Abstract
Poly(ADP‑ribose) polymerase (PARP) inhibitors have little effect on homologous recombination repair (HRR)‑proficient tumor types, such as cervical cancer. In addition to catalytic activity, the PARP inhibitor, BMN673, traps PARP1 on damaged DNA and induces cytotoxic effects. The aim of the present study was to evaluate the therapeutic effect of PI3K inhibitors and BMN673 on cervical cancer cells. The Chou‑Talalay method was used to assess the synergistic effect of drug combinations on cervical cancer cells. The effect of PI3K inhibitors and BMN673 on cell growth and survival were also assessed via a Cell Counting Kit‑8 assay and three‑dimensional sphere culture. Cell migration and invasion were assessed via Transwell migration and Matrigel invasion assays, respectively. In addition, DNA damage and HRR competency were assessed via immunofluorescent staining analysis of γH2AX and RAD51 foci, and tail moment in a comet assay. PARP1 binding in chromatin was assessed via a cellular trapping assay. Ex vivo cultured sections of patient‑derived cervical tumors were subjected to drug exposure followed by histological and immunohistochemical analyses. The results revealed that the PI3K p110α inhibitor BYL719 and the PARP inhibitor BMN673 synergized to inhibit cervical cancer cell proliferation, migration and invasion in vitro and ex vivo. However, the pan‑PI3K inhibitor BKM120 did not produce the aforementioned effects. Additionally, cervical cancer cells exhibiting aberrant PI3K activation were more responsive to the combined inhibition of PI3K p110α and PARP. Mechanistically, BYL719 co‑operated with BMN673 to increase PARP1 trapping on chromatin, induce severe DNA damage and exert cytotoxic effects. The combined use of BMN673 and BYL719 may serve as a promising therapeutic strategy for patients with cervical cancer exhibiting aberrant PI3K activation.