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2017 ; 102
(7
): 1173-1184
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Imatinib and spironolactone suppress hepcidin expression
#MMPMID28385785
Mleczko-Sanecka K
; da Silva AR
; Call D
; Neves J
; Schmeer N
; Damm G
; Seehofer D
; Muckenthaler MU
Haematologica
2017[Jul]; 102
(7
): 1173-1184
PMID28385785
show ga
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.
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