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Tamoxifen retards glycosphingolipid metabolism in human cancer cells
M C Cabot1, A E Giuliano, A Volner
1John Wayne Cancer Institute at Saint John's Hospital and Health Center, Santa Monica, CA 90404, USA.
Abstract:
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.
Insights
Tamoxifen, a breast cancer drug, significantly disrupts glycolipid metabolism. This study demonstrates tamoxifen
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Tamoxifen is a widely used breast cancer therapeutic.
- Its known mechanisms primarily involve estrogen receptor antagonism.
- Emerging evidence suggests non-estrogen receptor-dependent actions.
Purpose of the Study:
- To investigate the effect of tamoxifen on glycolipid metabolism.
- To explore potential estrogen receptor-independent mechanisms of tamoxifen.
- To assess tamoxifen's impact on multidrug-resistant (MDR) cancer cells.
Main Methods:
- Cultured multidrug-resistant (MDR) KB-V-1 carcinoma cells were treated with tamoxifen.
- Human melanoma cells were cultured with [3H]galactose and tamoxifen.
- Cell-free assays were performed to measure glucosylceramide synthase activity.
Main Results:
- Tamoxifen significantly reduced glucosylceramide (glc-cer) levels in MDR carcinoma cells.
- In melanoma cells, tamoxifen inhibited glc-cer formation by 44% and lactosylceramide/ganglioside synthesis.
- Tamoxifen inhibited cell-free glucosylceramide synthase activity by 50%.
Conclusions:
- Tamoxifen acts as a potent antagonist of glycolipid metabolism.
- This represents a novel, estrogen receptor-independent mechanism of action for tamoxifen.
- These findings have implications for understanding tamoxifen's effects on MDR cancers.
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