Role of breast cancer resistance protein in drug disposition / 药学学报

Human breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) efflux transporter, is mainly responsible for the transport of many endogenous and xenobiotics. BCRP is expressed in different tissues, such as placental, intestinal epithelium, endothelial cells of brain microvessels, and renal proximal tubular cells. BCRP is considered as one of the key factor for the drug-drug interaction and individual difference in drug therapy. The review will provide an overview of the current knowledge on the discovery of BCRP and its physical function, transport mechanism, substrate and inhibitors, as well as its effect on the drug pharmacokinetics.

Resistance reversal effect of a novel taxane compound NPB304 and its collaboration with verapamil / 药学学报

The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 μmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function.