The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons

Karen Flatten, Nga T. Dai, Benjamin T. Vroman, David Loegering, Charles Erlichman, Larry M Karnitz, Scott H Kaufmann

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14349-14355
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number14
DOIs
StatePublished - Apr 8 2005

Fingerprint

irinotecan
Type I DNA Topoisomerase
Poisons
Ataxia Telangiectasia
Phosphotransferases
Camptothecin
Cells
tanespimycin
Checkpoint Kinase 2
Down-Regulation
Topoisomerase I Inhibitors
Carcinoma
Metabolites
Checkpoint Kinase 1
Assays
Cell Survival

ASJC Scopus subject areas

  • Biochemistry

Cite this

The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. / Flatten, Karen; Dai, Nga T.; Vroman, Benjamin T.; Loegering, David; Erlichman, Charles; Karnitz, Larry M; Kaufmann, Scott H.

In: Journal of Biological Chemistry, Vol. 280, No. 14, 08.04.2005, p. 14349-14355.

Research output: Contribution to journalArticle

Flatten, Karen ; Dai, Nga T. ; Vroman, Benjamin T. ; Loegering, David ; Erlichman, Charles ; Karnitz, Larry M ; Kaufmann, Scott H. / The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 14. pp. 14349-14355.
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