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The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks.

Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors enhance DNA topoisomerase I (topo I) poison-induced cytotoxicity and antitumor activity in vitro and in vivo, but the mechanism has not been defined. We investigated the role of PARP-1 in the response to topo I poisons using PARP-1-/- and PARP-1+/+ mouse embryonic fibroblasts and the potent PARP-1 inhibitor, AG14361 (Ki < 5 nmol/L). PARP-1-/- mouse embryonic fibroblasts were 3-fold more sensitive to topotecan than PARP-1+/+ mouse embryonic fibroblasts (GI50, 21 and 65 nmol/L, respectively). AG14361 caused a >3-fold sensitization of PARP-1+/+ cells to topotecan compared with a <1.4-fold sensitization in PARP-1-/- cells. In human leukemia K562 cells, AG14361 caused a 2-fold sensitization to camptothecin-induced cytotoxicity. AG14361 did not affect the cellular activity of topo I as determined by measurement of cleavable complexes and topo I relaxation activity, showing that sensitization was not due to topo I activation. In contrast, repair of DNA following camptothecin removal, normally very rapid, was significantly retarded by AG14361, resulting in a 62% inhibition of repair 10 minutes after camptothecin removal. This led to a 20% increase in the net accumulation of camptothecin-induced DNA strand break levels in cells coexposed to AG14361 for 16 hours. We investigated the DNA repair mechanism involved using a panel of DNA repair-deficient Chinese hamster ovary cells. AG14361 significantly potentiated camptothecin-mediated cytotoxicity in all cells, except the base excision repair-deficient EM9 cells. Therefore, the most likely mechanism for the potentiation of topo I poison-mediated cytotoxicity by AG14361 is via PARP-1-dependent base excision repair.
AuthorsLisa M Smith, Elaine Willmore, Caroline A Austin, Nicola J Curtin
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 23 Pg. 8449-57 (Dec 01 2005) ISSN: 1078-0432 [Print] United States
PMID16322308 (Publication Type: Journal Article)
Chemical References
  • 1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one
  • Antineoplastic Agents, Phytogenic
  • Azulenes
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Topoisomerase I Inhibitors
  • Benzodiazepines
  • Topotecan
  • DNA Topoisomerases, Type I
  • Camptothecin
Topics
  • Animals
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Azulenes
  • Benzodiazepines (pharmacology)
  • CHO Cells (drug effects)
  • Camptothecin (toxicity)
  • Cricetinae
  • DNA Damage (drug effects)
  • DNA Repair (drug effects)
  • DNA Topoisomerases, Type I (metabolism)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Fibroblasts (drug effects, enzymology)
  • Humans
  • K562 Cells (drug effects)
  • Mice
  • Mice, Knockout
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Topoisomerase I Inhibitors
  • Topotecan (toxicity)
  • Tumor Stem Cell Assay

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