Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on estrogen-dependent tumors. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express estrogen receptors and have the ability to synthesize estrogens from androgens. In the present study we demonstrate that melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of estrogens, through the inhibition of aromatase, the enzyme that catalyzes the conversion of androgens into estrogens. 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 estrogens 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 estrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of estrogen-sensitive tumors, it is conceivable that the modulation of the aromatase by melatonin may play a role in the growth of glioblastomas.

Supported by the Spanish MCYT (BFI2003-06305) and Institute of Health "Carlos III" (PI042603).