title: Iodination increases the activity of verapamil derivatives in reversing PGP multidrug resistance.
abstract: Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.
authors.affiliation: University of Grenoble I, Department of Molecular Chemistry, UMR CNRS 5250, F-38041, Grenoble Cedex 9, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Barattin
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: Kevin
authors.initials: K
authors.lastname: Bourges
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Hardy
authors.forename: Jose
authors.initials: J
authors.lastname: Olivares
authors.forename: Jean
authors.initials: J
authors.lastname: Boutonnat
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.forename: Amaury D U Moulinet
authors.initials: AD
authors.lastname: D'Hardemare
authors.forename: Xavier
authors.initials: X
authors.lastname: Ronot
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020112:Rhodamine 123; D016572:Cyclosporine; D014700:Verapamil; D003630:Daunorubicin