Resistance is a major concern for colorectal cancer patients undergoing chemotherapy. Piperlongumine (PL) has been proven to effectively reverse drug resistance in several types of cancers; however, the mechanisms associated with the reversal effect and the targets of PL in cancer drug resistance are still unclear. In this research, the reversal effects and associated mechanisms of PL in 5-Fluorouracil (5-FU) resistance colorectal cancer were investigated both in vitro and in vivo. Our data revealed that PL acted as a ROS inducer via binding and inhibiting TrxR (IC around 10.17 μM). By inducing ROS accumulation, PL reversed resistance to 5-FU in HCT-8/5-FU cells (reversal ratio: 4.9-fold) and enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts. As a ROS inducer, PL reversed resistance to 5-FU by directly promoting inhibition of Akt phosphorylation, and further inhibited 5-FU efflux and promoted cell apoptosis through affecting the Akt/Foxo3/NRF2/P-gp and Akt/Foxo3/NRF2/BAD signaling pathway.
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