Mechanism of isoferulic acid in Bai-He-Gu-Jin-Tang inhibiting non-small cell lung cancer by suppressing epidermal growth factor receptor-mediated phosphoinositide 3-kinase/protein kinase B pathway.

BACKGROUND: Chemoresistance to paclitaxel (PTX) significantly compromises the prognosis of non-small cell lung cancer (NSCLC) patients. Although Bai-He-Gu-Jin-Tang (BHGJT) shows efficacy against lung diseases, its therapeutic components and mechanisms involved in reversing PTX resistance in NSCLC have not been fully elucidated. OBJECTIVE: We mainly explored the active components of BHGJT and the mechanism influencing PTX resistance in NSCLC. METHODS: NSCLC nude mouse model was established, and tumor-bearing mice received PTX and gavage with different BHGJT doses. Liquid Chromatography-Mass Spectrometry analysis was employed to analyze BHGJT and its blood-absorbed components and network pharmacology to analyze potential targets and pathways. PTX-resistant cells were constructed via intermittent PTX exposure and intervened with BHGJT-containing serum and isoferulic acid (IA). Their biologial behaviors were assessed by Flow cytometry, wound healing, and Transwell assay. The direct binding of IA to epidermal growth factor receptor (EGFR) was detected by cellular thermal shift assay. The effects of IA on NSCLC in relation to EGFR were assessed both in vivo and in vitro. RESULTS: Medium- and high-doses BHGJT further enhanced the anti-cancer effect of PTX. BHGJT-containing serum promoted apoptosis, suppressed migration and invasion, and increased sensitivity to PTX in PTX-resistant NSCLC cells. BHGJT contained 43 active components, in which IA and EGFR might be key active component and pathway. Intervention with 10% BHGJT-containing serum and IA dose-dependently lowered IC50 value, increased apoptosis, and inhibited migration and invasion of PTX-resistant cells. IA reduced levels of EGFR and p-PI3K/PI3K protein, and suppressed p-AKT/AKT in PTX-resistant cells. EGFR overexpression attenuated the anti-cancer effect of IA, whereas EGFR inhibition contributed to similar anti-cancer effect to IA. CONCLUSION: IA within BHGJT suppresses tumor growth and enhances the therapeutic effect of PTX in NSCLC by inhibiting the EGFR/PI3K/AKT pathway.