ABSTRACT
Bio-guided fractionation of the roots of Paris polyphylla (Trilliaceae), based on inhibition of P-glycoprotein-mediated daunorubicin efflux in K562/R7 cell line, led to isolation and identification of the three saponins 3-O-Rha(1-->2)[Ara(1-->4)]Glc-pennogenine, gracillin and polyphyllin D, and the two ecdysteroids 20-hydroxyecdysone and pinnatasterone. These compounds were tested for multidrug reversion on P-glycoprotein (ABCB1) with both drug-selected and transfected cell lines, and also on Breast Cancer Resistance Protein (BCRP/ABCG2). By contrast to a weak efficiency on BCRP, the three saponins displayed significant effects as inhibitors of P-glycoprotein-mediated drug efflux.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP-Binding Cassette Transporters/antagonists & inhibitors , Daunorubicin/metabolism , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Plant Extracts/pharmacology , Saponins/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Cyclosporine/pharmacology , Diosgenin/analogs & derivatives , Diosgenin/isolation & purification , Diosgenin/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Ecdysteroids/isolation & purification , Ecdysteroids/pharmacology , Ecdysterone/isolation & purification , Ecdysterone/pharmacology , Humans , Immunosuppressive Agents/pharmacology , K562 Cells , Leukemia/drug therapy , Leukemia/metabolism , Magnoliopsida/chemistry , Membrane Transport Modulators/pharmacology , Plant Extracts/chemistry , Rhizome , Saponins/isolation & purification , Spirostans/isolation & purification , Spirostans/pharmacology , Steroids/isolation & purification , Steroids/pharmacologyABSTRACT
Several aminomethylene analogs and a ketomethylene analog of reversins were synthesized in order to evaluate their ability to inhibit P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein. These analogs retained good activity compared to cyclosporin A and the original reversins.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Multiple/drug effects , Oligopeptides/pharmacology , Humans , K562 CellsABSTRACT
A set of 32 natural and synthetic coumarins were tested in order to evaluate their activity on human leukemic cells (K562/R7) overexpressing P-glycoprotein (P-gp). Their ability to reduce the P-gp-mediated drug efflux of daunorubicin out of cells was evaluated at 10 microM. Four natural compounds, previously isolated from Calophyllum dispar (Clusiaceae) and substituted by a common alpha-(hydroxyisopropyl)dihydrofuran moiety, exhibited a significant inhibitory effect on P-gp when compared to the positive control cyclosporin A. A 3D-quantitative structure-activity relationship (3D-QSAR) analysis of the coumarins was performed using the biological results obtained by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of P-gp. Results showed a favorable electrostatic and steric volume, like the alpha-(hydroxyisopropyl)dihydrofuran moiety, beside C(5)-C(6) or C(7)-C(8) positions. In addition, the analysis revealed an important hydrophobic, neutral charge group, like phenyl, in position C(4) on the coumarinic ring.
