Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation

• Published in: Blood Vol. 106; no. 9; pp. 3191 - 3199
• Main Authors: Turner, JoLyn, Koumenis, Constantinos, Kute, Timothy E., Planalp, Roy P., Brechbiel, Martin W., Beardsley, Dillon, Cody, Brooke, Brown, Kevin D., Torti, Frank M., Torti, Suzy V.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2005; The Americain Society of Hematology; 2005 by The American Society of Hematology
• Subjects: Antineoplastic agents; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell Cycle Proteins - metabolism; Cell Division - drug effects; Cell Division - radiation effects; Cell Line, Tumor; Checkpoint Kinase 1; Checkpoint Kinase 2; Chelating Agents - pharmacology; Chemotherapy; Cyclohexylamines - pharmacology; DNA-Binding Proteins - metabolism; Enzyme Activation - drug effects; Enzyme Activation - radiation effects; G2 Phase - drug effects; G2 Phase - radiation effects; Humans; Medical sciences; Metals - antagonists & inhibitors; Metals - metabolism; Neoplasia; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; Radiation, Ionizing; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Antineoplastic agent; Human; Checkpoint kinase; Enzyme; Transferases; Iron; Metal; Biological activity; Ionizing radiation; Radiosensitizing agent; Tachpyridine; Kinase; Cell cycle; Chelating agent; Mechanism of action
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-03-1263

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.