title: The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons.
abstract: Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs.
authors.affiliation: Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Flatten
authors.forename: Nga T
authors.initials: NT
authors.lastname: Dai
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Vroman
authors.forename: David
authors.initials: D
authors.lastname: Loegering
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D017353:Gene Deletion; D018816:Genes, cdc; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin