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Preferential potentiation of topoisomerase I poison cytotoxicity by PARP inhibition in S phase

Lookup NU author(s): Pawel Znojek, Dr Elaine Willmore, Professor Nicola Curtin

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Abstract

Background: Topoisomerase I (Topo I) poisons (e. g., camptothecin (CPT)), used to treat cancer, cause DNA breaks that are most cytotoxic during S phase. PARP-1 promotes DNA repair and PARP inhibitors (PARPi) sensitise cells to Topo I poisons. We aimed to determine whether chemosensitisation is also S phase specific using rucaparib, a potent PARPi in advanced clinical evaluation.Methods: The impact of rucaparib, on CPT-induced cytotoxicity was measured in human colon cancer (LoVo) and leukaemic (K562) cells in asynchronous and cell cycle phase-separated cultures. Topoisomerase I and PARP levels and activity and the effect of rucaparib on DNA single-strand breaks (SSBs), double-strand breaks (DSBs) and collapsed replication fork induction and repair were determined in cell cycle phase-separated cells.Results: The cytotoxicity of CPT was greatest during S phase, partially attributable to high Topo I activity, and rucaparib preferentially sensitised S-phase cells. Rucaparib increased CPT-induced DNA SSBs in all phases of the cell cycle, and increased DSB and gH2AX foci in S and G2, with gH2AX foci being highest in S-phase cells. Repair of SSBs and DSBs was most rapid during S then G2 phases and was substantially hindered by rucaparib.Conclusions: Rucaparib preferentially sensitises S-phase cells by increasing the frequency of collapsed replication forks.


Publication metadata

Author(s): Znojek P, Willmore E, Curtin NJ

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2014

Volume: 111

Issue: 7

Pages: 1319-1326

Online publication date: 08/07/2014

Acceptance date: 10/06/2014

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/bjc.2014.378

DOI: 10.1038/bjc.2014.378


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