application) Iron chelators have an expanding role in the treatment of disease. In addition to their importance in the treatment of iron overload, iron chelators have potential therapeutic benefit in other pathophysiological conditions, including ischemia/reperfusion, malaria and malignant disease. A detailed appreciation of modes of chelator action will be essential to the rational design of such therapies. To better understand cellular consequences of iron chelation, we have been studying cellular targets of iron chelators. Our recent experiments revealed that in addition to well-studied effects on proteins of iron metabolism, iron chelators affect an entirely different group of proteins: those involved in tumor suppression and cell death, Specifically, we have observed that iron chelators actively promote cell death by engaging apoptotic pathways. Cells treated with the chemically unrelated iron chelators tachpyridine, desferioxamine and 2,2'-bipyridyl exhibited characteristic morphological changes of apoptosis, including membrane blebbing, nuclear segmentation, and internucleosomal DNA strand breaks. Our preliminary results indicate that this apoptosis may be initiated through targeting of mitochondria: in response to chelator treatment, we observed the release of cytochrome c from mitochondria into the cytosol, a hallmark of mitochondrially mediated pathways of apoptosis. A further insight into mechanisms of iron chelator-mediated apoptosis derives from our observation that the oncogene E1A strikingly enhances sensitivity to iron chelators. Since E1A affects a restricted but critical set of cell regulatory proteins, this observation narrows the focus of potential molecular targets of iron chelators, and suggests that proteins such as p300 or pRb (E1A binding proteins) or p53 (stabilized by E1A) play important roles in chelator-mediated cell death. Indeed, we have observed that the iron chelators tachpyridine and desferioxamine activate the p53 tumor suppressor protein. The goal of this application is to define specific molecular mechanisms by which iron chelators induce apoptotic cell death. Independent of their ultimate clinical use (i.e., in the treatment of iron overload, cancer, or other diseases), these studies will provide insights into effects of iron chelators that will be important to consider in future chelator design and application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK057781-04S1
Application #
6786803
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Badman, David G
Project Start
2000-06-01
Project End
2004-04-30
Budget Start
2003-08-15
Budget End
2004-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$36,720
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Childers, Matt L; Cho, Joonhyung; Regino, Celeste A S et al. (2008) Influence of ligand structure on Fe(II) spin-state and redox rate in cytotoxic tripodal chelators. J Inorg Biochem 102:150-6
Regino, Celeste Aida S; Torti, Suzy V; Ma, Rong et al. (2005) N-picolyl derivatives of Kemp's triamine as potential antitumor agents: a preliminary investigation. J Med Chem 48:7993-9
Turner, Jolyn; Koumenis, Constantinos; Kute, Timothy E et al. (2005) Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation. Blood 106:3191-9
Torti, Suzy V; Ma, Rong; Venditto, Vincent J et al. (2005) Preliminary evaluation of the cytotoxicity of a series of tris-2-aminoethylamine (Tren) based hexadentate heterocyclic donor agents. Bioorg Med Chem 13:5961-7
Ye, Neng; Park, Gyungse; Przyborowska, Ann M et al. (2004) Nickel(II), copper(II) and zinc(II) binding properties and cytotoxicity of tripodal, hexadentate tris(ethylenediamine)--analogue chelators. Dalton Trans :1304-11
Zhao, Rong; Planalp, Roy P; Ma, Rong et al. (2004) Role of zinc and iron chelation in apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Biochem Pharmacol 67:1677-88
Chong, Hyun-Soon; Torti, Suzy V; Ma, Rong et al. (2004) Synthesis and potent antitumor activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives. J Med Chem 47:5230-4
Buss, Joan L; Greene, Bryan T; Turner, Jolyn et al. (2004) Iron chelators in cancer chemotherapy. Curr Top Med Chem 4:1623-35
Buss, Joan L; Torti, Frank M; Torti, Suzy V (2003) The role of iron chelation in cancer therapy. Curr Med Chem 10:1021-34
Planalp, R P; Przyborowska, A M; Park, G et al. (2002) Novel cytotoxic chelators that bind iron(II) selectively over zinc(II) under aqueous aerobic conditions. Biochem Soc Trans 30:758-62

Showing the most recent 10 out of 13 publications