1. Two curcumin analogs, (1E,6E)-1,7-bis(3,5-diethyl-4-hydroxyphenyl)hepta-1,6-diene-3,5- dione (N17) and its prodrug ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2,6-diethyl-4,1- phenylene)bis(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate) (N17'), were evaluated as breast cancer resistance protein (BCRP) inhibitors.2. MDCKII-BCRP and MDCKII-WT were used to evaluate the modulation effects of N17 and N17' on BCRP and to explore the relevant mechanism. Sprague-Dawley rats were orally administered rosuvastatin (ROS), a probe substrate of BCRP, without and with N17' (100 mg/kg) to investigate the effect of N17' on ROS pharmacokinetics.3. In cell studies, N17 and N17' were substrates of BCRP, and they decreased the activity and protein expression of BCRP. In rat study, N17' increased the systemic exposure of ROS by 218% (p = 0.058).4. N17 and N17' are potential BCRP inhibitors and will be promising candidates for overcoming the BCRP-mediated multidrug resistance.
Keywords: ATP-binding cassette transporters; Breast cancer resistance protein; Curcumin analogs; multidrug resistance; rosuvastatin.