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Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors
- Source :
- International Journal of Cancer. 131:2433-2444
- Publication Year :
- 2012
- Publisher :
- Wiley, 2012.
-
Abstract
- An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In the current study we have investigated the ability of APE1 inhibitors to induce synthetic lethality in a panel of DNA double strand break (DSB) repair deficient and proficient cells; a) Chinese hamster (CH) cells: BRCA2 deficient (V-C8), ATM deficient (V-E5), wild type (V79) and BRCA2 revertant (V-C8(Rev1)). b) Human cancer cells: BRCA1 deficient (MDA-MB-436), BRCA1 proficient (MCF-7), BRCA2 deficient (CAPAN-1 and HeLa SilenciX cells), BRCA2 proficient (PANC1 and control SilenciX cells). We also tested synthetic lethality (SL) in CH ovary cells expressing a dominant–negative form of APE1 (E8 cells) using ATM inhibitors and DNA-PKcs inhibitors (DSB inhibitors). APE1 inhibitors are synthetically lethal in BRCA and ATM deficient cells. APE1 inhibition resulted in accumulation of DNA DSBs and G2/M cell cycle arrest. Synthetic lethality was also demonstrated in CH cells expressing a dominant–negative form of APE1 treated with ATM or DNA-PKcs inhibitors. We conclude that APE1 is a promising synthetic lethality target in cancer.
- Subjects :
- Cancer Research
DNA Repair
Cell Survival
DNA repair
Synthetic lethality
Biology
Article
Cell Line
AP endonuclease
Cell Line, Tumor
Cricetinae
DNA-(Apurinic or Apyrimidinic Site) Lyase
Animals
Humans
Cytotoxic T cell
DNA Breaks, Double-Stranded
AP site
Enzyme Inhibitors
skin and connective tissue diseases
BRCA2 Protein
BRCA1 Protein
DNA-(apurinic or apyrimidinic site) lyase
Molecular biology
Oncology
Cell culture
biology.protein
REV1
Subjects
Details
- ISSN :
- 00207136
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi.dedup.....e763e7ef4c421ca6780a8327267bbd05