Triterpenoids fromAglaia abbreviataexert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen species induction and P-glycoprotein inhibition

Abstract

Triterpenoids from the Aglaia have been shown cytotoxicity on a broad spectrum of human tumor cells. In the present study, we extracted triterpenoids AA-5 (1) and AA-6 (2) from stems of Aglaia abbreviata, and studied their cytotoxicity in multidrug resistant (MDR) MCF-7/ADM cells. After 48 h treatment, AA-5 (1) and AA-6 (2) significantly increased mitochondrial-mediated apoptosis by enhancing reactive oxygen species (ROS) with depressed mitochondrial membrane potential and caspase-9 activities. The drug efflux transporter P-glycoprotein (P-gp) and the intracellular antioxidant systems, involving Glutathione S-Transferase π, Glutathione and heme oxygenase-1, were also inhibited via the ROS-depressed Akt/NF-E2-related factor 2 pathway. Furthermore, 2 h-treatment of AA-6 (2) at non-toxic concentrations exhibited MDR reversal effects with no alteration on P-gp expression but increased drug accumulation ability. AA-6 alos demonstrated synergetic effects with classic anti-tumor agents. Moreover, computational modeling studies showed that AA-6 (2) might bind to the modulator site on P-gp and act as an inhibitor, not a substrate of P-gp. Therefore, AA-5 (1) and AA-6 (2) may be effective anti-tumor and reversal agents for the further development of therapeutics against MDR breast cancer.