The protective role of melatonin in cadmium-induced proliferation of ovarian cancer cells (original) (raw)
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The oncostatic action of melatonin in an ovarian carcinoma cell line
Journal of Pineal Research, 1999
Abstract: Melatonin is reported to reduce proliferation in many cell types, but the effect is small and the results are inconsistent. Information on the mechanism by which melatonin exerts its antiproliferative effects might provide insight into the variability of the response. In an ovarian adenocarcinoma cell line (BG-1), we find that melatonin at concentrations of 10−9-10−7 M caused a 20–25% reduction in cell number. Melatonin also resulted in a similar reduction in [3H]-thymidine incorporation with no significant increase in cell death as measured by trypan blue incorporation. The Kd for melatonin reduction in cell number was ∼ 5 × 10−10 M. Melatonin ML2 receptors have a Kd for melatonin binding in the low nM range and are linked to the production of the calcium mobilizing agent inositol-1, 4, 5-trisphosphate (IP3). To investigate whether melatonin signaling involves an increase in cytosolic-free calcium, BG-1 cells were loaded with the calcium sensitive indicator, fura-2. Acute addition of melatonin (10−5-10−9 M) did not alter cytosolic calcium. Addition of the putative nuclear receptor agonist CGP52608 caused a dose-dependent inhibition of cell number with a Kd of ∼ 2 × 10−9 M. Addition of CGP52608 caused a similar reduction in [3H]-thymidine incorporation. Neither melatonin (10−8 M-10−5 M) nor CGP52608 at concentrations below 10−7 M induced cell death associated with the inhibition of cell proliferation; however, addition of CGP52608 at a high dose (10−7 M) caused an increase in cell death, consistent with apoptosis. Growth inhibition by melatonin or CGP52608 did not alter the percentage of cells in G1 versus S/G2/M.
Cancer Letters, 1995
The effect of various concentrations of melatonin on the growth of ME-180 human cervical cancer cells in vitro was examined. Melatonin at a concentration of 2 mM inhibited the growth of the cells after 48 h of melatonin treatment. At concentrations of 2 PM or 0.1 mM melatonin had no effect on cell proliferation. To determine whether the inhibitory effect of melatonin on the growth of the cervical cancer cells was linked to intracellular glutathione ccmcentrations, experiments were performed in which intracellular glutathione levels were depressed by the addition of buthionine sulfoximine to the incubation medium 24 h before the addition of melatonin. The results show that 2 mM melatonin treatment still inhibits the growth of cells when glutathione levels are depressed by 95% Even with depressed glutathione levels, 0.1 mM melatonin still had no effect on cell growth. Thus, melatonin's ability to inhibit ME-180 cervical cell growth in vitro may be independent of intracellular glutathione concentrations. It was also found that during one passage the intracellular glutathione levels of cervical cancer cells gradually decreases. When 4.5day-ald medium was replaced with new medium, intracellular glutathione levels partially recovered within 36 h. This suggests that the observed gradual reduction of cellular glutathione during incubation was a resutt of a reduction of some constituent in the medium after prolonged culture of the cells.
Scientific reports, 2017
There is an urgent need to identify targeting molecules to control invasion and metastasis in cancer patients. We first isolated cancer stem cells (CSCs) from SKOV3 ovarian cancer cells and then investigated the role of melatonin in invasiveness and migration of CSCs compared to SKOV3 cells. The proportion of CSCs in SKOV3 cells was as low as 1.28% with overexpression of both CD133 and CD44. The ability of spheroid formation along with SOX2 overexpression revealed a high self-renewal potential in isolated cells. Melatonin (3.4 mM) inhibited proliferation of CSCs by 23% which was confirmed by a marked decrease in protein expression of Ki67, as a proliferation marker. Applying luzindole, a melatonin receptor 1, 2 inhibitor, partially abolished anti-proliferative effect of melatonin. Melatonin also decreased Epithelial mesenchymal transition (EMT) related gene expressions including ZEB1, ZEB2, snail and vimentin with increase in E-cadherin as a negative EMT regulator. Incubation of CSC...
Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms
Carcinogenesis
Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers, and most patients develop chemoresistance after first-line treatments. Despite recent advances, the 5-year relative survival is ~45% for all OC subtypes, and invasive epithelial OC has only a 17% survival rate when diagnosed at a late stage. Identification of new efficacious molecules or biomarkers represents important opportunities in the treatment of OC. The pharmacological and physiological properties of melatonin indicate this agent could be useful against OC progression and metastasis. In normal cells, melatonin has potent antioxidant and anti-apoptotic actions. Conversely, melatonin has pro-oxidant as well as anti-proliferative, anti-angiogenic and immunomodulatory properties in many cancer types including hormone-dependent cancers. Although melatonin receptors have been identified in OC cells, the exact mechanism by which melatonin induces anticancer activities remains incompletely understood. Clinical studies have reported negative correlation between aggressiveness of OC and serum levels of melatonin, reinforcing the idea that melatonin may be a critical factor determining OC development. In vitro and in vivo studies suggest melatonin differentially regulates multiple signaling pathways in OC cells. This focused review explores the potential mechanisms of action of melatonin on cultured OC cells and in experimental models of OC in an attempt to clarify how melatonin modulates the signaling pathways involved in cancer cell apoptosis, survival, inflammation, proliferation and metabolic processes. Based on the evidence presented, we feel that melatonin, as an agent that controls cellular signals associated with malignancy, may be beneficial in combination with other therapeutics for OC treatment.
Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma
Endocrine-related cancer, 2015
Apoptosis plays an important role in the treatment of cancer and targeting apoptosis-related molecules in ovarian cancer (OC) is of great therapeutic value. Melatonin (Mel) is an indoleamine displaying several anticancer properties and has been reported to modulate apoptosis signaling in multiple tumor subtypes. We investigated OC and the role of Mel therapy on the pro-apoptotic (p53, BAX, caspase-3, and cleaved caspase-3) and anti-apoptotic (Bcl-2 and survivin) proteins in an ethanol (EtOH)-preferring rat model. To induce OC, the left ovary was injected directly with a single dose of 100 µg 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 µL of sesame oil under the bursa. Right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of Mel (200 µg/100 g b.w./day) for 60 days. Body weight gain, EtOH consumption and energy intake were unaffected by the treatments. Interestingly, absolute and relative OC masses showed a signif...
Research in Pharmaceutical Sciences
Cadmium (Cd) as a metalloesterogen may have a role in development of ovarian cancer. One of the critical target genes of estrogens is progesterone receptors (PRs). There are controversial studies on association between Cd, PRs, and cell proliferation. This study investigates the effect of Cd on proliferation of ovarian cancer cell lines, PRA and PRB expression and their relationship. OVCAR3 and SKOV3 cells were treated with CdCl 2 (1-100 nM) and cell proliferation was assayed using bromodeoxyuridine (BrdU) method. The mechanism underlying the proliferative effect of Cd mediated by PRs was examined using cell transfection with PR-small interfering RNA (siRNA) and western blot analysis. Our results showed the involvement of PRs in Cd induced proliferation of ovarian cancer cells. Progesterone receptors are involved in proliferative effect of Cd. Moreover, Cd modified the expression of PRA and PRB and induced ovarian cancer cell proliferation through the change of PRA/PRB ratio. In conclusion, there is a mechanistic association between Cd effects on ovarian cancer cell proliferation, estrogen receptors and PRs expression.
Melatonin attenuates estradiol-induced oxidative damage to DNA: relevance for cancer prevention
Experimental biology and medicine (Maywood, N.J.), 2001
Estrogens exert pro-oxidative effects and have been shown to damage DNA, potentially leading to cancer. Melatonin is a well-known antioxidant, free radical scavenger, and oncostatic agent. Changes in the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), an index of DNA damage, and the levels of malondialdehyde + 4-hydroxyalkenals, an index of lipid peroxidation, were measured in kidneys, liver, and testes from hamsters treated with E2 (75 mg/kg body wt) and were collected 3 or 5 hr later. Other animals were treated with melatonin (15 mg/kg body wt, 30 min before and 120 min after E2 treatment) or were given both compounds. Additionally, lipid peroxidation was measured in liver homogenates exposed to ferrous sulfate (15 microM) in vitro. E2 treatment caused an increase in 8-oxodGuo levels in kidneys collected 5 hr after E2 administration, and in liver 3 hr after estrogen treatment. Melatonin completely prevented E2-induced DNA damage in both organs. Melatonin alone or wh...