Effects of melatonin on the cell cycle kinetics and “estrogen‐rescue” of MCF‐7 human breast cancer cells in culture

Abstract

Melatonin has been shown to have a direct inhibitory action on the proliferation of estrogen-responsive MCF-7 human breast cancer cells in culture. In the present study, we examined by flow cytometry whether this inhibitory effect might be exerted on the G1 phase of the cell cycle, thus causing a transition delay into the S phase. In order to further verify this hypothesis we tested the ability of estradiol to "rescue" MCF-7 cells from melatonin inhibition, and the potential of this indoleamine to block the ability of estradiol to rescue the cells from tamoxifen inhibition. Following five days of incubation, melatonin (10(-9)M) increased the fraction of cells in G1 of the cell cycle while simultaneously causing a 50% reduction in the proportion of cells in S phase. The antiproliferative effect of melatonin (10(-5)M) was prevented by the simultaneous treatment of the cells with estradiol (10(-8)M) in clonogenic soft agar culture, or reversed by the addition of estradiol to cells previously incubated with and inhibited by melatonin (10(-9)M) in monolayer culture. Additionally, melatonin blocked the estrogen-rescue of tamoxifen-inhibited cells in both types of culture systems. These results support the hypothesis that the antiproliferative effect of melatonin, like tamoxifen, is cell cycle specific by causing a G1-S transition delay. These results also indicate an important interaction of melatonin with estrogen-mediated mechanisms of MCF-7 cell proliferation.

Melatonin and mammary cancer: a short review.

“…Melatonin, in the presence of normal serum or estradiol, has been shown to retard or block the progression of cells from G0-G1 into S phase; thus, when cells are incubated with 1 nM melatonin, an accumulation of cells in G0-G1 together with a decrease in the population of cells in S phase can be observed (Cos et al 1991, García-Rato et al 1999. Melatonin also increases the length of the MCF-7 cell cycle from 20.36 ± 0.52 to 23.48 ± 0.03 h (Cos et al 1996).…”

Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

“…It has been demonstrated that melatonin counteracts the effects of oestrogens on mammary tumoral cells, thus behaving as a selective oestrogen receptor modulator (SERM). Furthermore, melatonin regulates the expression and activity of the aromatase, the main enzyme responsible for the local synthesis of oestrogens, thus behaving as a selective oestrogen enzyme modulator (SEEM) (Cos et al, 1991(Cos et al, , 2006aMartínez-Campa et al, 2005).…”

Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity

“…3 In vitro, melatonin, at concentrations corresponding to the physiologic levels present in human blood during the night, inhibits proliferation, increases expression of p53 and reduces the invasiveness of the estrogen-responsive MCF-7 human breast cancer cells. [3][4][5][6][7][8][9] Different hypotheses, including the immunomodulatory actions of melatonin, 10 its antioxidative effects 11 or the inhibition of telomerase activity, 12 have been postulated to explain the oncostatic properties of melatonin. However, the effects of melatonin on mammary cancer have been mostly considered as a consequence of its interaction with the estrogen-signaling pathway 13 by 2 different mechanisms: (i) by downregulating gonadal synthesis of steroids and, consequently, decreasing their circulating levels; 2,4 (ii) by interacting with the estrogen receptor, decreasing its expression and inhibiting the binding of the estradiol-estrogen receptor complex to the estrogen-response element on the DNA, thus behaving as a selective estrogen receptor modulator.…”