Although the standard ginkgo biloba extract EGb 761 exhibits antioxidative, anti-apoptotic, and anticancer properties, there is no research focusing on the chemopreventive effects of EGb 761 in colorectal cancer (CRC). The present study investigated whether EGb 761 could increase 5-fluorouracil (5FU) sensitivity in CRC and its potential mechanism. We found that combined EGb 761 and 5FU treatment significantly elevated the chemosensitivity of CRC cells to 5FU in 5FU-resistant (5FUR) CRC cells, whereas no obvious cytotoxicity of EGb 761 was observed in parental cells. Then, real-time PCR and western blotting revealed that EGb 761 notably attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (increased E-cadherin and decreased vimentin). In addition, we found that EGb 761 significantly inhibited 5FU-induced upregulation of high mobility group-box 3 (HMGB3) expression in 5FUR CRC cells both at mRNA and protein levels. Knockdown of HMGB3 effectively reversed 5FU-induced EMT and attenuated 5FU-induced cytotoxicity in 5FUR CRC cells while overexpression of HMGB3 achieved the opposite results. Moreover, we found that knockdown of HMGB3 effectively reversed the EGb 761-induced inhibition of the Wnt/β-catenin pathway. The results of the current study collectively demonstrated that EGb 761 can chemosensitize 5FUR CRC cells by inhibiting an EMT phenotype via regulation of HMGB3 expression, suggesting it to be a novel chemoprotective agent in CRC.
Keywords: 5-fluorouracil; Colorectal cancer; chemosensitivity; ginkgo biloba extracts; high mobility group-box 3.