Dydrogesterone (Duphaston®) and its 20-Dihydro-derivative as Selective Estrogen Enzyme Modulators in Human Breast Cancer Cell Lines. Effect on Sulfatase and on 17β-Hydroxysteroid Dehydrogenase (17β-HSD) Activity

Estradiol (E 2 ) is one of the main factors which control the growth and evolution of breast cancer. Consequently, to block the formation of E 2 inside cancer cells has been an important target in recent years. Breast cancer cells possess all the enzymatic systems (e.g. sulfatase aromatase, 17β-hydroxysteroid dehydrogenase [17β-HSD]) involved in the conversion of estrogen precursors into E 2 . Sulfotransferase, which converts estrogen to its sulfate, is also present in this tumoral tissue. Duphaston® is a synthetic progeslagen with properties similar to the natural progesterone. In the present study we examined the effect of Duphaston® and its 20-dihydro-metabolite on the sulfatase and 17β-HSD activities in MCF-7 and T-47D breast cancer cells. The cells were incubated with estrone sulfate (E 1 S) (5x10-9M) in the absence or presence of Duphaston® or its 20-dihydro-metabolite (5x10 -5 to 5x10 -9 M) for 24h at 37°C. In another series of experiments, estrone (E 1 ) (5x10 -9 M) was incubated with T-47D cells in the absence or presence of the two pragestagens (5x10 -5 to 5x10 -9 M) for 24h at 37°C. E 1 S, E 1 and E 2 were characterized by thin layer chromatography and quantified using the corresponding standard. Duphaston® and its 20-dihydro-metabolite, at concentrations of 5x10 -7 and 5x10 -5 M, inhibited the conversion of E 1 S to E 2 by 14% and 63%, 65% and 74%, respectively, in MCF-7 cells; the values were 15% and 48% and 31% and 51%, respectively, in T-47D cells. In another series of experiments it was observed that, after 24-h incubation, E 1 (5x10 -9 M) was converted in a great proportion to E 2 in the T-47D cells and that this transformation was significantly inhibited by Duphaston® and its 20-dihydro-metabolite. The IC 50 value, corresponding to 50% of the inhibition in the conversion of E 1 to E 2 , was 9x10 -6 M for 20-dihydro-metabolite in this cell line. It was concluded that the progestogen Duphaston® and its 20-dihydro-metabolite are potent inhibitory agents on sulfatase and 17β-HSD activities in breast cancer cells. Duphaston® is a progestogen with properties similar to the endogenous progesterone. The data open interesting perspectives to study the biological responses of these progestogens in clinical trials of patients with breast cancer.