In vitro inhibition of human cytomegalovirus replication by calcium trinatrium diethylenetriaminepentaacetic acid

Cinatl, Jindrich; Hoffmann, Florian; Weber, Bernard; Scholz, Martin; Rabenau, Holger F.; Stieneker, F; Kabíčková, Hana; Blaŝko, M; Doerr, H. W.

doi:10.1016/0166-3542(95)00833-0

Cited by 29 publications

(8 citation statements)

References 36 publications

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“…In agreement, eltrombopag also inhibited murine cytomegalovirus replication in murine NIH/3T3 fibroblasts ( Figure 3A), although eltrombopag does not target the murine thrombopoietin receptor [29]. Eltrombopag is also an iron chelator [2,30,31], and iron chelators have been shown to inhibit HCMV replication [32][33][34][35][36][37][38]. The addition of equimolar Fe 3+ concentrations was shown to inhibit pharmacological action of eltrombopag that are caused via iron chelation [31].…”

Section: Eltrombopag Inhibits Hcmv Expression Via Iron Chelationsupporting

confidence: 53%

“…The combination of eltrombopag and foscarnet also displayed synergistic effects (Table S2). Eltrombopag is also an iron chelator [2,30,31], and iron chelators have been shown to inhibit HCMV replication [32][33][34][35][36][37][38]. The addition of equimolar Fe 3+ concentrations was shown to inhibit pharmacological action of eltrombopag that are caused via iron chelation [31].…”

Section: Eltrombopag Exerts Synergistic Effects With Ganciclovirmentioning

confidence: 99%

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The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation

Vogel

Schmidt

et al. 2019

Cells

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The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.

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Section: Eltrombopag Inhibits Hcmv Expression Via Iron Chelationsupporting

confidence: 53%

Section: Eltrombopag Exerts Synergistic Effects With Ganciclovirmentioning

confidence: 99%

The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation

Vogel

Schmidt

et al. 2019

Cells

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“…DTPA is an elongated version of EDTA and has been used to detoxify humans who are contaminated with plutonium, americium and other actinides (Westin & Rasmuson, 2005). Cinatl et al (1996) proposed that DTPA may directly interact with membrane associated proteins and lipids in in vitro study of virus for which Zn is a constituent of many proteins and enzymes. Previous studies have used DTPA in vitro in investigating the role of metal ions in cellular functions, particularly that of Zn (Chattopadhyay & Freake, 1998; Chesters et al, 1989; Lefebyre et al, 1998; Nakatani et al, 1998; Petrie et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Cellular Zn depletion by metal ion chelators (TPEN, DTPA and chelex resin) and its application to osteoblastic MC3T3-E1 cells

et al. 2007

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Trace mineral studies involving metal ion chelators have been conducted in investigating the response of gene and protein expressions of certain cell lines but a few had really focused on how these metal ion chelators could affect the availability of important trace minerals such as Zn, Mn, Fe and Cu. The aim of the present study was to investigate the availability of Zn for the treatment of MC3T3-E1 osteoblast-like cells and the availability of some trace minerals in the cell culture media components after using chelexing resin in the FBS and the addition of N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN, membrane-permeable chelator) and diethylenetriaminepentaacetic acid (DTPA, membrane-impermeable chelator) in the treatment medium. Components for the preparation of cell culture medium and Zn-treated medium have been tested for Zn, Mn, Fe and Cu contents by atomic absorption spectrophotometer or inductively coupled plasma spectrophotometer. Also, the expression of bone-related genes (ALP, Runx2, PTH-R, ProCOL I, OPN and OC) was measured on the cellular Zn depletion such as chelexing or TPEN treatment. Results have shown that using the chelexing resin in FBS would significantly decrease the available Zn (p<0.05) (39.4 ± 1.5 µM vs 0.61 ± 10.15 µM) and Mn (p<0.05) (0.74 ± 0.01 µM vs 0.12 ± 0.04 µM). However, levels of Fe and Cu in FBS were not changed by chelexing FBS. The use of TPEN and DTPA as Zn-chelators did not show significant difference on the final concentration of Zn in the treatment medium (0, 3, 6, 9, 12 µM) except for in the addition of higher 15 µM ZnCl2 which showed a significant increase of Zn level in DTPA-chelated treatment medium. Results have shown that both chelators gave the same pattern for the expression of the five bone-related genes between Zn- and Zn+, and TPEN-treated experiments, compared to chelex-treated experiment, showed lower bone-related gene expression, which may imply that TPEN would be a stronger chelator than chelex resin. This study showed that TPEN would be a stronger chelator compared to DTPA or chelex resin and TPEN and chelex resin exerted cellular zinc depletion to be enough for cell study for Zn depletion.

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“…Desferrioxamine (DFO) and calcium trinatrium diethylenctriaminepcntaacetic acid (DTPA. Antiron) have shown to inhibit CMV replication in vitro [99,100]. In a case report, CMV retinitis in an AIDS patient was suppressed by a daily dose of 1 g i.v.…”

Section: Chelatorsmentioning

confidence: 99%

Treatment of Cytomegalovirus Diseases

Vogel

Scholz²,

Cinatl³

1997

Intervirology

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This review summarizes current strategies for the treatment of human cytomegalovirus (CMV) infection/diseases in high-risk patients such as transplant recipients and AIDS patients. Since the major drugs ganciclovir (Cytovene), foscarnet (Foscavir) and cidofovir (Vistide) are frequently associated with severe side effects and the formation of viral resistance, it should be endeavored to develop better strategies in anti-CMV treatment. Moreover, blocking of the viral replication does not always resolve the manifestations which are often linked with CMV-associated immunopathomechanisms. Thus, the efficacy of the available drugs is also discussed in the light of their ability to modulate inflammatory components of the cell-mediated immune system.

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In vitro inhibition of human cytomegalovirus replication by calcium trinatrium diethylenetriaminepentaacetic acid

Cited by 29 publications

References 36 publications

The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation

The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation

Cellular Zn depletion by metal ion chelators (TPEN, DTPA and chelex resin) and its application to osteoblastic MC3T3-E1 cells

Treatment of Cytomegalovirus Diseases

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