Tamoxifen inhibits uptake and metabolism of ethanolamine and choline in multidrug-resistant, but not in drug-sensitive, MCF-7 human breast carcinoma cells.
Tamoxifen (TAM), a widely used agent in the hormonal therapy of breast cancer, is also an antagonist of P-glycoprotein (P-gp), a cell surface protein which confers drug resistance to cells. Here we report that in an estrogen receptor-deficient multidrug-resistant subline of MCF-7 human breast carcinoma cells (MCF-7/MDR), but not in the parent drug-sensitive cells (MCF-7/WT), clinically relevant concentrations (1-5 microM) of TAM inhibited the uptake and phosphorylation of ethanolamine and choline. These inhibitory effects resulted in decreased synthesis of the corresponding phospholipids. In view of the known dependence of P-gp function on phosphatidylethanolamine (PtdEtn), inhibition of PtdEtn synthesis may represent an additional mechanism by which TAM inhibits P-gp-mediated drug efflux.
Kiss
Z
Z
Hormel Institute, University of Minnesota, Austin 55912.
Crilly
K S
KS
D001692:Biological Transport / Q000187:drug effects; D002794:Choline / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019856:Ethanolamine; D004983:Ethanolamines / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D010713:Phosphatidylcholines / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004983:Ethanolamines; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D013629:Tamoxifen; D019856:Ethanolamine; D002794:Choline