The Effect of Desferoxamine on Fibroblasts and Collagen Formation in Cell Cultures

Hunt, Jennifer A.; Richards, Roy J.; Harwood, Richard R.; Jacobs, A.

doi:10.1111/j.1365-2141.1979.tb03682.x

Cited by 42 publications

(11 citation statements)

References 21 publications

(9 reference statements)

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“…This conclusion is consistent with the failure of DFOX to suppress HIV-1 gene expression and replication in culture [23], [87] and to prevent disease progression and death in HIV-infected patients [88]. DFOX is an effective inhibitor of iron-containing protein hydroxylases only at supraclinical concentrations [35], [89], [90]. As predicted from its structure, Agent P2 displays a CPX-like ability to form bidentate chelates with Fe 3+ that produce tris(N-hydroxypyridinone ligand) complexes (Fig.…”

Section: Resultssupporting

confidence: 73%

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

et al. 2013

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HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.

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Section: Resultssupporting

confidence: 73%

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

et al. 2013

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“…It has been shown that in connective tissue treated with an iron chelator such as 2,2'-dipyridyl, proline and lysine are incorporated into procollagen but there is no synthesis of hydroxyproline or hydroxylysine [24.26] . It has been recently demonstrated that fibroblast cultures treated with desferrioxamine show inhibition of DNA synthesis and reduced collagen formation, with an apparent increase in the amounts of collagen produced with reduced doses of the agent [27]. The present findings support the view that desferrioxamine effects on membrane-associated proteins involve collagen synthesis and inhibition of proline and lysine hydroxylase activity.…”

Section: :Tcsm Iron Starvation and Membrane Proteinssupporting

confidence: 87%

Isolation and immunological characterization of an iron‐regulated, transformation‐sensitive cell surface protein of normal rat kidney cells

Fernandez-Pol

1979

J Supramol Struct

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We have analyzed the surfacr proteins of cultured normal rat kidney (NRK) cells and virus-transformed NRK cells subjected to iron deprivation. Such a treatment specifically induces two transformation-sensitive plasma membrane-associated glycoproteins with a subunit molecular weight of 160,000 (160 K) and 130,000 (130 K) daltons in NRK cells. In these cells the 160 K glycoprotein is readily available to lactoperoxidase-mediated iodination, and the 130 K is apparently inaccessible to iodination. Major differences were revealed when iodinated membrane proteins of normal and virus-transformed cells subjected to iron deprivation were compared. In Kirsten sarcoma virus-transformed NRK cells the 160 K glycoprotein was weakly labeled. In two clones of simian virus 40-transformed NRK cells the 160 K glycoprotein was weakly labeled or not at all. The 130 K glycoprotein was inaccessible to iodination in all virus-transformed cell lines. The 160 K and 130 K glycoproteins were isolated from plasma membranes of NRK cells using preparative SDS gel electrophoresis. Antibodies generated against these glycoproteins stained the external surfaces of NRK cells and induced antigen redistribution. Evidence presented suggests that 160 K and 130 K are plasma membrane-associated procollagen molecules. A possible interaction of these proteins with transferrin is also described. The data suggest that these proteins may have an important role in the sequence of events leading to transformation.

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“…The observed decrease in granuloma tissue for mation can be explained because iron is a co-factor in collagen synthesis at the stage of proline and lysine hydroxylation [10,11], The observed increase in the number of leu kocytes has been interpreted as an inflam matory response [3], In our opinion this is only a reflection of the absence of iron in the system. Desferrioxamine by binding the iron necessary for the hydroxyl radical produc tion might well protect against lipid peroxi dation and increase the cell life span and thereby increase the cell number.…”

Section: Discussionmentioning

confidence: 87%

Role of Iron in Carrageenan-Induced Granuloma: Action of Desferrioxamine and Indometacin

Mitjavila

Carbonell²,

Sáiz³

et al. 1990

Pharmacology

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Iron has been implicated in the inflammatory process. In this paper we studied the modulating inflammatory activity of iron in the carrageenan-induced granuloma pouch, taking indometacin as a standard anti-inflammatory drug. Sprague-Dawley rats were injected subcutaneously with desferrioxamine (100 mg/kg) and indometacin (5 mg/kg) for 3 consecutive days before granuloma induction, followed by a daily administration in the granuloma pouch until the day before death. We determined the granuloma weight and assayed in the exudate: volume, number of leukocytes, PGE₂ levels and loosely bound iron content at 1 (acute inflammation) and 6 days (chronic inflammation) after granuloma induction. Our results show a dual effect of desferrioxamine, inflammatory in the acute phase and anti-inflammatory in the chronic phase. These results are discussed in relation to chemotaxis and to the potential role of iron on oxygen free radical production, collagen synthesis and hydroperoxide generation, while indometacin acts through the cyclooxygenase pathway.

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The Effect of Desferoxamine on Fibroblasts and Collagen Formation in Cell Cultures

Cited by 42 publications

References 21 publications

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

Isolation and immunological characterization of an iron‐regulated, transformation‐sensitive cell surface protein of normal rat kidney cells

Role of Iron in Carrageenan-Induced Granuloma: Action of Desferrioxamine and Indometacin

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