RRC ID 21522
Author Hung CC, Liou HH.
Title YC-1, a novel potential anticancer agent, inhibit multidrug-resistant protein via cGMP-dependent pathway.
Journal Invest New Drugs
Abstract The aim of the present study was to evaluate the effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) on multidrug resistance. Expression of human P-glycoprotein was assessed by realtime quantitative RT-PCR and western blot. The efflux function of P-glycoprotein was evaluated by rhodamine 123 accumulation and calcein-AM uptake models. The mechanisms of action of YC-1 on different signaling pathways were studied using series of antagonists and the kinetics was also assessed. Cytotoxicity was evaluated by MTT assay. The results demonstrated that increased intracellular accumulation of rhodamine 123 and increased fluorescence of calcein were observed after YC-1 treatment. Furthermore, increased YC-1 concentration resulted in significant decrease in Vmax while K(M) remained unchanged suggested that YC-1 acted as a noncompetitive inhibitor of P-glycoprotein. Moreover, the inhibition of Pgp efflux function by YC-1 was significantly reversed by NO synthase inhibitor, (L)-NAME, the sGC inhibitor, ODQ, the PKG inhibitor, Rp-8-Br-PET-cGMPS, and the PKG inhibitor KT5823. In addition, ERK kinase inhibitor PD98059 also significantly restored YC-1 inhibited Pgp efflux function. These results indicated that YC-1 inhibited Pgp efflux via the NO-cGMP-PKG-ERK signaling pathway through noncompetitive inhibition. The present study revealed that YC-1 could be a good candidate for development as a MDR modulator.
Volume 29(6)
Pages 1337-46
Published 2011-12
DOI 10.1007/s10637-010-9496-1
PMID 20676745
MeSH ATP-Binding Cassette, Sub-Family B, Member 1 / antagonists & inhibitors* ATP-Binding Cassette, Sub-Family B, Member 1 / genetics Blotting, Western Cell Line Cyclic GMP / metabolism* Cyclic GMP-Dependent Protein Kinases / metabolism Extracellular Signal-Regulated MAP Kinases / metabolism Fluoresceins / metabolism Fluorescent Dyes / metabolism Gene Expression Regulation / drug effects* Humans Indazoles / pharmacology* Nitric Oxide / metabolism Reverse Transcriptase Polymerase Chain Reaction Rhodamine 123 / metabolism Signal Transduction / drug effects
IF 3.484
Times Cited 13
WOS Category PHARMACOLOGY & PHARMACY ONCOLOGY
Resource
DNA material Human MDR1 cDNA (RDB01372)