Research Papers:

Triterpenoids from Aglaia abbreviata exert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen species induction and P-glycoprotein inhibition

Juan Cen, Beibei Zheng, Rubing Bai, Li Zhang, Feng Zhang and Xia Zhang _

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Oncotarget. 2017; 8:69465-69476. https://doi.org/10.18632/oncotarget.17287

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Juan Cen1,2, Beibei Zheng2, Rubing Bai1, Li Zhang2, Feng Zhang1 and Xia Zhang3

1College of Pharmacy, Henan University, Kaifeng, People’s Republic of China

2Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, People’s Republic of China

3State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China

Correspondence to:

Feng Zhang, email: [email protected]

Xia Zhang, email: [email protected]

Keywords: multidrug resistance, reactive oxygen species, Aglaia abbreviata, NF-E2-related factor 2, P-glycoprotein

Received: December 15, 2016     Accepted: April 11, 2017     Published: April 20, 2017


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.

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