Imatinib and spironolactone suppress hepcidin expression
EHA Learning Center. Mleczko-Sanecka K. Jul 1, 2017; 190343
Topic: 1A Red cell and iron disorders
Katarzyna Mleczko-Sanecka
Katarzyna Mleczko-Sanecka
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Co-Authors: Ana Rita da Silva, Debora Call, Joana Neves, Nikolai Schmeer, Georg Damm, Daniel Seehofer, Martina U. Muckenthaler

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.

Article Number: 1173

Doi: 10.3324/haematol.2016.162917
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