Iodination of verapamil for a stronger induction of death,through GSH efflux,of cancer cells overexpressing MRP1 |
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Authors: | Régis Barattin Thomas Perrotton Doriane Trompier Doriane Lorendeau Attilio Di Pietro Amaury du Moulinet d’Hardemare Hélène Baubichon-Cortay |
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Institution: | 1. Equipe Labellisée Ligue 2009, Institut de Biologie et Chimie des Protéines, UMR5086 CNRS-Université Lyon 1, IFR128, 7 passage du Vercors, Lyon F-69367, France;2. Département de Chimie Moléculaire, UMR 5250, CNRS/Université Joseph Fourier-Grenoble I, France |
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Abstract: | 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. |
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