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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.
Clin Cancer Res. 2005 Dec 01; 11(23):8449-57.CC

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.

Authors+Show Affiliations

Northern Institute for Cancer Research and Institute for Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16322308

Citation

Smith, Lisa M., et al. "The Novel poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons By Increasing the Persistence of DNA Strand Breaks." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 11, no. 23, 2005, pp. 8449-57.
Smith LM, Willmore E, Austin CA, et al. The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res. 2005;11(23):8449-57.
Smith, L. M., Willmore, E., Austin, C. A., & Curtin, N. J. (2005). The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 11(23), 8449-57.
Smith LM, et al. The Novel poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons By Increasing the Persistence of DNA Strand Breaks. Clin Cancer Res. 2005 Dec 1;11(23):8449-57. PubMed PMID: 16322308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. AU - Smith,Lisa M, AU - Willmore,Elaine, AU - Austin,Caroline A, AU - Curtin,Nicola J, PY - 2005/12/3/pubmed PY - 2006/1/25/medline PY - 2005/12/3/entrez SP - 8449 EP - 57 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 11 IS - 23 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/16322308/The_novel_poly_ADP_Ribose__polymerase_inhibitor_AG14361_sensitizes_cells_to_topoisomerase_I_poisons_by_increasing_the_persistence_of_DNA_strand_breaks_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=16322308 DB - PRIME DP - Unbound Medicine ER -