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

Abstract

Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of oestrogens, through the inhibition of aromatase, the enzyme that catalyses the conversion of androgens into oestrogens. These results are supported by three types of evidence. Firstly, melatonin counteracts the growth stimulatory effects of testosterone on glioma cells, which is dependent on the local synthesis of oestrogens from testosterone. Secondly, we found that melatonin reduces the aromatase activity of C6 cells, measured by the tritiated water release assay. Finally, by (RT) -PCR, we found that melatonin downregulates aromatase mRNA steady-state levels in these glioma cells. We conclude that melatonin inhibits the local production of oestrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of oestrogen-sensitive tumours, it is conceivable that the modulation of the aromatase by pharmacological melatonin may play a role in the growth of glioblastomas.

Do Steroid Hormones Play a Role in the Etiology of Glioma?

“…(Tibolone is referred to as "non-selective" because it binds to all major steroid receptors.) A recent report indicated that pharmacologic doses of melatonin inhibited the local production of estrogens but also seemed to inhibit the growth of C6 rat glioma cells, potentially suggesting that endogenous estrogens might promote tumor growth (70). However, it is also possible that inhibition of glioma cell proliferation by melatonin was unrelated to its effects on estrogen synthesis.…”

Shift work and cancer – considerations on rationale, mechanisms, and epidemiology

“…Melatonin down-regulates both the expression of protein growth factors and proto-oncogens stimulated by estrogen (101,102) and the epidermal growth factor receptor 2 (HER2/neu), the expression of which is associated with increased malignancy in some forms of human breast cancer (103). Melatonin modulates local estrogen biosynthesis (which is of special importance in post-menopausal breast cancer) by reducing aromatase expression and activity (104,105). It inhibits telomerase activity (98-100) and the transcription of Cyclin D1 expression.…”

Inhibitory effects of melatonin on sulfatase and 17β-hydroxysteroid dehydrogenase activity and expression in glioma cells

“…As occurs in other estrogen-responsive tissues, in the estrogen-sensitive cells of the normal brain and brain tumors, the binding of estradiol to membrane-associated and intracellular estrogen receptors allows these nonneuronal cells of the central nervous system to respond to estrogens (15)(16)(17)(18); thus, glioma cells are able to respond significantly to estradiol in the culture (33). In addition, previous studies have also shown that the human brain, human neuronal cell lines and glioma cell lines express aromatase and sulfatase and are, therefore, capable of producing estrogens from androgens or estrogen sulfates (19,20,38).…”

“…In previous studies (26,30,33) a strong inhibitory effect induced mainly by millimolar concentrations of melatonin on C6 glioma cells growth has been described. In the same way, high concentrations of melatonin are also necessary to obtain oncostatic actions in neuroblastoma cells and other kinds of tumor cells (42,43).…”

“…In other estrogen-dependent tumors, such as mammary tumors, the inhibition of aromatase activity by aromatase inhibitors is currently one of the first therapeutic strategies used against the growth of these tumors (32) and the inhibition of sulfatase activity offers a potential new additional option of endocrine therapy, initially in patients whose disease has progressed after prior aromatase inhibitor therapy. Since melatonin inhibits the growth of C6 cells (26,30,33), and this indoleamine has been demonstrated to be capable of decreasing aromatase expression and activity in glioma cells (33) and other tumor cell lines (9), our objective in the present study was to analyze the possible effects of melatonin on the local synthesis of estrogens in C6 glioma cells, particularly through the modulation of sulfatase and 17ß-hydroxysteroid dehydrogenase activity and expression.…”