Document Detail

Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin.
MedLine Citation:
PMID:  15485695     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: To study the mechanism involved in the cholesterol-lowering activity of tamoxifen, an estrogen receptor (ER) modulator widely used in breast cancer therapy. METHODS AND RESULTS: We used MOLT-4 cells, which do not express estrogen receptors and require important amounts of cholesterol for proliferation. We firstly confirmed that tamoxifen reduced cholesterol biosynthesis by inhibiting sterol Delta(8,7)-isomerase and Delta(24)-reductase activities, which resulted in the accumulation of zymosterol. In cells incubated in the presence of low-density lipoprotein (LDL) (120 microg cholesterol/ml), tamoxifen stimulated LDL receptor activity and expression in a dose-dependent manner, as determined by 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-labeled LDL uptake, LDL receptor expression on the cell surface and LDL receptor mRNA levels. Furthermore, tamoxifen, but not lovastatin, inhibited the egress of LDL-derived cholesterol from lysosomes, as ascertained by filipin staining in both MOLT-4 and HepG2 cells. When studied in combination, especially at relatively high LDL concentrations in the medium, tamoxifen and lovastatin stimulated LDL receptor activity synergistically, which is attributed to the different mechanism of action these drugs exhibit. CONCLUSIONS: The present study demonstrates the stimulation of the LDL receptor by tamoxifen. These results explain the long-known hypolipidemic effect of tamoxifen and support its use, or that of other intracellular cholesterol trafficking inhibitors, in combination with statins for the reduction of plasma LDL cholesterol levels.
Yajaira Suárez; Carlos Fernández; Diego Gómez-Coronado; Antonio J Ferruelo; Alberto Dávalos; Javier Martínez-Botas; Miguel A Lasunción
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular research     Volume:  64     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-15     Completed Date:  2005-01-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  346-55     Citation Subset:  IM    
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar, km 9, E-28034 Madrid, Spain.
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MeSH Terms
Cell Line, Tumor
Cholesterol / biosynthesis
Cholesterol, LDL / metabolism
Drug Synergism
Estrogen Receptor Modulators / pharmacology*
Gene Expression / drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Lovastatin / pharmacology*
Lysosomes / metabolism
Receptors, LDL / genetics,  metabolism*
Stimulation, Chemical
Tamoxifen / pharmacology*
Reg. No./Substance:
0/Cholesterol, LDL; 0/Estrogen Receptor Modulators; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Receptors, LDL; 10540-29-1/Tamoxifen; 57-88-5/Cholesterol; 75330-75-5/Lovastatin

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