Linked Life Data

15256468

Source:http://linkedlifedata.com/resource/pubmed/id/15256468

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2004-7-16
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
64
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4950-6
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1.
pubmed:affiliation
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.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't