Natural triterpenoid glycosides, astragaloside II and astragaloside IV resensitize multidrug-resistant cancer via interfering ATPase activity and inducing apoptosis in vitro and in vivo.

Chemoresistance, often associated with multidrug resistance (MDR), is a significant challenge in cancer treatment. P-glycoprotein (P-gp) is overexpressed in various MDR cancers and is a drug efflux transporter of chemotherapeutics. Astragaloside II (AST-II) and astragaloside IV (AST-IV) are bioactive compounds extracted from the plant species Astragalus membranaceus. This study investigated the MDR reverse ability in cancer and the underlying mechanisms of AST-II and AST-IV. Results demonstrated that both compounds inhibited P-gp efflux function by suppressing ATPase activity and non-competitively interacting with P-gp substrates rhodamine123 and doxorubicin. The MDR reversal effects of AST-II and AST-IV were observed in MDR KB-vin cells by suppressing ABCB1 mRNA expression, inducing G2/M cell cycle arrest as well as enhancing apoptosis. Both compounds exhibited synergistic effects with paclitaxel in inhibiting tumor growth in vivo. These findings suggested that AST- II and AST-IV are potential candidates for development as synergistic agents in MDR cancer treatments.