Iodination of verapamil for a stronger induction of death, through GSH efflux, of cancer cells overexpressing MRP1

A series of iodinated derivatives of verapamil were synthesized and tested on cells overexpressing the MRP1 drug transporter in order to design novel anti-cancer compounds targeting and killing resistant cancer cells. The multidrug resistance protein 1 (MRP1), involved in multidrug resistance (MDR)...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2010-09, Vol.18 (17), p.6265-6274
Main Authors: Barattin, Régis, Perrotton, Thomas, Trompier, Doriane, Lorendeau, Doriane, Pietro, Attilio Di, d’Hardemare, Amaury du Moulinet, Baubichon-Cortay, Hélène
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
Biological and medical sciences
Cell Death - drug effects
Cell Line, Tumor
Chemical Sciences
General aspects
Glutathione - metabolism
GSH efflux
Halogenation
Humans
Hydrocarbons, Iodinated - chemical synthesis
Hydrocarbons, Iodinated - chemistry
Hydrocarbons, Iodinated - pharmacology
Medical sciences
MRP1
Pharmacology. Drug treatments
Structure-Activity Relationship
Transfection
Tumor Cells, Cultured
Verapamil - analogs & derivatives
Verapamil - chemistry
Verapamil - pharmacology
Verapamil iodination
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Summary:A series of iodinated derivatives of verapamil were synthesized and tested on cells overexpressing the MRP1 drug transporter in order to design novel anti-cancer compounds targeting and killing resistant cancer cells. 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2010.07.031