Abstract 5550: Corilagin, an anti-tumor herb medicine, sensitizes paclitaxel and carboplatin by primarily inhibiting glycolysis pathways in epithelial ovarian cancer

Abstract

Abstract We have identified that Corilagin is a major anti-tumor active component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L. Our previous works found that Corilagin inhibited the growth of ovarian cancer cells via TGF-β/AKT/ERK signaling pathways. Recently, we have examined if Corilagin could enhance the sensitivity of chemotherapy in ovarian cancer cells. Different concentration of Corilagin were used in combination assays with paclitaxel and carboplatin in ovarian cancer cell lines SKOv3ip, Hey and HO-8910PM. Corilagin distinctly increased inhibition effects of paclitaxel and carboplatin (p<0.001 in all concentrations), specially at lower doses of drugs. To understand the mechanisms of sensitization by Corilagin, we performed reverse phase protein array (RPPA) analysis, it showed that both paclitaxel and carboplatin treatment upregulated several apoptotic and death proteins (Caspase 3, Caspase 7, PDCD4…), while combined with Corilagin, these apoptotic effects were enhanced. Meanwhile, Corilagin presented different pathways with paclitaxel and carboplatin. In HO-8910PM cells, Corilagin inhibited the expression of Snail, PLK1, DUSP4, ERA1, RB1, MDM2…, and enhanced the expression of E2F1, HIF1A, NDRG1… All these changes suggested that Corilagin acts not only via apoptotic pathways, but also via its distinct pathways. We also performed isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomics analysis in Corilagen treated ovarian cancer cells. In total, with FDR<0.01 and P-value<0.05 cutoff, we identified 108 proteins that were differentially expressed and mainly down-regulated (28 up, 80 down) by Corilagin treatment. The targeted proteins are cytoskeletal proteins and related enzymes (lipase, ATPase and kinase), mainly involved in glycolysis pathway. Enrichment results of both biological processes and KEGG pathways revealed that several pathways such as: glycolysis pathway, Focal adhesion, also the HIF-1 signaling pathway and proteoglycans were inhibited. Moreover, Corilagen may block glycolysis by inhibits several key proteins, such as: ENO1, LDHA, GPI, PGK1; further down regulates CD44, Cortactin, STAT3 and Filamin, and inhibits tumor cell growth and migration. Further investigations of direct targets are required to better understand the underlying molecular mechanism of Corilagen's pharmaceutical effects. In summary, our observations indicate that Corilagin sensitizes paclitaxel and carboplatin by primarily inhibiting glycolysis pathways in epithelial ovarian cancer cells. Corilagin is an herb medicine with lower toxic effects to normal cells, especially hepatoprotective, which could be an ideal complimentary medicine when combinating with highly toxic chemo-drugs. Citation Format: Luoqi Jia, Hongyan Jin, Minzhi Lv, Naiqing Zhao, Shaosong Liu, Zhizhong Zheng, Yiling Lu, Yanling Ming, Yinhua Yu. Corilagin, an anti-tumor herb medicine, sensitizes paclitaxel and carboplatin by primarily inhibiting glycolysis pathways in epithelial ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5550. doi:10.1158/1538-7445.AM2015-5550