Fluvastatin suppresses hemin-induced cell death, reactive oxygen species generation, and elevated labile iron pool.

Abstract

Background: In transfusion-related iron overload, macrophage/reticuloendothelial cells are the first site of haem-derived iron accumulation. The prevention of haem-induced cytotoxicity in macrophages may represent a target for iron overload treatment. Deferasirox, an oral iron chelator, has been used to treat transfusion-related iron overload however, low adherence to the therapy is an issue. Statins, which are widely used for the prevention of atherosclerotic cardiovascular diseases, also have anti-oxidative and anti-inflammatory effects independent of their lipid lowering ones. Whether statins can suppress hemin-induced cytotoxicity and enhance the cytoprotective effects of deferasirox are important considerations to improve transfusion-related iron overload treatment. This study also evaluated the effects of eltrombopag, a thrombopoietin receptor agonist.

Materials and methods: Human monocytic THP-1 cells were pretreated with statins, deferasirox, and/or eltrombopag, followed by treatment with hemin. Cell viability, reactive oxygen species generation, and the intracellular labile iron pool were measured using flow cytometry.

Results: Fluvastatin and another four statins suppressed hemin-induced cell death, reactive oxygen species generation, and increases in the labile iron pool. Moreover, fluvastatin enhanced the suppressive effect of deferasirox on hemin-induced cell death. The effects of eltrombopag were similar to those of the statins.

Conclusion: The safety of statins is well established. When used in combination with fluvastatin or other statins, the suppressive effects of deferasirox on hemin-induced cytotoxicity in THP-1 cells were amplified. Further research is necessary to see whether statins will act in the same way in vivo or in human primary monocytes/macrophages.