Inhibition of malignant trophoblastic cell proliferation in vitro and in vivo by melatonin

Melatonin inhibited thymidine incorporation into human choriocarcinoma JEG- 3 cells at physiological and pharmacological concentrations in the present study. Gene expression of MT, receptor, but not that of mt, receptor, was d etected in JEG-3 cells by reverse transcription-polymerase chain reaction ( RT-PCR). The gene expression profile of the two human melatonin receptor su btypes in JEG-3 cells was identical to that previously reported for JAr cel ls, whose proliferation had also been shown to be similarly inhibited by ph ysiological and pharmacological concentrations of melatonin. In contrast, m elatonin had no effect on thymidine incorporation into SA-Sub-E cells (a tr ansformed trophoblast cell line), in which gene expression of both receptor subtypes could not be detected. The data suggest that in human placental t rophoblasts, a correlation may exist between MT? receptor gene expression a nd the direct anti-proliferative action of melatonin. Although melatonin ha s been reported to induce G1/S delay in cell cycle progression of JAr cells , no significant changes in the percentages of JEG-3 cells in different cel l cycle phases upon melatonin treatment was recorded by flow cytometric ana lysis. This indicates that G1/S transition delay is probably not an importa nt cellular mechanism in the direct anti-proliferative action of melatonin on human JEG-3 cells in vitro. Furthermore, melatonin inhibited the growth of both JAr and JEG-3 xenograft tumors in athymic nude mice, and prolonged the survival of those animals that developed choriocarcinoma. While the num ber of apoptotic tumor cells was not increased by melatonin, the pineal hor mone induced significant decreases in the numbers of JAr and JEG-3 cells ex pressing proliferating cell nuclear antigen (PCNA) and cyclin A in the tumo rs. Taking into account both the in vitro and in vivo findings, it is likel y that the inhibitory effect of melatonin on choriocarcinoma JAr and JEG-3 cell proliferation in vivo is largely a direct action of the hormone on the tumor cells. (C) 2000 Elsevier Science Inc. All rights reserved.