LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells

Ovarian cancer is one of the most lethal gynecologic malignancies. It has been shown that PARP inhibitors can selectively target BRCA-mutated ovarian cancer and exert some effects on ovarian cancer without BRCA mutations. However, the mechanism is still unclear. In this study, wild-type BRCA ovarian cancer cells (A2780 and SKOV3) were used. Our results showed that using a PARP inhibitor (olaparib or AG14361) alone significantly inhibited the proliferation of A2780 cells but negligibly inhibited the proliferation of SKOV3 cells. We used RNA sequencing to explore differentially expressed genes and found that PARP inhibitors increased LDH-A in SKOV3 cells, which was confirmed by RT-PCR. Oxamate (a specific inhibitor of LDH-A) was used to investigate whether LDH-A inhibition enhances the suppressive effects of PARP inhibitors on ovarian cancer without BRCA mutations. CCK-8 assays, scratch assays and Transwell assays were used to determine cell proliferation, cell migration ability and invasion ability, respectively. Both olaparib and AG14361 significantly inhibited the proliferation/invasion ability of A2780 cells but not SKOV3 cells. Inhibition of LDH-A can remarkably promote the inhibitory effects of PARP inhibitors on both A2780 and SKOV3 cells. Thus, high expression level of LDH-A influenced the suppressive effects of PARP inhibitors on ovarian cancer with wild-type BRCA, and LDH-A inhibition notably enhanced this effect.