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.