Efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in treatment of iron-loaded hepatocyte cultures

Abstract

Excessive iron is toxic to cells and organelles, where it can generate harmful reactive oxygen species (ROS) resulting in oxidative tissue damage. Liver is the major organ for iron storage and redox active iron in this tissue can cause fibrosis and cirrhosis in β-thalassemia patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are clinically approved iron chelators used for the treatment of patients with iron overload, but none of these chelators are completely free of side effects. In this study we report the properties of a new iron chelator 1-(Nacetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1). The labile iron pool (LIP) content was measured by using a calcein fluorescence technique and the lipidperoxidation products were quantified using the thiobarbituric acid reactive substances (TBARS) method. The cytotoxicity of CM1 was also examined with the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. CM1 was demonstrated to reduce iron-induced redox damage and to decrease the levels of the intracellular iron pool in hepatocytes. CM1 is a potentially useful iron-chelating agent which has potential to ameliorate liver iron overload and ROS-induced lipid peroxidation. CM1 is currently under investigation for oral efficacy.

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

“…Plasma MDA level was slightly increased and hepatic MDA was markedly increased in the Fe diet-fed mice when compared to the N diet-fed mice, while liver fibrosis is likely to occur. Our recent study has demonstrated that the CM1 reduced levels of LIP in mouse hepatocyte and HepG2 cell cultures, effectively [28]. A previous study reported that reactive iron and redox ROS in the iron overloaded liver can induce fibrosis [61].…”

“…The compound was able to chelate plasma NTBI, but was not toxic to peripheral blood mononuclear cells (PBMC), cardiomyocytes and hepatocytes in vitro. Importantly, CM1 had reduction efficiency of LIP in ironloaded hepatocyte as well as in myocyte cultures [28]. In the present study, we investigated a potential role of our new chelator, CM1 in the treatment of iron-loaded mice.…”

Protection of Iron-Induced Oxidative Damage in Neuroblastoma (SH-SY5Y) Cells by Combination of 1-(N-Acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and Green Tea Extract

“…Our lead compound, CM1, is a synthetic bidentate chelator that is more lipophilic than DFP and can bind the iron efficiently [ 17 ]. Interestingly, the chelator is able to chelate NTBI in thalassemic serum, but is not toxic to peripheral blood mononuclear cells, hepatocytes, and myocytes in vitro [ 20 ]. Due to the high cost of chemical drugs, we are increasingly interested in alternative therapies that employ natural products.…”

“…It also reduces plasma non-transferrin bound iron and labile plasma iron [ 18 ]. Importantly, the compound shows low toxicity [ 19 , 20 ]. However, there are published reports of this compound processing a neuroprotective effect.…”

Combination Treatments of 1-(N-Acetyl-6-Aminohexyl)-3-Hydroxy-2- Methylpyridin-4-One (CM1) With Deferiprone and Desferrioxamine Reduced Labile Iron Pool and Protected Oxidative Stress in Iron-Loaded Cultured Hepatocytes

“…Recently, a novel orally active iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) has been designed [13] and preliminary results have demonstrated that the CM1 is an effective bidentate chelator which is slightly more lipophilic than the DFP. The compound has been shown to reduce iron-induced redox damage and to decrease the levels LIP in hepatocytes [14]. In the present study, we have investigated the effects of CM1 on LIP and ROS levels in primary hepatocyte and HepG2 cell cultures.…”