Flurazepam inhibits the P-glycoprotein transport function: An insight to revert multidrug-resistance phenotype

Abstract

AbstractP-glycoprotein mediated drug transport may lead to a multidrug resistance phenotype often associated with a poor response to the successfultreatment of a variety of human disorders. Several agents have been found to modulate P-glycoprotein drug resistance, most probably by blockingits transport function. The aim of this study was to examine the effects of some benzodiazepines (bromazepam, chlordiazepoxide, diazepam andflurazepam) able to bind to P-glycoprotein in proteoliposomes on its transport function and ATPase activity in the human cancer cell line, KB-V1.The toxicity of the benzodiazepines drugs towards KB-V1 cells was first evaluated and the non toxic drugs concentrations were used to assess thedrug efflux and the ATPase activity. Using the flow cytometry approach, the accumulation and efflux of daunorubicin were followed by measuringthe daunorubicin associated geometric mean fluorescence intensity. Vanadate was employed as a comparative inhibitory compound. Flurazepamwas able to inhibit the daunorubicin efflux in 80%. ATPase activity determined by a colorimetric assay revealed that flurazepam inhibits the Pglycoproteinenzymatic activity, indicating coupling between drug transport and ATP hydrolysis. Bromazepam, chlordiazepoxide and diazepambehaved as activators of the P-glycoprotein ATPase activity, suggesting a role as transported substrates and did not interfere in the daunorubicintransport.<br><br>Keywords: P-glycoprotein inhibitor; KB-V1 cell; ATPase activity; Daunorubicin accumulation; Daunorubicin efflux; Benzodiazepines<br><a target="_blank" href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4R7J89M-F&_user=2460038&_coverDate=02%2F26%2F2008&_alid=894400556&_rdoc=5&_fmt=high&_orig=search&_cdi=4892&_sort=d&_docanchor=&view=c&_ct=28&_acct=C000057398&_version=1&_urlVersion=0&_userid=2460038&md5=d0d66aaa2b77e3ac9824d08b44bb2590"> Full text</a><br><br>