20(R)-Ginsenoside Rg3 Suppresses P-Glycoprotein-Mediated Multidrug Resistance in A549/Taxol Cells by Targeting MDM2-IκB-α Signaling Axis

Overexpression of P-glycoprotein (P-gp) in non-small cell lung Cancer (NSCLC) cells is one of the primary causes of multidrug resistance (MDR), but the molecular mechanism remains obscure. Murine double minute 2 (MDM2) has been implicated in drug resistance across multiple Cancer types. In this study, we investigated the potential mechanism of MDM2 on P-gp-mediated MDR of NSCLC and explored the potential therapeutic effects of 20(R)-ginsenoside Rg3 (Rg3). Western blot, RT-PCR, and immunohistochemistry (IHC) were applied to analyze the expression of critical signaling markers. The drug accumulation in resistant cells was measured using flow cytometry and confocal microscopy. Bioinformatics analysis, co-immunoprecipitation (co-IP), and immunofluorescence were conducted to confirm the protein-protein interactions. MTT, colony formation, EdU, and in vivo cell line derived xenograft (CDX) models were applied to validate therapeutic agents and molecular mechanisms. We demonstrated that MDM2 acted as a positive upstream regulator of P-gp, and the inhibition of MDM2 by Rg3 increased the sensitivity of resistant cells to taxol treatment both in vivo and in vitro. Mechanistically, we uncovered that MDM2 bound to IκB-α, facilitating its ubiquitination degradation, which subsequently promoted NF-κB pathway activation to drive the high expression of P-gp. Notably, Rg3 blocked this process by inhibiting MDM2. Moreover, interference with the NF-κB pathway reversed the regulation of P-gp expression by MDM2. Our findings elucidate the molecular mechanisms of Rg3 in the treatment of P-gp-mediated MDR in NSCLC. This study also provides a new strategy to overcome P-gp-mediated MDR by inhibiting the MDM2-IκB-α signaling axis.

20(R)‐ginsenoside Rg3; P‐glycoprotein; multidrug resistance; murine double minute 2; non‐small cell lung cancer.