title: Synthetic lethal targeting of DNA double-strand break repair deficient cells by human apurinic/apyrimidinic endonuclease inhibitors.
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 this study, we have investigated the ability of APE1 inhibitors to induce synthetic lethality (SL) in a panel of DNA double-strand break (DSB) repair deficient and proficient cells; i) Chinese hamster (CH) cells: BRCA2 deficient (V-C8), ATM deficient (V-E5), wild type (V79) and BRCA2 revertant [V-C8(Rev1)]. ii) 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 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. SL 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 SL target in cancer.
authors.affiliation: Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, Nottingham University Hospitals, University of Nottingham, Nottingham, NG51PB, United Kingdom.
authors.forename: Rebeka
authors.initials: R
authors.lastname: Sultana
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McNeill
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbotts
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Mohammed
authors.forename: Malgorzata Z
authors.initials: MZ
authors.lastname: Zdzienicka
authors.forename: Haitham
authors.initials: H
authors.lastname: Qutob
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Poulam M
authors.initials: PM
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency; D024682:BRCA2 Protein / Q000172:deficiency; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase