Corilagin Reduces Resistance to PARP Inhibitors by Inhibiting the ERK Signaling Pathway in Ovarian Cancers

Abstract Background: Corilagin is a compound with hepatoprotective and antiviral activity extracted from Phyllanthus niruri L. Our previous work demonstrated that corilagin inhibits the growth of ovarian cancer cells by regulating the TGF-β/AKT/ERK signaling. Corilagin was also found to sensitize ovarian cancer cells to paclitaxel and carboplatin by inhibiting the Snail-glycolysis pathway. We have now studied whether corilagin could overcome resistance of ovarian cancer cells to poly ADP ribose polymerase inhibitors (PARPi). PARPi block DNA base excision repair and have been approved for treatment of ovarian cancers. Drug resistance has limited efficacy of PARPi. Methods: We have assessed the effect of corilagin alone and in combination with PARPi in two pairs of ovarian cancer cell lines-A2780CP/A2780CP_R and UWB1.289/UWB1.289_R-that are sensitive or resistant to PARPi. CulcuSyn software (BIOSOFT-Software for Science, Cambridge, U.K.) was used to calculate synergy between two drug combinations. Results: Corilagin was active against all four cell lines and enhanced BMN673 activity synergistically in both PARPi resistant cell lines. PARPi-BMN673 down-regulated the expression levels of PARP and up-regulated pH2AX, it decreased pERK activity in sensitive cell lines, but not in resistant cell lines. While corilagin affected DNA repair function to some extent, it inhibited pERK activity in both PARPi sensitive and resistant cells in a dose dependent manner. Corilagin, but not the BMN673, inhibited ZEB1 in resistant cells. Conclusions: Corilagin deserves further evaluation as a drug that could enhance the activity of PARPi in PARPi-resistant ovarian cancer cells.