Document Detail

Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1.
MedLine Citation:
PMID:  15256468     Owner:  NLM     Status:  MEDLINE    
This study demonstrates that verapamil and a newly synthesized verapamil derivative, NMeOHI(2), behave as apoptogens in multidrug resistance protein 1 (MRP1)-expressing cells. When treated with either verapamil or NMeOHI(2), surprisingly, baby hamster kidney-21 (BHK) cells transfected with human MRP1 were killed. Because parental BHK cells were not, as well as cells expressing an inactive (K1333L) MRP1 mutant, this indicated that cell death involved functional MRP1 transporter. Cell death was identified as apoptosis by using annexin V-fluorescein labeling and was no longer observed in the presence of the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH(2)F (Z-VAD-FMK). In vitro, both verapamil and its derivative inhibited leukotriene C4 transport by MRP1-enriched membrane vesicles in a competitive manner, with a K(i) of 48.6 microm for verapamil and 5.5 microm for NMeOHI(2,) and stimulated reduced glutathione (GSH) transport 3-fold and 9-fold, respectively. Treatment of MRP1-expressing cells with either verapamil or the derivative quickly depleted intracellular GSH content with a strong decrease occurring in the first hour of treatment, which preceded cell death beginning at 8-16 h. Furthermore, addition of GSH to the media efficiently prevented cell death. Therefore, verapamil and its derivative trigger apoptosis through stimulation of GSH extrusion mediated by MRP1. This new information on the mechanism of induced apoptosis of MDR cells may represent a novel approach in the selective treatment of MRP1-positive tumors.
Doriane Trompier; Xiu-Bao Chang; Régis Barattin; Amaury du Moulinet D'Hardemare; Attilio Di Pietro; Hélène Baubichon-Cortay
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  64     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-07-16     Completed Date:  2004-09-09     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4950-6     Citation Subset:  IM    
Laboratoire des Protéines de Résistance aux Agents Chimiothérapeutiques, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université Claude Bernard LYON 1, IFR 128 Biosciences Lyon-Gerland, 7 passage du Vercors, 69367 Lyon Cedex 07, France.
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MeSH Terms
Apoptosis / drug effects*,  physiology
Cell Line
Glutathione / deficiency,  metabolism*,  pharmacology
Leukotriene C4 / metabolism
Membranes / metabolism
Multidrug Resistance-Associated Proteins / genetics,  metabolism*
Verapamil / analogs & derivatives,  pharmacology*
Grant Support
Reg. No./Substance:
0/Multidrug Resistance-Associated Proteins; 0/alpha-(3-((2-(4-hydroxy-3,5-diiodophenyl)ethyl)methylamino)propyl) -3,4-dimethoxy-alpha-(1-methylethyl)benzeneacetonitrile; 0/multidrug resistance-associated protein 1; 52-53-9/Verapamil; 70-18-8/Glutathione; 72025-60-6/Leukotriene C4

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