Variation in iron accumulation, transferrin membrane binding and DNA synthesis in the K‐562 and U‐937 cell lines induced by chelators and their iron complexes

Abstract

Eight chelators – 8‐hydroxyquinoline, 1‐hydroxypyridine‐2‐thione (omadine), tropolone, pyridoxal isonicotinoyl hydrazone, 2‐methyl‐3‐hydroxypyr‐4‐one (maltol), 1‐methyl‐3‐hydroxypyrid‐2‐one, 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one and mimosine – and their iron complexes were tested on cells of the established human tumour cell lines K‐562 (erythroleukaemic) and U‐937 (monoblastoid) for their effects on a) cellular accumulation of iron provided by transferrin (Tf) via receptor‐mediated endocytosis, b) specific cell surface binding of Tf, c) cell viability and, d) DNA synthesis. The lipophilic chelators suppressed the accumulation of Tf‐supplied iron in the K‐562 cells and less so in the U‐937 cells, whereas the effects of the other chelators were closer to control range. The lipophilic chelators pyridoxal isonicotinoyl hydrazone, tropolone, 8‐hydroxyquinoline and omadine were found to be cytotoxic in this order, with the U‐937 being generally more sensitive than K‐562. The presence of iron diminished the toxicity. The DNA synthesis was also affected, from a partial suppression in K‐562 to a slight increase in U‐937 in the presence of pyridoxal isonicotinoyl hydrazone and to strong suppression with 8‐hydroxyquinoline and omadine. Addition of iron partially reversed the inhibition. The other chelators had low cytotoxic effects that disappeared upon iron saturation. Maltol, particularly in the absence of iron, 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one and 1‐methyl‐3‐hydroxypyrid‐2‐one supported DNA synthesis. Long‐term culturing (24 h) of both cell types in the presence of the non‐cytotoxic chelators resulted in increased specific Tf binding, which was interpreted as the result of an increased Tf‐receptor synthesis. This is presumably triggered via the chelators' interaction with a certain cellular iron pool.

Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

“…For example, the lipid–water partition coefficient of the chelators and their iron complexes has been shown to affect the transfer of iron across the cell membrane in different cell types, as well as to cause variable effects related to the intracellular iron-metabolism pathways in these cells. 40 – 42 …”

Chelators Controlling Metal Metabolism and Toxicity Pathways: Applications in Cancer Prevention, Diagnosis and Treatment

“…Similar effects can be achieved by targeting the metal transporting proteins or their cell membrane receptors. This form of targeting may be more effective in certain types of cancer such as breast, prostate and bladder cancers, which appear to have an increased expression of transferrin receptors at the cell surface suggesting that they have increased iron requirements (12,13). In these cases, the iron removal effects of L1 from transferrin can be used to control the proliferation of neoplasmic cells (14).…”

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

“…However, the iron uptake and release processes that are involved intracellularly to and from the naturally occurring chelators and their complexes, are expected to be governed by the same thermodynamic and kinetic parameters as for other chelators and their complexes [ 23 , 24 , 25 ]. The distribution of the natural chelator and chelator iron complexes into lipophilic and hydrophilic intracellular compartments, is expected to depend on their lipid/water partition coefficient and other physicochemical properties, similar to that of other chelators ( Table 6 ) [ 180 , 181 , 182 , 183 ].…”

“…In contrast to iron removal, iron donation to cells by lipophilic chelators could increase the size of the intracellular LMWt iron pool, ferritin iron levels and the production of heme in hemopoietic cells [ 180 , 181 , 182 ]. These non-transferrin iron delivery effects to cells could be used as therapeutic tools for pathways involving the low turnover of iron-containing proteins and especially in abnormal conditions related to low heme production and insufficient transferrin iron delivery, e.g., in the anemia of chronic disease [ 122 , 123 ].…”

“…Within this context none of the chelators showed exclusive delivery to or rejection of a particular cellular iron compartment such as ferritin or heme [ 180 ]. However, some lipophilic chelators appear to inhibit iron incorporation into heme originating from transferrin and similar interactions are anticipated with iron delivery for other iron-containing proteins [ 182 ]. Furthermore, such lipophilic chelators could probably be substituted for transferrin and be used to probe metabolic events.…”