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.

Iron metabolism gene expression and prognostic features of hepatocellular carcinoma

“…22 Iron metabolism in HCC tissue is distinct from adjacent tissue, 45 and iron metabolism genes contribute to HCC progression. [46][47][48] High level of cellular iron promotes tumor proliferation, invasion, and migration. 42 Therefore, iron metabolism genes might be promising targets for cancer therapy.…”

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

“…Two clinically approved drugs (imatinib and spironolactone) were identified that decrease hepcidin through the BMP6 pathway in a variety of cell types (HuH7 and primary hepatocytes of both human and mouse origin) and in male wild-type C57BL/6 mice [100]. Unfortunately, imatinib is not a suitable target for drug re-purposing due to several adverse effects including fatigue, nausea, vomiting, rash, peripheral oedema and abdominal pain.…”

Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology

“…It is interesting to notice that drugs used in cardiac pharmacotherapy, such as spironolactone and heparins, are known suppressors of liver hepcidin, although it is not known whether they can affect iron metabolism in HF. 112,113 Increased serum hepcidin levels in MI might be deleterious for cardiac function. This happens because increased serum hepcidin in this setting, at least partially, originates from activated macrophages of the atherosclerotic arteries, where excess hepcidin induces plaque instability, probably through increased oxidative stress.…”