Novel 3,4-Dihydroisocoumarins Inhibit Human P-gp and BCRP in Multidrug Resistant Tumors and Demonstrate Substrate Inhibition of Yeast Pdr5

In this study, the three natural compounds 6-methoxymellein (3), angelicoin B (4) and ellagic acid as well as nine novel 3,4-dihydroisocoumarins (Figure 1) were analyzed regarding their cytotoxicity in cancer cells and inhibition of the endogenously expressed human ABC transporters P-gp, BCRP, and MRP1 and of the yeast transporter Pdr5. For further insights into the mechanism of action, Pdr5 ATPase and substrate transport assays were performed. These results were complemented with molecular docking studies that indicate that differences in the inhibitory power of the investigated 3,4-dihydroisocoumarins with respect to P-gp-mediated transport result from differences in the compounds’ binding affinities to P-gp. FIGURE 1 Figure 1. Structures of natural and synthetic 3,4-dihydroisocoumarins. Materials and Methods Chemicals and Reagents A549 and HCT-15 cells were purchased from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany) and H69AR cells from the American Type Culture Collection (Manassas, VA, United States). Dr. Erasmus Schneider (Wadsworth Center, New York State Department of Health, Albany, NY, United States) kindly provided the MCF-7/MX cells. Cell culture media and supplements were purchased from Thermo Fisher Scientific (Waltham, MA, United States). Yeast extract, peptone, and D-glucose were purchased from Carl Roth (Karlsruhe, Germany). Hoechst 33342, rhodamine 6G (R6G) and adenosine 5′-triphosphate (AT...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research