Preliminary study of apatinib combined with fluzoparib in the treatment of HRP ovarian cancer via the HR pathway.

BACKGROUND

Ovarian cancer is the gynecological malignancy with the highest mortality rate. Due to late detection and easy recurrence, the 5-year survival rate of advanced ovarian cancer patients is less than 30%. The current standard treatment for ovarian cancer includes platinum-based combination therapy. Most ovarian cancer patients achieve clinical remission; however, the short-term recurrence rate is still high. For patients with recurrent ovarian cancer, who are unwilling to receive chemotherapy or cannot tolerate chemotherapy after multiple lines of chemotherapy, "chemotherapy-free" treatment may be appropriate. This study aimed to investigate the preliminary mechanism of action of the antiangiogenic drug apatinib combined with poly ADP ribose polymerase (PARP) inhibitor fluzoparib as a "chemotherapy-free" regimen in the treatment of ovarian cancer patients with homologous recombination proficiency (HRP).

METHODS

The HRP cell line SKOV3 was used for the experiments. The cells were treated with apatinib, fluzoparib, and apatinib combined with fluzoparib, respectively. The cell proliferation rate and migration rate were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and scratch assays. Western blot was used to detect the expression of phosphorylated mitogen-activated protein kinase kinase (, recombination activating gene 51 (, and phosphorylated histone cluster 2 H2A family member X (. Animal experiments were performed to evaluate the effects of the combined therapy on tumor growth and drug toxicity by constructing a cell-line transplanted tumor model. Western blot was used to detect the expression of , , and . Immunohistochemistry (IHC) was used to detect the expression of , phosphorylated extracellular signal-regulated kinase (, and breast cancer 1 ).

RESULTS

, apatinib combined with fluzoparib significantly inhibited the growth and migration of the SKOV3 cells. Western blot showed that apatinib combined with fluzoparib induced the down-regulation of and homologous recombination (HR) pathway-related protein expression, and increased DNA damage-related protein expression in the SKOV3 cells. The animal experiment results showed that apatinib combined with fluzoparib had a better antitumor effect than single-drug therapy without obvious toxicity. The western blot results showed that protein expression was increased, and protein expression was decreased in the apatinib combined with fluzoparib group. The IHC results showed that protein expression was increased and protein expression was decreased in the apatinib combined with fluzoparib group.

CONCLUSIONS

The combination of apatinib and fluzoparib may cause changes in the HR pathway by down-regulating signaling in ovarian cancer, leading to the down-regulation of . This eventually leads to the increased expression of DNA damage-related protein , which plays a therapeutic role in ovarian cancer and .