Abstract
P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells.
Highlights
Multidrug resistance (MDR) has become a major cause of chemotherapy failure [1].Many chemotherapeutic agents that are widely used for cancer treatment have been reported to cause multidrug resistance
Our results indicated that OPD inhibited P-gp-mediated drug efflux may not be related to competitively binding with P-gp
Our result indicated that OPD could suppress P-gp transport activity in Mardin Darby canine kidney (MDCK)-MDR1 cells
Summary
Multidrug resistance (MDR) has become a major cause of chemotherapy failure [1]. Many chemotherapeutic agents that are widely used for cancer treatment have been reported to cause multidrug resistance. Taxanes, vinca alkaloids, paeoniflorin and doxorubin, etc. Recent studies have revealed that overexpression of P-glycoprotein (P-gp) is the primary mechanism leading to the occurrence of drug efflux multidrug resistance [3]. P-gp, a 170-kDa energy-dependent transmembrane glycoprotein transporter encoded by human MDR1 gene, is widely expressed in the epithelial cells of normal tissues including intestine, liver, kidney, blood-brain barrier and placental barrier [4] and affects the absorption, distribution, metabolism and excretion of drugs. P-gp is overexpressed in cancer cells and it can transport chemotherapeutic drugs out of the cells using the Molecules 2018, 23, 1841; doi:10.3390/molecules23081841 www.mdpi.com/journal/molecules
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