Suramin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of NF-κB activity

doi:10.1016/j.cyto.2005.11.012

Cytokine

Volume 33, Issue 1, 7 January 2006, Pages 28-35

https://doi.org/10.1016/j.cyto.2005.11.012 Get rights and content

Abstract

Aim

Suramin is a symmetrical polysulfonated naphthylamine derivative of urea. There have been few studies on the effect of suramin on cytokines. We examined the effects of suramin on production of inflammatory cytokines.

Methods

We made an acute liver injury model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). Plasma AST, ALT, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels were measured. We compared with survival rate, histological found and NF-κB activity between with and without treatment of suramin. In macrophage like cell line, TNF-α and IL-6 production, TNF-α and IL-6 mRNA expression, and NF-κB activity was measured.

Results

The lethality of mice administered suramin with GalN/LPS was significantly decreased compared with that in mice without suramin. Changes of hepatic necrosis and apoptosis were slight in suramin-treated mice. Serum AST, ALT, TNF-α, IL-6 levels and NF-κB activity in the liver were significantly lower in mice administered suramin. In an in vitro model, suramin preincubation inhibited TNF-α and IL-6 production, TNF-α and IL-6 mRNA expression, and NF-κB activity.

Conclusions

Suramin inhibits TNF-α and IL-6 production through the suppression of NF-κB activity from macrophages and shows therapeutic effects on acute liver damage.

Introduction

Suramin, a symmetrical polysulfonated urea derivative, is widely used as an antitrypanosomal and antifilarial drug. Because of its anti-reverse transcriptase activity and antiproliferative activity, suramin is also used for the treatment of acquired immunodeficiency syndrome [1]. It has been showed to possess some antitumor activity to some kinds of cancers such as melanoma, prostate cancer [2], lung cancer [3] and adrenocortical cancer [4]. Suramin, a small molecular weight naphthylurea, which mainly acts on G-proteins and on P2X/P2Y receptors, promotes expansion of hen eggwhite lysozyme (HEL)-specific Th1 and Th2 cells upon immunization of BALB/c mice with HEL in aluminum hydroxide [5]. It is also effective for treating infections of Onchocerca volvulus. Recently, suramin inhibits the binding of dengue virus to its target cell receptor [6] and hepatitis C binding to human hepatoma cells [7]. Suramin also inhibits fulminant apoptotic liver damage in mice [8]. Suramin is one of candidate for treatment of liver diseases. But there were few studies about effect of suramin on cytokine in liver disease. We examined the effects of suramin on production of inflammatory cytokines in vivo and in vitro models treated with lipopolysaccharide (LPS).

Section snippets

Materials

Lipopolysaccharide (LPS) (from Salmonella enteritidis) and d-galactosamine (GalN) were obtained from Sigma (St. Louis, MO, USA). Suramin was obtained from Wako (Osaka, Japan).

Animals

Male C57BL/6 mice (6–8 weeks of age) were obtained from the animal facilities of the Institute of Japan SLC (Shizuoka, Japan). All mice received human care according to the guidelines of Akita University School of Medicine. They were maintained under controlled conditions and fed a standard laboratory chow.

In vivo model procedures

For preparation

Effects of suramin on survival rate of mice

When GalN (700 mg/kg body weight) and LPS (5 μg/kg body weight) in phosphate-buffered saline (PBS) was injected i.p. in 6–8-week-old male C57BL/6 mice, severe hepatic failure rapidly developed and the mice began to die 7 h after GalN/LPS administration. Finally, all mice not given suramin died within 12 h. But in mice given suramin (125 mg/kg or 250 mg/kg body weight) i.p. concomitantly with injection of GalN and LPS, the mice began to die at 8 h after GalN/LPS administration and 2 of the 10 mice

Discussion

Suramin is a symmetrical polysulfonated naphthylamine derivative of urea. Suramin has been widely used to treat trypanosomiasis and onchocerciasis. Recently, new findings of suramin have been reported. Suramin inhibits the binding of neutrophils and T lymphocytes to LPS and IL-1β in activated human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner [11]. Suramin has been found to specifically promote dissociation of the biologically active trimeric form of TNF-α into inactive

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Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future
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In the collagen induced arthritis rat model for RA, suramin showed in vivo activity to reduce inflammation and repair joint destruction at a dose of 10 mg/kg/day for 3 weeks by intraperitoneal injection.44 Suramin also showed activity in an acute liver injury model induced by d-galactosamine (GalN) and lipopolysaccharide (LPS).45 SPD304 is a small TNFα inhibitor that destabilizes the TNFα trimer.46
In the past 20 years, patients with rheumatoid arthritis (RA), Crohn's disease (CD), and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFα inhibitors. With 5 approved anti-TNFα biologics on the market and soon available biosimilars, patients have more treatment options and have benefited from understanding the biology of TNFα. Nevertheless, many unmet needs remain for people living with TNFα-related diseases, namely some side effects and tolerance of current anti-TNFα biologics and resistance to therapies. Furthermore, common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFα therapies at early onset of symptoms. Development of new TNFα inhibitors focusing on TNFR1 specific inhibitors, preferably small molecules that can be delivered orally, is much needed.
γ-Oryzanol supplementation modifies the inflammatory and oxidative response in fulminant hepatic failure in mice
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A marked decrease in albumin levels was also noted which confirms an acute hepatotoxicity (Table 3). The LPS/D-GalN toxicity was further confirmed by histopathological analysis, which revealed extensive hepatocellular degeneration, necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation [38], as showed in Fig. 1D. It is known that, serum aminotransferase activities has been considered as sensitive indicators of hepatic injury [39].
The lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced hepatotoxicity is a classical model to elucidate the mechanisms and explore potential therapeutic drugs for fulminant hepatic failure (FHF). γ-Oryzanol (γ-ORY) has been showed to possess both antioxidant and anti-inflammatory properties in several pathological models. However, it remains unclear whether γ-ORY could protect against LPS/D-GalN-induced hepatotoxicity. Thus, the aim of the current study was to evaluate the effects of γ-ORY supplementation (for 7 consecutive days) in LPS/D-GalN-induced FHF in mice. One hour after the last supplementation with γ-ORY, the animals received LPS/D-GalN (50 and 500 mg/kg, respectively; i.p.). Twenty-four hours after LPS/D-GalN administration, biochemical assays were performed. LPS/D-GalN administration caused severe histological damage in the liver, such as vascular congestion and megalocytosis, as well as elicited hepatic failure. LPS/D-GalN treatment also caused alterations in liver function, increased levels of oxidative stress and inflammatory markers. In contrast, γ-ORY supplementation protected against histological, oxidative and inflammatory alterations induced by LPS/D-GalN exposure. Collectively, our data supports the notion that both oxidative stress and inflammatory responses are two key pathogenic factors that contribute to LPS/D-GaIN-mediated FHF. Due to its antioxidant and anti-inflammatory actions, our study indicates γ-ORY as a putative pharmacological option to prevent LPS/D-GalN-induced hepatotoxicity.
Altered expression of P2Y2 and P2X7 purinergic receptors in the isolated rat heart mediates ischemia-reperfusion injury
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Suramin may have antiapoptotic and anti-inflammatory effects in kidney, brain and myocardium [18], and may protect against ischemic injury in kidney [35] and brain [15]. This protection may be mediated by antagonism of purinergic receptors or by other effects of suramin, as this substance also may reduce conexin-mediated membrane permeability [7], inhibit tyrosine kinase [13] and metalloprotease activity [29] and block NF-KappaB activation [11]. During ischemia–reperfusion the concentration of nucleotides such as ATP and UTP in myocardial tissue is increased [32,33].
The aim of this study is to analyze the expression of purinergic receptors in the heart after ischemia–reperfusion, and their possible role in ischemia–reperfusion injury. Rat hearts were perfused according to the Langendorff technique and subjected to 30 min ischemia followed by 15 min reperfusion. Ischemia–reperfusion reduced the gene expression and protein content of purinergic receptors of the P2Y2 subtype, and increased the gene expression and protein content of the P2X7 subtype. Treatment with the agonist of the P2Y2 subtype 2-thio-UTP and with the antagonist of the P2X7 subtype Brilliant Blue improved myocardial function parameters, reduced cell death and increased the myocardial expression of antiapoptotic markers after ischemia–reperfusion. These results suggest that the myocardial expression of the protective P2Y2 subtype of purinergic receptors is reduced, whereas that of the harmful subtype P2X7 subtype is increased during coronary ischemia–reperfusion. This may contribute to myocardial injury in this condition.
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However, we have experienced instances in which dextran sulfate increased cell viability in cultures where no significant cell aggregation was observed (data not shown), suggesting that dextran sulfate may also protect culture viability by directly inhibiting cell death through interfering with the apoptotic pathway. Support that dextran sulfate may directly affect the apoptotic pathway also comes from studies on the anti-apoptotic mechanisms of suramin [13–18]. These studies focused on apoptosis mediated by the death receptors that are induced by TNF-α and CD-95 in HepG2 cells, Jurkat cells, renal tubular cells and tubular epithelial cells, and they theorized that suramin was either able to change the environment of the binding matrix or competitively bind to the death receptor.
Dextran sulfate has been reported to reduce cell aggregation and increase culture viability in suspension cultures of CHO cells. However, only a few of these reports have focused on the effects of dextran sulfate at the cellular level, especially with respect to cell viability. The goal of this study was to examine whether dextran sulfate inhibits CHO cell death through interference with the cellular apoptotic pathway. Apoptosis was induced using staurosporine, and the addition of dextran sulfate was shown to prevent apoptosis, as evident by a reduction in DNA laddering. Dextran sulfate also affected other events in the apoptotic pathway following the addition of staurosporine. Specifically, dextran sulfate decreased pro-caspase-9 activation, cleaved caspase-3 levels, cytochrome c release into the cytosol and mitochondrial transmembrane potential collapse. This data indicates that the mechanism by which dextran sulfate decreases staurosporine-induced apoptosis involves the mitochondrial pathway as early as cytochrome c release, but without caspase-8 activation. This study advances the understanding of the anti-apoptotic action of dextran sulfate on CHO cells and provides a rationale for the application of dextran sulfate in CHO cell culture processes.
Hepatoprotective effect of 3-alkynyl selenophene on acute liver injury induced by D-galactosamine and lipopolysaccharide
2009, Experimental and Molecular Pathology
The aim of this study was to investigate the hepatoprotective effect of 3-alkynyl selenophene (compound a), a selenophene compound, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in rats. The animals received compound a (25 and 50 mg/kg; per oral, p.o.) in the first day of treatment. In the second day, the rats received D-GalN (500 mg/kg; intraperitoneal, i.p.) and LPS (50 μg/kg; intraperitoneal, i.p.). Twenty-four hours after D-GalN/LPS administration animals were euthanized to the biochemical and histological analysis. Compound a (25 and 50 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by D-GalN/LPS. Compound a at 50 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by D-GalN/LPS. The inhibition of δ-aminolevulinic dehydratase (δ-ALA-D) activity and the decrease of ascorbic acid levels caused by D-GalN/LPS were protected by compound a (25 and 50 mg/kg). Glutathione S-transferase (GST) and catalase activities were not altered in all groups. The histological data showed that sections of liver from D-GalN/LPS-treated rats presented massive hemorrhage, the presence of inflammatory cells and necrosis. Compound a attenuated D-GalN/LPS-induced hepatic histopathological alterations. Based on the results, we demonstrated the hepatoprotective effect of compound a on acute liver injury induced by D-GalN/LPS.
Suramin inhibits the CD40-CD154 costimulatory interaction: A possible mechanism for immunosuppressive effects
2009, Biochemical Pharmacology
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There is also a possibility that some of the effects of CD154, and in particular its inflammatory effects, are mediated by other receptors; Mac-1 has been suggested recently as a possibility [36]. Suramin has been reported recently to dose-dependently suppress TNFα and IL-6 production with a suppression of macrophage NF-κB activity as a suggested mechanism [37]. Suramin can be considered a ‘colorless dye’, since it is structurally related to certain polysulfonated azo dyes such as trypan blue or Evans blue, but it does not contain the aryl azo moiety causing their vivid color.
Suramin is a symmetric polysulfonated naphthylamine–benzamide urea derivative approved for the treatment of trypanosomiasis and onchocerciasis and a known P2 (ATP/UTP purine receptor) antagonist. Here, we report its ability to inhibit the important CD40–CD154 costimulatory interaction required for T cell activation and the development of an effective immune response. In vitro, it inhibited the binding of both human and murine CD154 (CD40L) to their receptor (CD40) even in the presence of protein-containing media and prevented the CD154-induced proliferation of human B cells as well as the corresponding increase in surface expression of CD86, CD80, CD40, and MHC class II in a concentration-dependent manner. Furthermore, in isolated human islets, it also decreased the CD154-induced release of inflammatory cytokines such as IFN-γ, interleukin-6 (IL-6), and IL-8. Suramin was selected for investigation because it has been reported to be an inhibitor of the interaction of TNF-α with its receptor and CD154 is a member of the TNF-family. However, it turned out to be a considerably, about 30-fold, more effective inhibitor of the CD40–CD154 protein–protein interaction than of the corresponding TNF interaction. Its median inhibitory concentration (IC₅₀ ≈ 50 μM) is somewhat higher than for the P2-receptor, but well within the range of its therapeutic concentration levels. Suramin shows considerable polypharmacology, but its interference with the positive costimulatory interaction might provide a possible, not yet identified mechanism for its ability to suppress T cell activity and induce immunosuppression, which might also have limited its clinical usefulness in the treatment of AIDS and cancer.

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View full text

Suramin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of NF-κB activity

Abstract

Aim

Methods

Results

Conclusions

Introduction

Section snippets

Materials

Animals

In vivo model procedures

Effects of suramin on survival rate of mice

Discussion

Int Immunopharmacol

Cytokine

Biochem Biophys Res Commun

Toxicology

Cancer Treat Rev

Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III

Science

Suramin; prototype of a new generation of antitumor compounds

Cancer Cells

Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs

Proc Natl Acad Sci USA

Treatment of metastatic adrenal carcinoma with suramin

Dtsch Med Wochenschr

Dengue virus infectivity depends on envelope protein binding to target cell heparan sulphate

Nat Med

Suramin blocks hepatitis C binding to human hepatoma cells in vitro

J Med Virol