- Katarzyna Mleczko-Sanecka1,
- Ana Rita da Silva1,
- Debora Call1,
- Joana Neves1,
- Nikolai Schmeer1,
- Georg Damm2,
- Daniel Seehofer2 and
- Martina U. Muckenthaler1,*
- 1 Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Germany;
- 2 Department of General, Visceral and Transplantation Surgery, Charite University Hospital Berlin
- ↵* Corresponding author; email:
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 reevaluated 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 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 women 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.
- Received December 27, 2016.
- Accepted April 5, 2017.
- Copyright © 2017, Ferrata Storti Foundation