Cytotoxic effects of the lipophilic iron chelator omadine

Kontoghiorghes, George J.; Piga, Andrea; Hoffbrand, A. V.

doi:10.1016/0014-5793(86)80813-4

Cited by 36 publications

(24 citation statements)

References 22 publications

(15 reference statements)

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“…This observation, together with the high sensitivity of both CHP134 and SiMa cells to omadine, suggests a mechanism of action not related to its property of binding intracellular iron. Indeed, the cytotoxic effects of omadine are almost immediate, and not reversed upon withdrawal of the compound from the culture media or addition of iron, confirming a mechanism unrelated to iron binding (Kontoghiorghes et al, 1986;Blatt et al, 1989).…”

Section: Iron Chelators Inhibit Hsp90 Translation In Neuroblastoma Rementioning

confidence: 91%

Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells

et al. 2015

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Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared with normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for the promising anticancer activity of iron chelators. In this work, we evaluated the effects of molecules with iron chelation activity on neuroblastoma (NB) cell lines. Of the 17 iron chelators tested, six reduced cell viability of two NB cell lines with an inhibition of growth of 50% below 10 mM; four of the six molecules-ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, and deferasirox-were also shown to efficiently chelate intracellular iron within minutes after addition. Effects on cell viability of one of the compounds, CPX, were indeed dependent on chelation of intracellular iron and mediated by both G 0 /G 1 cell cycle block and induction of apoptosis. By combined transcriptome and translatome profiling we identified early translational downregulation of several members of the heat shock protein group as a specific effect of CPX treatment. We functionally confirmed iron-dependent depletion of HSP90 and its client proteins at pharmacologically achievable concentrations of CPX, and we extended this effect to piroctone, 8-hydroxyquinoline, and deferasirox. Given the documented sensitivity of NB cells to HSP90 inhibition, we propose CPX and other iron chelators as investigational antitumor agents in NB therapy.

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Section: Iron Chelators Inhibit Hsp90 Translation In Neuroblastoma Rementioning

confidence: 91%

Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells

et al. 2015

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“…Its anticancer activity was first reported in the 1980s, though it was thought to be functioning as an iron chelator (35,36). When added to cells along with zinc it induced apoptosis (37)(38)(39).…”

Section: Recognition That Some Metal-binding Compounds Act As Ionophomentioning

confidence: 99%

Metal ionophores – An emerging class of anticancer drugs

2009

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SummaryCompounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.

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“…Further experiments with omadine showed that this compound was almost immediately cytotoxic to NB cells, since if the ligand was removed from cells within 3 h, the cells continued to die (Blatt et al 1989). Addition of Fe to omadine did not prevent or enhance the ability of this chelator to inhibit NB growth (Blatt et al 1989), which is in contrast with other work with leukemic cells, which showed that the addition of Fe to this ligand enhanced its cytotoxicity (Kontoghiorghes et al 1986a(Kontoghiorghes et al , 1986b. This latter investigation suggested that the ability of omadine to inhibit proliferation was probably not by the same mechanism as that found for DFO.…”

Section: (A) Effect Of Dfo On Human Tumor Growthmentioning

confidence: 73%

“…However, several studies have indicated that some of these ligands also effectively inhibit tumor growth. Kontoghiorghes et al (1986aKontoghiorghes et al ( , 1986b have examined the effect of the lipophilic Fe chelator omadine on the proliferation of human leukemic cells and found that its activity was comparable with the cytotoxic drug doxorubicin. At the same concentration two other chelators, namely DFO and L1, did not show cytotoxic activity (Kontoghiorghes et al 1986b).…”

Section: (B) A-ketohydroxypyridonesmentioning

confidence: 99%

Potential of iron chelators as effective antiproliferative agents

Richardson¹

1997

Can. J. Physiol. Pharmacol.

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Initially the impetus to develop iron (Fe) chelators for clinical use was based upon the need for a drug to treat Fe-overload diseases such as beta-thalassemia. However, it has become clear that Fe chelators may be useful for the treatment of a wide variety of disease states, including cancer, malaria, and free radical mediated injury. In particular, over the last 10 years a number of studies have shown that Fe chelators may be of use in the treatment of a number of aggressive human cancers, including neuroblastoma and leukemia, and several clinical trials have substantiated their potential. In the current review the role of Fe in cellular proliferation will be discussed, followed by the possible sites and mechanism of action of some of the most effective ligands. Attention will then be turned to examine the Fe chelators shown to possess antiproliferative activity and the clinical trials performed to assess their efficacy.

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Cytotoxic effects of the lipophilic iron chelator omadine

Cited by 36 publications

References 22 publications

Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells

Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells

Metal ionophores – An emerging class of anticancer drugs

Potential of iron chelators as effective antiproliferative agents

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