title: Imatinib and spironolactone suppress hepcidin expression.
abstract: Disorders of iron metabolism are largely attributed to an excessive or insufficient expression of hepcidin, the master regulator of systemic iron homeostasis. Here, we investigated whether drugs targeting genetic regulators of hepcidin can affect iron homeostasis. We focused our efforts on drugs approved for clinical use to enable repositioning strategies and/or to reveal iron-related side effects of widely prescribed therapeutics. To identify hepcidin-modulating therapeutics, we re-evaluated data generated by a genome-wide RNAi screen for hepcidin regulators. We identified 'druggable' screening hits and validated those by applying RNAi of potential drug targets and small-molecule testing in a hepatocytic cell line, in primary murine and human hepatocytes and in mice. We initially identified spironolactone, diclofenac, imatinib and Suberoylanilide hydroxamic acid (SAHA) as hepcidin modulating drugs in cellular assays. Among these, imatinib and spironolactone further suppressed liver hepcidin expression in mice. Our results demonstrate that a commonly used anti-hypertensive drug, spironolactone, which is prescribed for the treatment of heart failure, acne and female hirsutism, as well as imatinib, a first-line, lifelong therapeutic option for some frequent cancer types suppress hepcidin expression in cultured cells and in mice. We expect these results to be of relevance for patient management, which needs to be addressed in prospective clinical studies.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany martina.muckenthaler@med.uni-heidelberg.de kmsanecka@iimcb.gov.pl.|International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mleczko-Sanecka
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: da Silva
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: Call
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Joana
authors.initials: J
authors.lastname: Neves
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Schmeer
authors.affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University of Berlin, Germany.|Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Damm
authors.affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University of Berlin, Germany.|Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, Heidelberg, Germany martina.muckenthaler@med.uni-heidelberg.de kmsanecka@iimcb.gov.pl.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D034622:RNA Interference; D013148:Spironolactone / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D064451:Hepcidins; D000451:Mineralocorticoid Receptor Antagonists; D047428:Protein Kinase Inhibitors; D013148:Spironolactone; D000068877:Imatinib Mesylate