Affiliation:
1. From the Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec, Canada; and the Department of Medicine, McGill University, Montréal, Québec, Canada.
Abstract
AbstractWe have recently screened 36 analogues of the lipophilic iron (Fe) chelator, pyridoxal isonicotinoyl hydrazone (PIH), for their antiproliferative effect (Richardson et al, Blood 86:4295, 1995). Of these compounds, 1 chelator derived from salicylaldehyde benzoyl hydrazone (206) and 4 ligands derived from 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone (308, 309, 311, and 315) showed pronounced antiproliferative activity, being far more effective than desferrioxamine (DFO). The present study was designed to investigate in detail the mechanism of action of these PIH analogues in a variety of neoplastic cell lines. This investigation showed that the analogues were far more active than DFO at inhibiting cellular proliferation and 3H-thymidine, 3H-leucine, and 3H-uridine incorporation. Additional experiments showed that, in contrast to DFO, the 5 analogues were potent at preventing 59Fe uptake from transferrin (Tf ) and increasing 59Fe release from cells at concentrations as low as 10 μmol/L. Examination of the distribution of 59Fe in neoplastic cells using native polyacrylamide gel electrophoresis (PAGE)/59Fe-autoradiography showed that most of the 59Fe taken up from Tf was incorporated into ferritin, although 3 other previously unrecognized components (bands A, B, and C) were also identified. Band C comigrated with 59Fe-citrate and was chelated on incubation of neuroblastoma cells with DFO, PIH, or the PIH analogues, with this compartment being the main intracellular target of these ligands. Further work showed that the effects of the chelators at inducing characteristics consistent with apoptosis or necrosis were cell line-specific, and while DFO increased the percentage of cells in the Go/G1 phases in all cell types, the effect of analogue 311 on the cell cycle was variable depending on the cell line. This study provides further evidence for the potential use of these Fe chelators as anticancer agents.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Reference46 articles.
1. Effect of iron deficiency and desferrioxamine on DNA synthesis in human cells.;Hoffbrand;Br J Haematol,1976
2. In vivo and in vitro effects of desferrioxamine in neonatal acute leukemia.;Estrov;Blood,1987
3. Antileukemic effects of desferrioxamine on human myeloid leukemia cell lines.;Becton;Cancer Res,1989
4. Inhibition of hematopoietic tumor growth by combined treatment with deferoxamine and an IgG monoclonal antibody against the transferrin receptor: Evidence for a threshold model of iron deprivation toxicity.;Kemp;Cancer Res,1992
Cited by
207 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献