Carcinogenesis, Vol. 22, No. 10, 1607-1614,
October 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator
1 Department of Biochemistry,
2 Department of Cancer Biology,
3 Department of Pathology and
4 Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC,
5 Department of Chemistry, University of New Hampshire, Durham, NH and
6 Radiation Oncology Branch, National Institutes of Health, Bethesda, MD, USA
Iron is involved in essential biochemical reactions ranging from respiration to DNA synthesis. Consequently, iron deprivation has been proposed as a strategy for inhibition of tumor cell growth. We recently described a novel iron chelator, tachypyridine [N,N',N''-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane], and demonstrated that it not only inhibited growth of cultured tumor cells, but was actively cytotoxic. Here we explore the mechanisms underlying tachpyridine cytotoxicity. Using several criteria, including time-lapse video microscopy, DNA staining and TUNEL assays, tachpyridine was shown to specifically induce apoptotic cell death. Further, unlike numerous cytotoxic chemotherapeutic drugs which induce apoptosis by activating p53-dependent pathways, tachpyridine-mediated cell death did not require p53 activation. Although immunoblotting revealed rapid accumulation of p53 following treatment with tachpyridine, p21WAF1 was not induced. Further, neither cytotoxicity nor apoptosis required p53. p53 null human lung cancer H1299 cells transfected with an ecdysone-inducible p53 exhibited equivalent sensitivity to tachpyridine in the presence and absence of p53, demonstrating the lack of requirement for p53 in an isogenic cell system. Further, time-lapse video microscopy and TUNEL assays demonstrated that both p53 null and p53 wild-type cells underwent apoptotic cell death in response to tachpyridine. In addition, in 55 human cancer cell lines the mean GI50 of tachpyridine in cells with mutant p53 was virtually identical to the GI50 in cells with wild-type p53. These results demonstrate that tachpyridine initiates an apoptotic mode of cell death that does not require functional p53. Since over 50% of human tumors contain a functionally defective p53 that reduces sensitivity to commonly used chemotherapeutic agents, such as etoposide and cisplatin, the ability of tachpyridine to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy.
CiteULike 
Connotea 
Del.icio.us 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]
|
|
|
|
|
|
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. 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]
|
|
|
|
 |
|
 W.-Q. Ding, B. Liu, J. L. Vaught, H. Yamauchi, and S. E. Lind Anticancer Activity of the Antibiotic Clioquinol Cancer Res., April 15, 2005; 65(8): 3389 - 3395. [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]
|
|
|
|
 |
|
 D. Szuts and T. Krude Cell cycle arrest at the initiation step of human chromosomal DNA replication causes DNA damage J. Cell Sci., October 1, 2004; 117(21): 4897 - 4908. [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]
|
|
|
|
 |
|
 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]
|
|