Document Detail

BCRP transports dipyridamole and is inhibited by calcium channel blockers.
MedLine Citation:
PMID:  16247709     Owner:  NLM     Status:  MEDLINE    
PURPOSE: We investigated whether dipyridamole and various calcium channel blockers are inhibitors and/or substrates of breast cancer resistance protein (BCRP). METHODS: The effect of dipyridamole and the calcium channel blockers on mitoxantrone efflux by BCRP-overexpressing human embryonic kidney (HEK) cells was determined by flow cytometry. The ability of some of these compounds to reverse BCRP-mediated mitoxantrone resistance was measured by cytotoxicity assays. Transport studies were performed using radiolabeled compounds. RESULTS: Dipyridamole, nicardipine, nitrendipine, and nimodipine effectively inhibited BCRP-mediated mitoxantrone efflux; however, bepridil, diltiazem, and verapamil had no significant effect. Nifedipine is a much weaker BCRP inhibitor compared with other dihydropyridines tested. Nicardipine and dipyridamole were the most potent BCRP inhibitors among the compounds tested with IC50 values of 4.8 +/- 1.3 and 6.4 +/- 0.9 microM, respectively. Nicardipine and dipyridamole also effectively reversed BCRP-mediated mitoxantrone resistance in HEK cells. [3H]Nitrendipine was found not to be transported by BCRP. However, the transport of [3H]dipyridamole by BCRP was observed in both HEK and Madin-Darby canine kidney cells stably expressing the transporter, and this transport was completely abolished by fumitremorgin C, a known BCRP inhibitor. CONCLUSIONS: Dipyridamole and several dihydropyridines are effective BCRP inhibitors, but bepridil, diltiazem, and verapamil are not. We also identified a new BCRP substrate, dipyridamole.
Yi Zhang; Anshul Gupta; Honggang Wang; Lin Zhou; R Robert Vethanayagam; Jashvant D Unadkat; Qingcheng Mao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-11-01
Journal Detail:
Title:  Pharmaceutical research     Volume:  22     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-12-20     Completed Date:  2006-03-09     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2023-34     Citation Subset:  IM    
Department of Pharmaceutics, School of Pharmacy, University of Washington, Box 357610, Seattle, Washington 98195-7610, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / antagonists & inhibitors*,  metabolism*
Antineoplastic Agents / pharmacology
Biological Transport, Active
Calcium Channel Blockers / metabolism,  pharmacology*
Cell Line
Cell Survival / drug effects
Dihydropyridines / metabolism,  pharmacology
Dipyridamole / metabolism*
Electrophoresis, Polyacrylamide Gel
Flow Cytometry
Microscopy, Confocal
Mitoxantrone / pharmacology
Neoplasm Proteins / antagonists & inhibitors*,  metabolism*
Nitrendipine / metabolism
Platelet Aggregation Inhibitors / metabolism*
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents; 0/Calcium Channel Blockers; 0/Dihydropyridines; 0/Neoplasm Proteins; 0/Platelet Aggregation Inhibitors; 39562-70-4/Nitrendipine; 58-32-2/Dipyridamole; 65271-80-9/Mitoxantrone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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