|
|
 Previous Article | Table of Contents | Next Article 
The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone
class as effective antiproliferative agents II: the mechanism of action of
ligands derived from salicylaldehyde benzoyl hydrazone and
2-hydroxy-1-naphthylaldehyde benzoyl hydrazone
DR Richardson and K Milnes
Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-
Jewish General Hospital, Montreal, Quebec, Canada.
We 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 micromol/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 G0/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.
Volume 89,
Issue 8,
pp. 3025-3038,
04/15/1997
Copyright © 1997 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
X. Xu, R. Sutak, and D. R. Richardson
Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking
Mol. Pharmacol.,
March 1, 2008;
73(3):
833 - 844.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Fu and D. R. Richardson
Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion
Blood,
July 15, 2007;
110(2):
752 - 761.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Nurtjahja-Tjendraputra, D. Fu, J. M. Phang, and D. R. Richardson
Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression
Blood,
May 1, 2007;
109(9):
4045 - 4054.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski, and D. R. Richardson
Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond
Clin. Cancer Res.,
December 1, 2006;
12(23):
6876 - 6883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Whitnall, J. Howard, P. Ponka, and D. R. Richardson
A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics
PNAS,
October 3, 2006;
103(40):
14901 - 14906.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J R Butterworth
Another important function for an old friend! The role of iron in colorectal carcinogenesis.
Gut,
October 1, 2006;
55(10):
1384 - 1386.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Kalinowski and D. R. Richardson
The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer
Pharmacol. Rev.,
December 1, 2005;
57(4):
547 - 583.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Turner, C. Koumenis, T. E. Kute, R. P. Planalp, M. W. Brechbiel, D. Beardsley, B. Cody, K. D. Brown, F. M. Torti, and S. V. Torti
Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation
Blood,
November 1, 2005;
106(9):
3191 - 3199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T.V. Le and D. R. Richardson
Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation
Blood,
November 1, 2004;
104(9):
2967 - 2975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Yuan, D. B. Lovejoy, and D. R. Richardson
Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment
Blood,
September 1, 2004;
104(5):
1450 - 1458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Kwok and D. R. Richardson
Examination of the Mechanism(s) Involved in Doxorubicin-Mediated Iron Accumulation in Ferritin: Studies Using Metabolic Inhibitors, Protein Synthesis Inhibitors, and Lysosomotropic Agents
Mol. Pharmacol.,
January 1, 2004;
65(1):
181 - 195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.X. Liang and D.R. Richardson
The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1
Carcinogenesis,
October 1, 2003;
24(10):
1601 - 1614.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T.V. Le and D. R. Richardson
Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1, but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation
Carcinogenesis,
June 1, 2003;
24(6):
1045 - 1058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Kwok and D. R. Richardson
Anthracyclines Induce Accumulation of Iron in Ferritin in Myocardial and Neoplastic Cells: Inhibition of the Ferritin Iron Mobilization Pathway
Mol. Pharmacol.,
April 1, 2003;
63(4):
849 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Chaston, D. B. Lovejoy, R. N. Watts, and D. R. Richardson
Examination of the Antiproliferative Activity of Iron Chelators: Multiple Cellular Targets and the Different Mechanism of Action of Triapine Compared with Desferrioxamine and the Potent Pyridoxal Isonicotinoyl Hydrazone Analogue 311
Clin. Cancer Res.,
January 1, 2003;
9(1):
402 - 414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Kwok and D. R. Richardson
Unexpected Anthracycline-Mediated Alterations in Iron-Regulatory Protein-RNA-Binding Activity: The Iron and Copper Complexes of Anthracyclines Decrease RNA-Binding Activity
Mol. Pharmacol.,
October 1, 2002;
62(4):
888 - 900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Lovejoy and D. R. Richardson
Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells
Blood,
June 28, 2002;
100(2):
666 - 676.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Green, W. E. Antholine, S. J. Wong, D. R. Richardson, and C. R. Chitambar
Inhibition of Malignant Cell Growth by 311, a Novel Iron Chelator of the Pyridoxal Isonicotinoyl Hydrazone Class: Effect on the R2 subunit of Ribonucleotide Reductase
Clin. Cancer Res.,
November 1, 2001;
7(11):
3574 - 3579.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Abeysinghe, B. T. Greene, R. Haynes, M. C. Willingham, J. Turner, R. P. Planalp, M.W. Brechbiel, F. M. Torti, and S. V. Torti
p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator
Carcinogenesis,
October 1, 2001;
22(10):
1607 - 1614.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Gao and D. R. Richardson
The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression
Blood,
August 1, 2001;
98(3):
842 - 850.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Dennery
The Biology of Heme Oxygenase During Development
NeoReviews,
March 1, 2001;
2(3):
e67 - 73.
[Full Text]
|
|
|
|
|
|
|
N. Rakba, P. Loyer, D. Gilot, J. G. Delcros, D. Glaise, P. Baret, J. L. Pierre, P. Brissot, and G. Lescoat
Antiproliferative and apoptotic effects of O-Trensox, a new synthetic iron chelator, on differentiated human hepatoma cell lines
Carcinogenesis,
May 1, 2000;
21(5):
943 - 951.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Darnell and D.R. Richardson
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
Blood,
July 15, 1999;
94(2):
781 - 792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. N. Watts and D. R. Richardson
Nitrogen Monoxide (NO) and Glucose. UNEXPECTED LINKS BETWEEN ENERGY METABOLISM AND NO-MEDIATED IRON MOBILIZATION FROM CELLS
J. Biol. Chem.,
February 9, 2001;
276(7):
4724 - 4732.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
