Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway.
Melatonin, the chief hormone secreted by the pineal gland, has been previously shown to inhibit human breast cancer cell growth at the physiological concentration of 1 nM in vitro. In this study, using the estrogen receptor (ER)-positive human breast tumor cell line MCF-7, we have shown that 10 microM L-buthionine-[S,R]-sulfoximine (L-BSO), an inhibitor of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis), blocks the oncostatic action of 1 nM melatonin over a 5-day incubation, indicating that glutathione is required for melatonin action. The result was repeated with ZR75-1 cells, suggesting that the glutathione requirement is a general phenomenon among ER+ breast cancer cells. Addition of exogenous glutathione (1 microM) to L-BSO-treated groups restored the melatonin response in both cell lines. Further demonstration of the importance of glutathione was shown using the ER- breast tumor cell line HS578T, which is normally unresponsive to melatonin. Growth in this cell line was inhibited in the presence of 1 microM ethacrynic acid (an inhibitor of glutathione S-transferase) plus 1 nM melatonin, and this effect was blocked with 10 microM L-BSO. We also observed a steady decrease of intracellular glutathione in MCF-7 cells over a 5-day incubation, suggesting that these cells metabolize glutathione differently than do normal cells.
Blask
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DE
Bassett Research Institute, Cooperstown, New York 13326-1394, USA.
Wilson
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Zalatan
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F
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D004232:Diuretics; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008550:Melatonin; D004976:Ethacrynic Acid