Ginsenoside Rg3 enhances the anticancer effects of 5-fluorouracil in colorectal cancer and reduces drug resistance and the Hedgehog pathway activation.

BACKGROUND AND STUDY AIMS

This study aimed to ascertain the inhibitory effect of ginsenoside Rg3 (Rg3) combined with 5-fluorouracil (5-FU) on 5-FU-resistant cells HCT116/5-FU and its molecular mechanism.

MATERIAL AND METHODS

The HCT116 cell line resistant to 5-FU (HCT116/5-FU) was established by repeated exposure to gradually increasing 5-FU concentrations. The effects of different concentrations of Rg3 and 5-FU on colorectal cancer (CRC) cell proliferation were evaluated, and suitable concentrations were screened for subsequent experiments. The treatment efficacy of Rg3 and 5-FU alone and in combination with CRC cell activity was observed, and the inhibitory effect of Rg3 and 5-FU on the Hedgehog pathway was verified. Finally, the effects of Rg3 and 5-Fu on in vivo tumor formation were evaluated in vivo.

RESULTS

Rg3 enhanced the therapeutic efficacy of 5-FU in HCT116 cells by inducing apoptosis and suppressing cell activities and epithelial-mesenchymal transition (EMT), showing strong anti-tumor effects. Rg3 enhances the chemosensitivity of drug-resistant HCT116/5-FU cells to 5-FU. Additionally, the expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells. Rg3 reversed 5-FU resistance via by modulating the Hedgehog pathway. Rg3, in combination with 5-FU, repressed human CRC xenograft growth in nude mice, suppressed the expression of the proliferative nuclear factor KI67 in tumors, and promoted apoptosis.

CONCLUSION

Rg3 enhances the anticancer effects of 5-FU in CRC cells that are sensitive and resistant to 5-FU, and its mechanism of action may be related to the inhibition of Hedgehog pathway activation.