Abstract
P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors.
Highlights
Multidrug resistance (MDR) is a major cause of chemotherapy failure, and P-glycoprotein (P-gp) up-regulation is a classical MDR mechanism in cancer
An obvious protein band of 170 kDa was observed in MDCK-MDR1 cell extracts, but no band was present at the corresponding position in MDCK extracts (Figure 1)
Expression levels can affect drug physical state of cell membranes affects the function of membranes, including cellabsorption
Summary
Multidrug resistance (MDR) is a major cause of chemotherapy failure, and P-glycoprotein (P-gp) up-regulation is a classical MDR mechanism in cancer. Molecules 2016, 21, 1606 administered drugs and active components, including drugs with strong pharmacological activity, e.g., doxorubicin, taxanes, vincristine, and peoniflorin, have poor bioavailability as a result of P-gp efflux, which makes oral preparation development difficult [9,10,11]. The study of these substances and tactics for overcoming or regulating P-gp efflux is important for increasing oral bioactivity and aiding in novel drug development [12,13]. This study investigated the mechanism by which imperatorin inhibits P-gp-mediated drug efflux. This study used MDCK-MDR1 cells to investigate the mechanism by which imperatorin inhibits. The research could provide a feasible method for the research and development of potential P-gp inhibitors and could offer a foundation for imperatorin to be used as a P-gp mediated MDR reversal agent in the future
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