Toggle Main Menu Toggle Search

Open Access padlockePrints

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 WillmoreORCiD, Professor Caroline AustinORCiD, Professor Nicola CurtinORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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


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

PubMed id: 16322308


Altmetrics provided by Altmetric