Alisol Triterpenoids Exhibit Triple Modulatory Mechanisms on the Cell Membrane to Overcome Cancer Multidrug Resistance.

PURPOSE AND STUDY DESIGN: Multi-drug resistance (MDR) in cancer significantly hinders effective treatment, leading to poor patient outcomes. The study investigates the potential of natural compounds, Alisol B 23-acetate (B23) and Alisol A 24-acetate (A24), to reverse MDR through various mechanisms on cancer cell membranes. RESULTS: Cytotoxicity assays established non-toxic concentrations of B23 and A24, which were then tested in drug-sensitive and drug-resistant cancer cell lines with or without chemotherapeutic drugs. Both compounds significantly enhanced reactive oxygen species (ROS) production and apoptosis in HepG2/VIN MDR cells while preserving cell membrane integrity. They also improved membrane fluidity and inhibited the function of P-glycoprotein (P-gp) efflux transporters in both HepG2/VIN and ABCB1/Flp-In(TM)-293, leading to increased drug accumulation. Molecular docking studies revealed that B23 and A24 interact with distinct binding sites on P-gp, demonstrating allosteric and competitive inhibition. CONCLUSION: B23 and A24 effectively reverse cancer MDR by (1) modulating ROS levels and inducing apoptosis, (2) maintaining membrane integrity but improving membrane fluidity, and (3) inhibiting drug efflux by membrane transporters. These findings provide a promising basis for developing new therapeutic strategies to combat MDR in cancer, highlighting the potential use of these natural product derivatives in adjunctive cancer therapy.