Esculetin (6,7-dihydroxycoumarin) and
daphnetin (7,8-dihydroxycoumarin) are secondary metabolites of plants used in
folk medicine. These compounds have showed great antiproliferative activity in several tumor cell lines and have been proposed as potential
anticancer agents. However, the estrogenic potential of these two compounds has to date not been reported. The present study compared
esculetin and
daphnetin on the inhibition of cell proliferation and cell cycle progression of the MCF-7
estrogen-responsive human
carcinoma cell line. In vivo and in vitro estrogenic activity for both compounds was also evaluated.
Esculetin inhibited cell proliferation after 72 h exposure (IC50=193 ± 6.6 μM), while
daphnetin evidenced inhibiting effects starting at 24-h exposure (72 h, IC50=73 ± 4.1 μM). Both effects showed changes in cyclin D1 gene expression. In non-estrogenic conditions (E-screening assay),
esculetin produced biphasic response on proliferation of the MCF-7 cells; at 10(-8)-10(-6)M, concentrations induced proliferative effects as EC50=4.07 × 10(-9)M (E(2)=2.91 × 10(-12)M); at higher concentrations (10(-5)-10(-4)M), cell proliferation was inhibited. Relative proliferative effect at E(2) was 52% (E(2)=100), relative proliferative potency was 0.072 (E(2)=100). Additionally,
esculetin tested in vivo showed
estrogenic effects at 50-100mg/kg doses; relative uterotrophic effect at E(2) was 37%, with relative uterotrophic potency registered at 0.003. In contrast,
daphnetin did not induce
estrogenic effects in vitro or with in vivo models. The low estrogenic activity of
esculetin could prove useful in postmenopausal
therapy but not as a safe
antitumor agent in
estrogen-dependent
tumors.
Daphnetin-based antiproliferative selectivity with MCF-7 cells showed that
daphnetin is a promising antitumoral agent also acting on
estrogen dependent
tumors.