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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

Lookup NU author(s): Lisa Smith, Dr Elaine Willmore, Professor Caroline Austin, Professor Nicola Curtin

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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 (Gl50, 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. © 2005 American Association for Cancer Research.


Publication metadata

Author(s): Smith LM, Willmore E, Austin C, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2005

Volume: 11

Issue: 23

Pages: 8449-8457

Print publication date: 01/12/2005

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

URL: http://dx.doi.org/10.1158/1078-0432.CCR-05-1224

DOI: 10.1158/1078-0432.CCR-05-1224

PubMed id: 16322308


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