Corilagin sensitizes epithelial ovarian cancer to chemotherapy by inhibiting Snail-glycolysis pathways

We identified that corilagin is a major component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L with antitumor activity. Our previous study found that corilagin inhibited the growth of ovarian cancer cells via the TGF-β/AKT/ERK signaling pathways. Recently, we demonstrated that corilagin enhanced the sensitivity of ovarian cancer cells to chemotherapy. Ovarian cancer cell lines, SKOv3ip, Hey and HO-8910PM-Snail, were treated with different concentrations of corilagin in combination with paclitaxel and carboplatin. Corilagin distinctly enhanced the inhibitory effects of paclitaxel and carboplatin. To understand the mechanisms involved in the chemo-sensitization by corilagin, we performed reverse phase protein array analysis to determine the signaling networks induced by corilagin. We observed that both paclitaxel and carboplatin upregulated the expression levels of several apoptotic and death-related proteins, such as caspase 3, caspase 7 and PDCD4, which were further enhanced when combined with corilagin. Meanwhile, corilagin induced distinct pathways to paclitaxel and carboplatin treatment. We also performed isobaric tags for relative and absolute quantitation proteomics analysis in corilagen-treated ovarian cancer cells. This analysis indicated that corilagin is mainly involved in the glycolysis pathway. Seahorse XF96 extracellular acidification rate analysis confirmed that corilagin inhibited glycolysis by downregulation of CD44 and STAT3. In summary, our observations indicate that corilagin sensitized epithelial ovarian cancer cells to paclitaxel and carboplatin treatment by primarily inhibiting Snail-glycolysis pathways. Corilagin is a herbal medicine with low toxic effects to normal cells, particularly hepatoprotective, and may be an ideal complimentary medicine when combined with highly toxic chemotherapeutic agents.