Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation.
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.
Turner
Jolyn
J
Department of Biochemistry, Wake Forest University Health Scieces, Winston-Salem, NC 27157, USA.
Koumenis
Constantinos
C
Kute
Timothy E
TE
Planalp
Roy P
RP
Brechbiel
Martin W
MW
Beardsley
Dillon
D
Cody
Brooke
B
Brown
Kevin D
KD
Torti
Frank M
FM
Torti
Suzy V
SV
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002614:Chelating Agents / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D008670:Metals / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D002614:Chelating Agents; D003514:Cyclohexylamines; D004268:DNA-Binding Proteins; D008670:Metals; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C114047:tachpyr; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases