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

Abstract

Abstract. 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. IntroductionCorilagin (C 27 H 22 O 18 ), a gallotannin found in many plants, is a major active component of many ethnopharmacological plants, such as Phyllanthus niruri L., P. emblica L. and P. urinaria L. Corilagin was first isolated in 1951 by Schmidt and Lademann from Divi-divi (Caesalpina coriaria) plants (1). In the past few decades, corilagin has been reported to display several pharmacological activities, including antioxidant (2), hepatoprotective (3), anti-inflammatory (4), neural system protective (5) and cardiovascular protective (6) activities, and has been found to be beneficial in managing type 2 diabetes (7). Recently, its antitumor effects in hepatocellular carcinoma (8,9), ovarian cancer (10) and cholangiocarcinoma (11) have attracted attention.Since 2005, we screened hundreds of herbs, among which Phyllanthus niruri L. has the highest anticancer potential. The present study further identified that corilagin is a major active component from P. niruri L. extracts and has broadspectrum antitumor activity, a better antitumor potential but lower toxicity to normal cells (12). It is effective in retarding the growth of he...

CD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3

“…More importantly, in ovarian cancer cells, a natural compound from Tripterygium wilfordii , Celastrol, promotes apoptosis by decreasing CD44 expression and STAT3 phosphorylation ( 240 ). Additionally, ovarian cancer cell stemness is reduced by the FK506-binding protein like (FKBPL) peptide via inhibiting the CD44/STAT3 signaling axis ( 241 ) and the medicinal herb corilagin sensitizes human ovarian cancer cell lines to chemotherapy by glycolysis inhibition via downregulation of both CD44 and STAT3 expression ( 242 ). Finally, an orally administered small molecule STAT3 inhibitor Napabucasin, which is currently being tested in several clinical trials against various cancer models ( 243 ), have been shown to decrease both STAT3 activation and CD44 expression in biliary tract cancer cells ( 244 ).…”

Corilagin induces the apoptosis of hepatocellular carcinoma cells through the mitochondrial apoptotic and death receptor pathways

“…In vitro , corilagin inhibited CCA cell proliferation, migration and invasion, and induced the apoptosis of CCA cells by inhibiting the Notch signaling pathway. Moreover, corilagin has shown the potential to promote the antitumor activity of cisplatin and doxorubicin in HCC cells ( 11 , 21 ) and to sensitize ovarian cancer cells to paclitaxel and carboplatin by inhibiting the Snail-glycolysis pathways ( 22 ).…”

Bruceine D inhibits Cell Proliferation Through Downregulating LINC01667/MicroRNA-138-5p/Cyclin E1 Axis in Gastric Cancer

“…Such as, scutellarin enhanced the sensitivity of prostate cancer cells to cisplatin (Gao et al, 2017). Corilagin sensitized epithelial ovarian cancer cells to paclitaxel and carboplatin treatment by inhibiting snailglycolysis pathways (Jia et al, 2017). Triptolide enhanced the sensitivity of breast cancer cells to doxorubicin (Deng et al, 2018).…”