Iron chelator deferasirox rescued mice from Fas‐induced fulminant hepatitis

Sato, Tsutomu; Kobune, Masayoshi; Murase, Kazuyuki; Kado, Yukari; Okamoto, Takahiro; Tanaka, Shingo; Kikuchi, Shohei; Nagashima, Hiroyuki; Kawano, Yutaka; Takada, Kohichi; Iyama, Satoshi; Miyanishi, Koji; Sato, Yasushi; Takimoto, Rishu; Kato, Junji

doi:10.1111/j.1872-034x.2011.00821.x

Cited by 18 publications

(14 citation statements)

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“…A beneficial effect of dietary iron restriction or DFO iron chelation on liver inflammation was previously reported in experimental animal models of thioacetamide-induced toxic hepatitis [ 5 ] and Fas-induced fulminant hepatitis [ 6 ]. The anti-inflammatory effects of iron restriction were attributed to a reduction in oxidative stress, and a decreased Kupffer and hepatic stellate cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Iron also contributes to the formation of potent reactive radicals, which promote oxidative stress and induce inflammation and tissue injury. Thus, iron restriction has been shown to ameliorate oxidative stress and inflammatory organ damage in models of murine acute hepatitis [ 5 , 6 ], experimental autoimmune encephalomyelitis (EAE) [ 7 ], renal interstitial fibrosis [ 8 ] and type 2 diabetes in rats [ 9 ]. In addition to its effects on innate immune responses and inflammation, iron is also required for the function and differentiation of adaptive immune cells such as T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

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Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

et al. 2015

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Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

et al. 2015

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“…ROS modulated hepatocyte death by decreasing FLIP level and by increasing cytochrome C release in a BID-dependent manner after TNFα- and Fas-induced death receptors activation [ 40 ]. In addition, iron chelation, that prevents the transition from superoxide to hydroxyl radical by the Fenton reaction, rescued mice from Fas-induced hepatitis [ 41 ]. Currently, the unique antidote for acute liver failure is an antioxidant therapy, i.e.…”

Section: Discussionmentioning

confidence: 99%

The Reg3α (HIP/PAP) Lectin Suppresses Extracellular Oxidative Stress in a Murine Model of Acute Liver Failure

et al. 2015

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Background and AimsAcute liver failure (ALF) is a rapidly progressive heterogeneous illness with high mortality rate and no widely accessible cure. A promising drug candidate according to previous preclinical studies is the Reg3α (or HIP/PAP) lectin, which alleviates ALF through its free-radical scavenging activity. Here we study the therapeutic targets of Reg3α in order to gain information on the nature of the oxidative stress associated with ALF.MethodsPrimary hepatocytes stressed with the reactive oxygen species (ROS) inducers TNFα and H2O2 were incubated with a recombinant Reg3α protein. ALF was induced in C57BL/6J mice by an anti-CD95 antibody. Livers and primary hepatocytes were harvested for deoxycholate separation of cellular and extracellular fractions, immunostaining, immunoprecipitation and malondialdehyde assays. Fibrin deposition was studied by immunofluorescence in frozen liver explants from patients with ALF.ResultsFibrin deposition occurs during experimental and clinical acute liver injuries. Reg3α bound the resulting transient fibrin network, accumulated in the inflammatory extracellular matrix (ECM), greatly reduced extracellular ROS levels, and improved cell viability. Hepatocyte treatment with ligands of death receptors, e.g. TNFα and Fas, resulted in a twofold increase of malondialdehyde (MDA) level in the deoxycholate-insoluble fractions. Reg3α treatment maintained MDA at a level similar to control cells and thereby increased hepatocyte survival by 35%. No antioxidant effect of Reg3α was noted in the deoxycholate-soluble fractions. Preventing fibrin network formation with heparin suppressed the prosurvival effect of Reg3α.ConclusionsReg3α is an ECM-targeted ROS scavenger that binds the fibrin scaffold resulting from hepatocyte death during ALF. ECM alteration is an important pathogenic factor of ALF and a relevant target for pharmacotherapy.

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“…2; Table 1), we next examined whether deferasirox could inhibit the growth of DMS-53 lung carcinoma tumor xenografts in BALB/c nude mice. As deferasirox is given to patients orally (in tablet form), we administered deferasirox as a saline suspension by oral gavage in accordance with previous studies (Sato et al, 2011). Initially, we attempted to define a maximum tolerated dose to determine an optimal treatment regimen.…”

Section: Resultsmentioning

confidence: 99%

The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action

et al. 2012

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Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular 59 Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21 CIP1/WAF1 while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

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Iron chelator deferasirox rescued mice from Fas‐induced fulminant hepatitis

Abstract: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.

Cited by 18 publications

References 19 publications

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

The Reg3α (HIP/PAP) Lectin Suppresses Extracellular Oxidative Stress in a Murine Model of Acute Liver Failure

The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action

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