|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1384-1389
Tumor Cell Cytotoxicity of a Novel Metal Chelator
S.V. Torti,
F.M. Torti,
S.P. Whitman,
M.W. Brechbiel,
G. Park, and
R.P. Planalp
From the Departments of Biochemistry, Cancer Biology, and Internal
Medicine, Wake Forest University School of Medicine and the
Comprehensive Cancer Center of Wake Forest University, Winston-Salem,
NC; the Radiation Oncology Branch, National Institutes of Health,
Bethesda, MD; and the Department of Chemistry, University of New
Hampshire, Durham, NH.
We have synthesized a novel six-coordinate metal chelator from the
triamine cis-1,3,5-triaminocyclohexane by the addition of a
2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr.
The experiments described here were designed to explore whether this
compound exhibits potential antitumor activity. When added to MBT2 or
T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic,
with an IC50 of approximately 4.6 µmol/L compared with 70 µmol/L for desferioxamine. To explore the mode of action of tachpyr,
several metal complexes were prepared, including Fe(II), Ca(II),
Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the
Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas
the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further
probe the role of Zn(II) and Cu(II) chelation in the
cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were
prepared through N-alkylation of tachpyr. These derivatives were unable
to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and
Cu(II). When added to cells, these sterically hindered tachpyr
derivatives were nontoxic, consistent with a role of iron depletion in
the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to
proliferating cultures resulted in an early and selective inhibition of
ferritin synthesis, an iron storage protein whose translation is
critically dependent on intracellular iron pools. Taken together, these
experiments suggest that tachpyr is a cytotoxic metal chelator that
targets intracellular iron, and that the use of tachpyr in cancer
therapy deserves further exploration.
© 1998 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:
|
|
|
|
 
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
M.-H. Hou and A. H.-J. Wang
Mithramycin forms a stable dimeric complex by chelating with Fe(II): DNA-interacting characteristics, cellular permeation and cytotoxicity
Nucleic Acids Res.,
March 1, 2005;
33(4):
1352 - 1361.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
B. T. Greene, J. Thorburn, M. C. Willingham, A. Thorburn, R. P. Planalp, M. W. Brechbiel, J. Jennings-Gee, J. Wilkinson IV, F. M. Torti, and S. V. Torti
Activation of Caspase Pathways during Iron Chelator-mediated Apoptosis
J. Biol. Chem.,
July 5, 2002;
277(28):
25568 - 25575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Thompson, M. G. Fried, Z. Ye, P. Boyer, and J. R. Connor
Regulation, mechanisms and proposed function of ferritin translocation to cell nuclei
J. Cell Sci.,
May 15, 2002;
115(10):
2165 - 2177.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
