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Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1

Lookup NU author(s): Dr Stephany Veuger, Professor Nicola Curtin, Emeritus Professor Barbara Durkacz

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Abstract

The DNA repair enzymes, DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase-1 (PARP-1), are key determinants of radio- and chemo-resistance. We have developed and evaluated novel specific inhibitors of DNA-PK (NU7026) and PARP-1 (AG14361) for use in anticancer therapy. PARP-1- and DNA-PK-deficient cell lines were 4-fold more sensitive to ionizing radiation (IR) alone, and showed reduced potentially lethal damage recovery (PLDR) in G0 cells, compared with their proficient counterparts. NU7026 (10 μm) potentiated IR cytotoxicity [potentiation factor at 90% cell kill (PF90) = 1.51 ± 0.04] in exponentially growing DNA-PK proficient but not deficient cells. Similarly, AG14361 (0.4 μ) potentiated IR in PARP-1+/+ (PF90 = 1.37 ± 0.03) but not PARP-1-/- cells. When NU7026 and AG14361 were used in combination, their potentiating effects were additive (e.g., PF90 = 2.81 ± 0.19 in PARP-1+/+ cells). Both inhibitors alone reduced PLDR -3-fold in the proficient cell lines. Furthermore, the inhibitor combination completely abolished PLDR. IR-induced DNA double strand break (DNA DSB) repair was inhibited by both NU7026 and AG14361, and use of the inhibitor combination prevented 90% of DNA DSB rejoining, even 24-h postirradiation. Thus, there was a correlation between the ability of the inhibitors to prevent IR-induced DNA DSB repair and their ability to potentiate cytotoxicity. Thus, individually, or in combination, the DNA-PK and PARP-1 inhibitors act as potent radiosensitizers and show potential as tools for anticancer therapeutic intervention.


Publication metadata

Author(s): Veuger, S., Curtin, N.J., Richardson, C., Smith, G., Durkacz, B.W.

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2003

Volume: 63

Issue: 18

Pages: 6008-6015

Print publication date: 15/09/2003

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

PubMed id: 14522929


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