The Potential of Iron Chelators of the Pyridoxal Isonicotinoyl Hydrazone Class as Effective Antiproliferative Agents III: The Effect of the Ligands on Molecular Targets Involved in Proliferation

Abstract

We have identified specific iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class that are far more effective ligands than desferrioxamine (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood 89:3025, 1997). In the present study, we have compared the effect of DFO and one of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 311) on molecular targets involved in proliferation. This was performed to further understand the mechanisms involved in the antitumor activity of Fe chelators. Ligand 311 was far more active than DFO at increasing Fe release from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells and preventing Fe uptake from transferrin. Like DFO, 311 increased the RNA-binding activity of the iron-regulatory proteins (IRPs). However, despite the far greater Fe chelation efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was not inhibited by cycloheximide. These results suggest that, irrespective of the Fe chelation efficacy of a ligand, an increase IRP-RNA binding activity occurred via a time-dependent step that did not require protein synthesis. Further studies examined the effect of 311 and DFO on the expression of p53-transactivated genes that are crucial for cell cycle control and DNA repair, namely WAF1,GADD45, and mdm-2. Incubation of 3 different cell lines with DFO or 311 caused a pronounced concentration- and time-dependent increase in the expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the distinct differences in Fe chelation efficacy and antiproliferative activity of DFO and 311, much higher concentrations of DFO (150 μmol/L) than 311 (2.5 to 5 μmol/L) were required to markedly increase GADD45 and WAF1 mRNA levels. The increase in GADD45 and WAF1 mRNA expression was seen only after 20 hours of incubation with the chelators and was reversible after removal of the ligands. In contrast to the chelators, the Fe(III) complexes of DFO and 311 had no effect on increasing GADD45 and WAF1 mRNA levels, suggesting that Fe chelation was required. Finally, the increase in GADD45 and WAF1 mRNAs appeared to occur by a p53-independent pathway in SK-N-MC and K562 cells, because these cell lines lack functional p53. Our results suggest that GADD45 and WAF1 may play important roles in the cell cycle arrest observed after exposure to these chelators.

The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1

“…The antiproliferative effect of iron chelating agents has been well recognized. ( 4,7,16–18 ) However, in the past, the exact mechanism of the antineoplastic effects of iron chelator were not clearly determined. Among iron chelators, deferasirox has been shown to have higher antiproliferative effects by apoptosis in cultured human hepatocytes and hepatocellular carcinoma cell lines than O‐trensox, ( 19,20 ) and deferasirox is now available as an oral iron chelator.…”

Synthesis, characterization and biological activities of semicarbazones and their copper complexes

“…We were specifically interested in the recent application of coordination complexes of Group 13 metal ions with fluoride. McBride et al and others [41][42][43][44][45][46][47][48] have reported the formation of inorganic aluminium complexes with the radioisotope 18 F which show excellent stability, and have highlighted that these provide simple moieties which can be incorporated into a wide range of biomolecules with potential as positron emitting tomography (PET) imaging agents. We prepared new semicarbazones and thiosemicarbazones and their copper complexes, studied their structural characteristics and evaluated their biological profiles.…”

“…In the recent years attention has focussed on the biological applications of these compounds. In this regard, it has been found that some thiosemicarbazones have potent anticancer activity [4][5][6][7][8][9][10][11][12][13][14] The use of iron chelators containing thiosemicarbazones has also been extensively studied [15][16][17][18][19][20][21][22][23][24][25][26] as has the anticancer activity of novel thiosemicarbazones generated through the combination of retro fragments. Some thiosemicarbazones have been found to have antibacterial and antifungal activity [27][28][29] and the pharmacological profile of thiosemicarbazones attached to a heterocyclic core has been reported by Singhal et al [30] The biological profile exhibited by these thiosemicarbazone and semicarbazone derivatives has led to work in which these compounds have been complexed with positron emitting isotopes (e.g.…”

Iron and Microbial Growth

“…14 Iron chelators enhance the expression of several genes, involved in the downregulation of cell cycle progression, such as WAF1 and GADD45, in a p53-independent mechanism. 15 In addition, cdc2 (p34) protein levels, which regulate the checkpoint of the G2/M phase transition, are decreased following incubation with iron chelators. 16 A group from Sydney, Australia, specialized on iron metabolism has reported that iron depletion with deferroxamine (DFO) is associated with substantial decrease of cyclin D1 levels, through post-transcriptional modification of the protein, in a ubiquitin-independent manner, in contrast to what happens under normal conditions, in which cyclin D1 is cleared through proteasomal degradation.…”