxane / Q000008:administration & dosage / Q000494:pharmacology*; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D011929:Razoxane; D007501:Iron