Tamoxifen retards glycosphingolipid metabolism in human cancer cells.
In this study we provide evidence that tamoxifen, the widely used breast cancer drug, is a potent antagonist of glycolipid metabolism. When added to the medium of cultured multidrug resistant (MDR) KB-V-1 carcinoma cells, tamoxifen, at 5.0 microM, drastically lowered the levels of glucosylceramide (glc-cer), as evidenced by a reduction in glc-cer mass. In a similar fashion, in cultured human melanoma cells grown with [3H]galactose, tamoxifen inhibited formation of glc-cer by 44%, and retarded lactosylceramide and ganglioside formation by 50 and 35%, respectively. When glc-cer synthase of melanoma was assayed in cell-free incubations, the inclusion of tamoxifen, at a 1:10 molar ratio with ceramide, inhibited glc-cer synthesis by 50%. These results clearly reveal a new action of tamoxifen and thereby pose intriguing questions regarding mechanisms of action in the realm of estrogen receptor-independent modalities, including effects on MDR.
Cabot
M C
MC
John Wayne Cancer Institute at Saint John's Hospital and Health Center, Santa Monica, CA 90404, USA.
Giuliano
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AE
Volner
A
A
Han
T Y
TY
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D018432:Drug Resistance, Multiple; D005963:Glucosylceramides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006028:Glycosphingolipids / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007624:KB Cells; D008545:Melanoma / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D005963:Glucosylceramides; D006028:Glycosphingolipids; D013629:Tamoxifen; C016601:afimoxifene; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase