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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 29, 2005 Accepted June 30, 2005 Tachpyridine, a metal chelator, induces G2 cell cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation JoLyn Turner, Costantinos Koumenis, Timothy E Kute, Roy P Planalp, Martin W Brechbiel, Dillon I Beardsley, Brooke Cody, Kevin D Brown, Frank M Torti, and Suzy V Torti* Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA Department of Radiation Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA Department of Chemistry, University of New Hampshire, Durham, NH, USA National Cancer Institute, Bethesda, MD, USA Department of Biochemistry and Molecular Biology, Universitiy of Florida College of Medicine, Gainesville, FL, USA Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA * Corresponding author; email: storti{at}wfubmc.edu. 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 non-transformed 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 knockout 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 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 anti-tumor 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: V. A. Rao, S. R. Klein, K. K. Agama, E. Toyoda, N. Adachi, Y. Pommier, and E. B. Shacter The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase II{alpha} in Breast Cancer Cells Cancer Res., February 1, 2009; 69(3): 948 - 957. [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] 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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