Deferoxamine: a reversible S-phase inhibitor of human lymphocyte proliferation

Abstract

Deferoxamine is widely used therapeutically as a chelator of ferric ion in disorders of iron overload. This study demonstrates that this drug is a potent inhibitor of DNA synthesis by human B and T lymphocytes in vitro, but has relatively little effect on the synthesis of RNA and protein. The inhibitory effects of deferoxamine are completely reversible by washing or by adding stoichiometric amounts of Fe3+. Micromolar concentrations of deferoxamine decrease intracellular levels of deoxyribonucleoside triphosphates, which is similar to the effects of hydroxyurea. The binding of iron by deferoxamine likely causes an inhibition of ribonucleotide reductase activity, thereby preventing cells from completing the S phase of the cell proliferation cycle. As a reversible and nontoxic S-phase inhibitor, it may have important experimental and therapeutic applications.

Therapeutic targets and potential of the novel brain‐ permeable multifunctional iron chelator–monoamine oxidase inhibitor drug, M‐30, for the treatment of Alzheimer's disease1

“…All three drugs were shown to induce the characteristics of neuronal differentiation, including cell body elongation, stimulation of neurite outgrowth, arrest of the cell cycle in G 0 /G 1 and specific upregulation of the expression of the neuronal marker GAP-43. These findings are in accordance with results of previous studies suggesting that the cell cycle-blocking activity of iron chelators triggers the process of differentiation through various iron-associated biological events (Lederman et al 1984;Bergeron and Ingeno 1987;Tomoyasu et al 1993;Renton and Jeitner 1996;Tanaka et al 1999). Indeed, many cell cycle-regulating factors require iron ions for their function (Rubin et al 1993;Evans et al 1995) and it was reported that preincubation of iron chelators with Fe 3+ ions abolished their differentiation induction activity (Tanaka et al 1995;Tanaka et al 1997).…”

The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis

“…Because the HIF-1-dependent reporter gene activity still increased with increasing iron chelator concentrations that did not further reduce MTT conversion, the reduction in cellular proliferation/viability apparently is not related to HIF-1 induction. It has been reported previously that iron chelators, including CPX and DFX, can reversibly inhibit the cell cycle at the G 1 /S phase boundary (51)(52)(53)(54)(55)(56). Thus, the decrease in dehydrogenase activity probably is due to reduced proliferation rather than increased toxicity.…”

Two saturable mechanisms of iron uptake from transferrin in human melanoma cells: The effect of transferrin concentration, chelators, and metabolic probes on transferrin and iron uptake

“…Iron is essential for cell growth and division as Fecontaining enzymes catalyse key reactions involving energy metabolism (e.g., cytochromes), oxygen transport (e.g., haemoglobin), and DNA synthesis (e.g., ribonucleotide reductase) (Kuhn et al, 1990). Without Fe, cells are unable to proceed from the G, phase to the S phase of the cell cycle (Lederman et al, 1984). Therefore, all cells require Fe, and neoplastic cells have a high Fe requirement which is reflected by a n increase in the expression of the transferrin receptor (Omary et al, 1980).…”