Iodination of verapamil for a stronger induction of death, through GSH efflux, of cancer cells overexpressing MRP1.
The multidrug resistance protein 1 (MRP1), involved in multidrug resistance (MDR) of cancer cells, was found to be modulated by verapamil, through stimulation of GSH transport, leading to apoptosis of MRP1-overexpressing cells. In this study, various iodinated derivatives of verapamil were synthesized, including iodination on the B ring, known to be involved in verapamil cardiotoxicity, and assayed for the stimulation of GSH efflux by MRP1. The iodination, for nearly all compounds, led to a higher stimulation of GSH efflux. However, determination of concomitant cytotoxicity is also important for selecting the best compound, which was found to be 10-fold more potent than verapamil. This will then allow us to design original anti-cancer compounds which could specifically kill the resistant cancer cells.
Barattin
Régis
R
Département de Chimie Moléculaire, UMR 5250, CNRS/Université Joseph Fourier-Grenoble I, France. regis_barattin@yahoo.fr
Perrotton
Thomas
T
Trompier
Doriane
D
Lorendeau
Doriane
D
Di Pietro
Attilio
A
d'Hardemare
Amaury du Moulinet
Adu M
Baubichon-Cortay
Hélène
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D054879:Halogenation; D006801:Humans; D006847:Hydrocarbons, Iodinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006847:Hydrocarbons, Iodinated; D014700:Verapamil; D005978:Glutathione