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.