Antiproliferative Effect Of Melatonin Research Articles

The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment.

The circadian clock is a regulatory system, with a periodicity of approximately 24 h, which generates rhythmic changes in many physiological processes, including mitochondrial activity. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases such as cancer. Melatonin, whose production and secretion oscillates according to the light-dark cycle, is the principal regulator of clock gene expression. In addition, the oncostatic effects of melatonin correlate with an increase in mitochondrial activity. However, the direct links between circadian clock gene expression, mitochondrial activity, and the antiproliferative effects of melatonin in cancers, including head and neck squamous cell carcinoma (HNSCC), remain largely unknown. In this study, we analyzed the effects of melatonin on HNSCC cell lines (Cal-27 and SCC9), which were treated with 500 and 1000 µM melatonin. We found that the antiproliferative effect of melatonin is not mediated by the Bmal1 clock gene. Additionally, high doses of melatonin were observed to result in resynchronization of oscillatory circadian rhythm genes (Per2 and Sirt1). Surprisingly, the resynchronizing effect of melatonin on Per2 and Sirt1 did not produce alterations in the oscillation of mitochondrial respiratory activity. These results increase our understanding of the possible antiproliferative mechanisms in melatonin in the treatment of head and neck squamous cell carcinoma and suggest that its antiproliferative effects are independent of clock genes but are directly related to mitochondrial activity.

Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition

Hepatocellular carcinoma (HCC) is the major lethal primary liver malignant worldwide. Although, melatonin has various antitumor bioactivities; there is a requirement for more investigations to elucidate the not discussed effects, and the controversial responses of the treatment with melatonin on targets mediated in HCC. To achieve the aim of the present study, HCC-HepG2 cells were treated with different concentrations of melatonin at various time intervals. The selected minimal proliferation inhibition doses of melatonin were then incubated with cells to examine the arresting effect of melatonin on dividing cells using flow cytometry. Furthermore, the molecular patterns of genes that contributed to apoptosis, drug resistance development, antioxidation, and melatonin crossing were quantified by qRT-PCR. Additionally, the Human inflammation antibody array membrane (40 targets) was used to check the anti-inflammatory effect of melatonin. Our results validated that, melatonin shows anti-proliferative action through preserving cells in G0/G1 phase (P < 0.001) that is associated with a highly significant increase in the expression level of the P53 gene (P < 0.01). On contrary, as a novelty, our data recorded decreases in expression levels of genes involved in the pro-apoptotic pathway; with a significant increase (P < 0.05) in the expression level of an anti-apoptotic gene, Bcl2. Interestingly, we detected observed increases in the expression levels of genes responsible for conferring drug resistance including ABCB1, ABCC1, and ABCC5. Our study proved the anti-inflammatory activity of 1 mM melatonin in HCC-HepG2 cells. Accordingly, we can conclude that melatonin facilitates the anti-proliferation of cells at doses of 1 mM, and 2.5 mM after 24 h. This action is initiated through cell cycle arrest at G0/G1 phase via increasing the expression of P53, but independently on apoptosis. Collectively, melatonin is an effective anti-inflammatory and anti-proliferative promising therapy for the treatment of HCC. However, its consumption should be cautious to avoid the development of drug resistance and provide a better treatment strategy.

Melatonin modulates the Warburg effect and alters the morphology of hepatocellular carcinoma cell line resulting in reduced viability and migratory potential

AimsHepatocellular Carcinoma (HCC) is a primary neoplasm derived from hepatocytes with low responsiveness and recurrent chemoresistance. Melatonin is an alternative agent that may be helpful in treating HCC. We aimed to study in HuH 7.5 cells whether melatonin treatment exerts antitumor effects and, if so, what cellular responses are induced and involved. Main methodsWe evaluated the effects of melatonin on cell cytotoxicity and proliferation, colony formation, morphological and immunohistochemical aspects, and on glucose consumption and lactate release. Key findingsMelatonin reduced cell motility and caused lamellar breakdown, membrane damage, and reduction in microvillus. Immunofluorescence analysis revealed that melatonin reduced TGF and N-cadherin expression, which was further associated with inhibition of epithelial-mesenchymal transition process. In relation to the Warburg-type metabolism, melatonin reduced glucose uptake and lactate production by modulating intracellular lactate dehydrogenase activity. SignificanceOur results indicate that melatonin can act upon pyruvate/lactate metabolism, preventing the Warburg effect, which may reflect in the cell architecture. We demonstrated the direct cytotoxic and antiproliferative effect of melatonin on the HuH 7.5 cell line, and suggest that melatonin is a promising candidate to be further tested as an adjuvant to antitumor drugs for HCC treatment.

Melatonin Inhibits in Vitro Smooth Muscle Cell Inflammation and Proliferation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

Chronic inflammation and proliferation play important roles in atherosclerosis progression. This study aimed to identify the mechanisms responsible for the anti-inflammatory and antiproliferative effects of melatonin on tumor necrosis factor-α (TNF-α)- and platelet-derived growth factor-BB (PDGF-BB)-treated rat aortic smooth muscle cells (RASMCs). Melatonin reduced TNF-α-induced RASMC inflammation by decreasing vascular cell adhesion molecule-1 (VCAM-1) expression and nuclear factor-kappa B (NF-κB) P65 activity by inhibiting P38 mitogen-activated protein kinase phosphorylation ( P < 0.05). Additionally, melatonin inhibited PDGF-BB-induced RASMC proliferation by reducing mammalian target of rapamycin (mTOR) phosphorylation ( P < 0.05) but not migration in vitro. Melatonin also reduced TNF-α- and PDGF-BB-induced reactive oxygen species (ROS) production ( P < 0.05). Furthermore, melatonin treatment (prevention and treatment groups) significantly repressed high cholesterol diet-stimulated atherosclerotic lesions in vivo (19.59 ± 4.11%, 20.28 ± 5.63%, 32.26 ± 12.06%, respectively, P < 0.05). Taken together, the present study demonstrated that melatonin attenuated TNF-α-induced RASMC inflammation and PDGF-BB-induced RASMC proliferation in cells and reduced atherosclerotic lesions in mice. These results showed that melatonin has anti-inflammatory and antiproliferative properties and may be a novel therapeutic target in atherosclerosis.

MELO-D: Antiproliferative effects of melatonin and vitamin D in breast cancer.

TPS1616 Background: Vitamin D and melatonin have been associated with anti-cancer activity in epidemiological and experimental studies. However, evidence from controlled trials on their efficacy in...

Melatonin inhibits the proliferation of human osteosarcoma cell line MG-63

It seems established that the onset of osteosarcoma and the reduction in melatonin production run in parallel; this suggests that the decline in the cancer-inhibiting agent, melatonin, may contribute to the occurrence of osteosarcoma and that melatonin supplementation may have promise for preventing the development and progression of this condition. There is, however, no direct evidence regarding an antiproliferative effect of melatonin in osteosarcoma cells. In the current study, we examined whether melatonin inhibits the proliferation of human osteosarcoma cell line MG-63. MTT staining showed that at 4mM–10mM concentrations, melatonin significantly reduced the MG-63 cell proliferation in a dose-dependent and time-dependent manner. Flow cytometry documented that 4mM melatonin significantly increased the fraction of cells in the G0/G1 phase of the cell cycle, while simultaneously reducing the proportion in the S and G2/M phases. Western blot and real-time PCR analyses further confirmed that melatonin's inhibitory effect was possibly because of downregulation of cyclin D1 and CDK4, related to the G1 phase, and of cyclin B1 and CDK1, related to the G2/M phase. There was no downregulation of cyclin E, CDK2, and cyclin A, which are related to G1/S transition and S phase. These findings provide evidence that melatonin may significantly inhibit human osteosarcoma cell proliferation in a dose-dependent and time-dependent manner and this inhibition involves the downregulation of cyclin D1, CDK4, cyclin B1 and CDK1.

Abstract 5478: Melatonin, a novel Sirt1 inhibitor, imparts anti-proliferative effects against PCa in vitro in cell culture and in vivo in transgenic adenocarcinoma of mouse prostate (TRAMP) model

Abstract Prostate cancer (PCa) is a major age-related malignancy because an increase in age correlates with increased risk for developing this neoplasm. Recently, we have shown that Sirt1, a member of the NAD+ dependent histone deacetylase family of sirtuin proteins, was overexpressed in PCa cells and human PCa tissues compared to normal prostate cells and the adjacent normal prostate tissue, respectively. We also demonstrated that chemical inhibition or genetic knockdown of Sirt1 resulted in a significant inhibition in the growth and viability of human PCa cells while having no effect on normal human prostate epithelial cells (PrEC). Studies have suggested a link between the cellular metabolic function of Sirt1 and the circadian rhythm, and the disruption of circadian rhythm has been linked with an increased risk for some cancers. Interestingly, a decreased production of the pineal hormone melatonin, a known regulator of circadian rhythm, has been shown to cause deregulation in the circadian rhythm and an increase in susceptibility to cancer. Further, disruption in circadian rhythmicity has also been associated with aging. It has been reported that as an individual ages, the ability to produce melatonin at night is decreased and PCa patients have been reported to have decreased levels of melatonin. Here we tested the hypothesis that the circadian rhythm regulator melatonin will impart anti-proliferative response against PCa via inhibiting Sirt1. Our data demonstrated that melatonin treatments (high, low acute, low chronic doses) significantly inhibited Sirt1 protein and activity in vitro in multiple PCa cell lines (LNCaP, 22Rv1, DU145, and PC3). Melatonin-mediated Sirt1 inhibition was accompanied with a significant decrease in the proliferative capacity of PCa cells while having no effect on PrEC, as assessed by Trypan blue and anchorage-independent growth assays. Further, we found that overexpression of Sirt1 in PCa cells was able to partially rescue the cells from the anti-proliferative effects of melatonin, suggesting that Sirt1 is a direct target of the anti-proliferative effects of melatonin. Finally, employing male TRAMP mice, we found that oral administration of melatonin at human achievable doses significantly inhibited PCa growth. Melatonin treatment was found to result in a significant decrease in (i) prostate and genitourinary weight, (ii) serum IGF-1/IGFBP3 ratio, (iii) mRNA and protein levels of the proliferation markers (PCNA, Ki-67), and (iv) a down-regulation of Sirt1 in prostatic tissue. Our data identified melatonin as a novel inhibitor of Sirt1 and suggested that this pineal hormone can inhibit PCa growth via Sirt1 inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5478.

The role of melatonin on gastric mucosal cell proliferation and telomerase activity in ageing

Despite antiproliferative effects of melatonin on cultured tumor cells, its effects on normal cells are less clear. The action of melatonin on telomerase activity in ageing of gastric mucosal tissues also is not known. In this study, we investigated the age-related changes in telomerase activity and cellular proliferation rate of gastric mucosa and the effect of melatonin. A total of 37 young (4 months old), and aged (20 months old) Wistar rats, kept under equal periods of light and dark, were divided into control [(PBS), i.p. for 21 days] and melatonin-treated (10 mg/kg melatonin, i.p. for 21 days) groups. Telomerase activity, cell proliferation rate, malondialdehyde (MDA) and glutathione (GSH) levels of the stomach were determined. Melatonin significantly inhibited the gastric mucosal proliferation rate of both young and aged rats. Telomerase activity was significantly reduced in aged rats compared to young animals. Melatonin significantly increased the telomerase activity of both young and aged rats. The MDA levels of gastric mucosa in the aged rats were significantly higher than those of the younger rats. On the contrary, the GSH levels of gastric mucosa of the aged group were significantly lower than that of the young rats. While melatonin had no effect on GSH levels of either young or aged rats, it significantly decreased the MDA levels in aged animals. In conclusion, melatonin may delay the ageing of gastric mucosa by inhibiting the replicative cellular senescence via its stimulatory effect on telomerase activity and suppressive effect on cellular proliferation and lipid peroxidation.

Antiproliferative effects of melatonin on the growth of rat pituitary prolactin‐secreting tumor cells in vitro

Earlier studies showed that melatonin reduced the growth of 17-beta-estradiol (E(2))-induced rat pituitary prolactin-secreting tumor (prolactinoma) in vivo. The mechanisms of melatonin's inhibitory action on the prolactin-secreting tumor were further explored by investigating the in vitro effects of melatonin on the growth of pituitary prolactin-secreting tumor cells. Primary cultured prolactinoma cells from E(2)-induced rat pituitary prolactin-secreting tumor were treated with 10(-5), 10(-4) or 10(-3) m melatonin for 5 days. Apoptosis was evaluated using flow cytometry and the TdT-mediated dUTP nick-end labeling (TUNEL) method. In addition, cell viability was analyzed by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. It was found that incubation of prolactinoma cells with 10(-5), 10(-4) or 10(-3) m melatonin for 5 days inhibited cell growth and increased cell apoptosis. Furthermore, melatonin increased caspase-3 activity, Bax mRNA expression, and cytochrome c protein expression. Conversely, Bcl-2 mRNA expression and mitochondrial membrane potential were inhibited by melatonin treatment. Our results further suggest that melatonin inhibits tumor growth by inducing apoptosis of rat pituitary prolactin-secreting tumor directly via the damage of mitochondria.

Inhibitory effect of melatonin on the growth of H22 hepatocarcinoma cells by inducing apoptosis.

Whether melatonin not only inhibits the growth of H22 hepatocarcinoma cells but also induces apoptosis in vitro was assessed. The anti-proliferative effects of melatonin on tumor cells was observed by MTT assay and tumor cells growth curve assay. And the apoptosis of the cells was studied by acridine orange fluorescence assay and flow cytometry. The cell cycle of the tumor cells was also observed by flow cytometry. It was found that melatonin could significantly inhibit the growth of H22 hepatocarcinoma cells. Incubated with melatonin, chromatin condensation of the tumor cells was observed by fluorescence microscopy. Compared with control, the percentage of apoptotic cells was increased, and the proportion of G0/S increased but that of G2/M decreased. It was suggested that melatonin could directly inhibit the growth of H22 hepatocarcinoma cells by inducing apoptosis and extending the length of cell cycle of the tumor cells.

Author index

Our previous work showed that melatonin (N-acetyl-5-methoxytryptamine) inhibits proliferation of the human endometrial cancer cell line, Ishikawa, which is estrogen receptor-positive. The aim of the present study was to determine whether Ishikawa cells possess membrane melatonin receptors. Binding of the radioligand 2-[125I]-iodomelatonin to membrane preparations obtained from Ishikawa cells was detectable, saturable and stable. Scatchard analysis revealed that the dissociation constant (Kd) of the binding sites was 179.0 pm (similar to that of the MT2 [Mel1b] melatonin receptor subtype), and that the concentration (Bmax) of the binding sites was 12.9 fmol/mg protein. Luzindole, a selective MT2 melatonin receptor antagonist, significantly suppressed binding of 2-[125I]-iodomelatonin at all concentrations tested (10(-8) to 10(-4) m). These results suggest that the MT2 melatonin receptor subtype is present in the membranes of Ishikawa cells, and that the antiproliferative effect of melatonin on Ishikawa cells is mediated via the MT2 receptor. This may have implications for the use of melatonin in endometrial cancer therapy.

Melatonin binding sites in estrogen receptor‐positive cells derived from human endometrial cancer

Abstract: Our previous work showed that melatonin (N‐acetyl‐5‐methoxytryptamine) inhibits proliferation of the human endometrial cancer cell line, Ishikawa, which is estrogen receptor‐positive. The aim of the present study was to determine whether Ishikawa cells possess membrane melatonin receptors. Binding of the radioligand 2‐[125I]‐iodomelatonin to membrane preparations obtained from Ishikawa cells was detectable, saturable and stable. Scatchard analysis revealed that the dissociation constant (Kd) of the binding sites was 179.0 pm (similar to that of the MT2 [Mel1b] melatonin receptor subtype), and that the concentration (Bmax) of the binding sites was 12.9 fmol/mg protein. Luzindole, a selective MT2 melatonin receptor antagonist, significantly suppressed binding of 2‐[125I]‐iodomelatonin at all concentrations tested (10−8 to 10−4 m). These results suggest that the MT2 melatonin receptor subtype is present in the membranes of Ishikawa cells, and that the antiproliferative effect of melatonin on Ishikawa cells is mediated via the MT2 receptor. This may have implications for the use of melatonin in endometrial cancer therapy.

Potentiation of antiproliferative effects of tamoxifen and ethanol on mouse hepatoma cells by melatonin: possible involvement of mitogen-activated protein kinase and induction of apoptosis.

Melatonin, the major secretory product of the pineal gland, is in focus of many research areas because of its ability to scavenge free oxygen radicals and thereby protect cells and tissues from radical damage. Some studies suggest melatonin may be a possible therapeutic agent with potential clinical applications against pathological states due to reactive oxygen species. Here, we investigated the effects of melatonin on the mouse hepatoma cell line HEPA 1-6, coincubated with ethanol, and tamoxifen, respectively. Cell proliferation rates were detected by the 3-[4,5 dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide (MTT) proliferation assay. A dose-dependent inhibition of the proliferative activity by melatonin was observed from 640 microM to 3 mM, which was significantly higher (P < 0.01) than with the solvent (ethanol) alone. Concentrations of 320 microM and less had no effect on cell proliferation. This antiproliferative effect might be because of the prolonged activation of mitogen-activated protein kinase which was activated by phosphorylation 15 min after the induction with melatonin. Furthermore, apoptosis was found to be enhanced by melatonin (75% more than with the solvent alone, P < 0.001). Finally, we show that the inhibitory effect of tamoxifen (25 microM) is markedly enhanced by the coincubation with melatonin (1.3 mM) up to 75% (P < 0.001). These data show that the antiproliferative effects of tamoxifen and ethanol, respectively, on mouse hepatoma cell line HEPA 1-6 are enhanced by melatonin. Although at the conditions described here the antiproliferative effects of melatonin occur at supraphysiological concentrations, these data may help to support clinical studies where melatonin is given simultaneously with tamoxifen or other standard chemotherapeutica.

The antiproliferative effects of melatonin on experimental pituitary and colonic tumors. Possible involvement of the putative nuclear binding site?

The antiproliferative effects of melatonin on experimental pituitary and colonic tumors. Possible involvement of the putative nuclear binding site?

Magnetic fields (MF) of 50 Hz at 1.2 microT as well as 100 microT cause uncoupling of inhibitory pathways of adenylyl cyclase mediated by melatonin 1a receptor in MF-sensitive MCF-7 cells.

Magnetic fields (MF) of 60 Hz at 1.2 microT were previously shown to inhibit the antiproliferative effect of melatonin on MCF-7 cells (Liburdy,R.P., 1993, J. Pimeal Res. 14, 89-97). In addition, three laboratories (Blackman,C.F. and Benane,S.G., 1998; Luben,R.A. and Morgan,A.P., 1998; Morris,J.E., Chrisler,W.B., Miller,D.L., Sasser,L.B. and Anderson,L.E., 1998; 20th Annual Meeting of the Bioelectromagnetics Society, At. Pete Beach, FL) independently reported results consistent with this finding. In this study, we investigated the molecular basis of the biological effects of MF using MCF-7 cells. Only 1a melatonin receptors were identified by the [125I]melatonin binding assay and RT-PCR analysis. Moreover, preceding exposures to MF of 100 microT for 3, 5 and 7 days blocked the melatonin-induced inhibition of cAMP accumulation in a time-dependent manner, while none of the melatonin receptor functions or GTPase and adenylyl cyclase activities were affected. Estrogen-evoked cell proliferation was not altered by MF either. Exposure to 1.2 microT MF exerted the same effects on the melatonin-signaling pathway as that to 100 microT. Thus, this is the first study to provide evidence that MF may cause uncoupling of signal transduction from melatonin receptors to adenylyl cyclase.

Antiproliferative Effects of Melatonin and CGP 52608

The antiproliferative effects of melatonin and CGP 52608, an exogenous ligand for RZR/ROR receptors, are compared in the present paper. Both compounds exerted similar inhibitory effects on the proliferation of neoplastic cells in mouse colonic adenocarcinoma, DU 145 human prostate cancer, MCF-7 human breast carcinoma, and rat diethylstilbestrol-induced prolactinoma. Although it has been suggested that melatonin may influence the proliferation of tumor cells via RZR/ROR receptors, it cannot be excluded that the antiproliferative effects of melatonin and CGP 52608 are unrelated and mediated by different intracellular mechanisms.

Melatonin decreases mRNA for histone h4 in thymus of young rats

The antiproliferative properties of melatonin have been previously demonstrated for several normal and tumoral tissues. In a recent report we have shown that melatonin is able to inhibit programmed cell death in thymus both, in vivo and in vitro. Given that other authors have related programmed cell death and cell proliferation and that no previous reports on melatonin and cell division exist on thymus, we decide to study the possible antiproliferative effect of melatonin in this organ measured as the levels of mRNA for the histone H4. We found that melatonin inhibits cell division on thymus when administered chronically both, at high (500 μg/body weight) and low (50 μg/body weight) dose. We also found a circadian rhythm of the mRNA for histone H4, opposed to the one previously described for melatonin, supporting the negative regulation by this hormone of cell division on thymus. A single dose of melatonin (50 μg/body weight) was not able to decrease the levels of mRNA for H4 in the time-points studied but after two hours of its administration. Finally, we report the inhibitory effect of melatonin in the cell proliferation of Harderian gland, brain, lung and kidney.

Interaction between melatonin and estradiol on morphological and morphometric features of MCF-7 human breast cancer cells.

Melatonin has been shown to have a direct inhibitory effect on the proliferation of estrogen-responsive MCF-7 human breast cancer cells, involving an interaction with estradiol. The anti-proliferative effect of melatonin is reversed by the addition of estradiol to the culture. In the present study, we examined whether inhibition by melatonin and subsequent estrogen rescue of MCF-7 cells are correlated with morphological and morphometric changes in these cells. After 4 days of exposure to melatonin, MCF-7 cells showed significantly smaller cell and nuclear sizes than other groups. These morphometric results were closely related to the ultrastructural features observed in these cells. While control and estradiol-treated cells showed increased tumor characteristics, melatonin-treated cells presented greater differentiation, in keeping with their epithelial origin (presence of cytokeratin filament bundles, conspicuous rough endoplasmic reticulum, and Golgi cisternae together with the presence of prominent nucleoli at the nuclear level). Additionally, some melatonin-treated cells displayed degenerative features (mitochondrial swelling with disruption of cristae, cytoplasmic vacuolation, nuclear chromatin disgregation and cell lysis). The addition of estradiol to cells previously incubated with melatonin reversed the changes induced by the latter and these cells showed the same ultrastructural features as the control cells. Our results support the notion that melatonin exerts its antitumor effect through a cell-cycle-specific mechanism by delaying the entry of MCF-7 cells into mitosis. This allows the tumor cells to achieve greater differentiation. The fact that the morphometric and morphological effects induced by melatonin are counteracted by estrogens suggests a cell-cycle acceleration induced by estradiol.

Melatonin inhibits the proliferation of retinal pigment epithelial (RPE) cells in vitro.

The possible antiproliferative effect of melatonin on retinal pigment epithelial (RPE) cells in vitro was investigated. Bovine RPE cells cultured in Ham's F12 medium supplemented with 10% fetal bovine serum had a nuclear density of 73.6 +/- 6.1 nuclei/mm2 at 72 h after seeding. The nuclear density at this time-point was doubled if either 50 or 100 ng/ml human epidermal growth factors (hEGF) was added to the culture medium. When these hEGF-stimulated cells were treated with melatonin from 10 to 500 pg/ml, the proliferation was suppressed with a dose-response relationship. At 250 and 500 pg/ml melatonin, the nuclear densities of the melatonin-treated cells were similar to those of the control cells. Using mitotically active SV-40 transformed human fetal RPE cells cultured in a serum-free medium, melatonin was also shown to be antiproliferative. In the presence of 500 pg/ml melatonin, the proliferation of these cells was inhibited to 77% as compared to the control. These results were further supported by the reduced [H3]thymidine uptake in the melatonin-treated cells. We propose that melatonin, at physiologic concentrations, has an antiproliferative effect, and that cultured RPE cells stimulated to proliferate by either hEGF treatment or SV-40 transfection are responsive to melatonin. Melatonin may either inhibit mitosis in actively dividing cells or modulate hEGF action.

The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system

The pineal hormone, melatonin, was examined for its capacity to modulate the proliferation of a panel of human breast cancer cell lines. Melatonin inhibited, to a varying extent, the proliferation of all three estrogen-responsive cell lines, but had no effect on estrogen-insensitive breast tumor cell lines. Melatonin was also able to specifically block estrogen-induced proliferation in MCF-7 breast cancer cells. However, this action was abolished in the presence of tamoxifen. Therefore, it appears that the antiproliferative effects of melatonin are mediated through the estrogen-response pathway.