PHYSIOLOGICAL MELATONIN INHIBITION OF HUMAN BREAST-CANCER CELL-GROWTHIN-VITRO - EVIDENCE FOR A GLUTATHIONE-MEDIATED PATHWAY

Melatonin, the chief hormone secreted by the pineal gland, has been pr eviously shown to inhibit human breast cancer cell growth at the physi ological concentration of 1 nM in vitro, In this study, using the estr ogen receptor CER)-positive human breast tumor cell Line MCF-7, we hav e shown that 10 mu M L-buthionine-[S,R]-sulfoximine (L-BSO), an inhibi tor 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, suggestin g that the glutathione requirement is a general phenomenon among ER+ b reast cancer cells, Addition of exogenous glutathione (1 mu M) to L-BS O-treated groups restored the melatonin response in both cell lines, F urther 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 o f 1 mu M ethacrynic acid (an inhibitor of glutathione S-transferase) p lus 1 nM melatonin, and this effect was blocked with 10 mu M 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.