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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3191-3199. Prepublished online as a Blood First Edition Paper on July 12, 2005; DOI 10.1182/blood-2005-03-1263. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-1263v1 106/9/3191    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Turner, J. Articles by Torti, S. V. Search for Related Content PubMed PubMed Citation Articles by Turner, J. Articles by Torti, S. V. Related Collections Neoplasia Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation JoLyn Turner, Constantinos Koumenis, Timothy E. Kute, Roy P. Planalp, Martin W. Brechbiel, Dillon Beardsley, Brooke Cody, Kevin D. Brown, Frank M. Torti, and Suzy V. Torti From the Department of Biochemistry, Wake Forest University Health Sciences; the Department of Radiation Biology, Wake Forest University Health Sciences; the Department of Pathology, Wake Forest University Health Sciences; the Department of Chemistry, University of New Hampshire, Durham, NH; the National Cancer Institute, Bethesda, MD; the Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL; the Department of Cancer Biology, Wake Forest University Health Sciences; and the Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC. Iron is critical for cell growth and proliferation. Iron chelators are being explored for a number of clinical applications, including the treatment of neurodegenerative disorders, heart disease, and cancer. To uncover mechanisms of action of tachpyridine, a chelator currently undergoing preclinical evaluation as an anticancer agent, cell-cycle analysis was performed. Tachpyridine arrested cells at G2, a radiosensitive phase of the cell cycle, and enhanced the sensitivity of cancer cells but not nontransformed cells to ionizing radiation. G2 arrest was p53 independent and was accompanied by activation of the checkpoint kinases CHK1 and CHK2. G2 arrest was blocked by UCN-01, a CHK1 inhibitor, but proceeded in CHK2 knock-out cells, indicating a critical role for CHK1 in G2 arrest. Tachpyridine-induced cell-cycle arrest was abrogated in cells treated with caffeine, an inhibitor of the ataxia-telangiectasia mutated/ataxia-telangiectasia-mutated and Rad3-related (ATM/ATR) kinases. Further, G2 arrest proceeded in ATM-deficient cells but was blocked in ATR-deficient cells, implicating ATR as the proximal kinase in tachpyridine-mediated G2 arrest. Collectively, our results suggest that iron chelators may function as antitumor and radioenhancing agents and uncover a previously unexplored activity of iron chelators in activation of ATR and checkpoint kinases. 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]

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