Downregulation of APE1 potentiates breast cancer cells to olaparib by inhibiting PARP-1 expression

PurposeTargeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanismof olaparib treatment in breast cancer cell lines.MethodsWe investigated the cytotoxic effect of various doses ofolaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and proteinlevels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study.Results2 mu M or higher concentrations of olapariblead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showedthat reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment.ConclusionTo acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.