TY - JOUR
T1 - Differential effects of esculetin and daphnetin on in vitro cell proliferation and in vivo estrogenicity
AU - Jiménez-Orozco, Fausto Alejandro
AU - Rosales, Ana Alejandra Román
AU - Vega-López, Armando
AU - Domínguez-López, Maria Lilia
AU - García-Mondragón, Ma Juana
AU - Maldonado-Espinoza, Amelia
AU - Lemini, Cristina
AU - Mendoza-Patiño, Nicandro
AU - Mandoki, Juan José
N1 - Funding Information:
We thank Dr. Ingrid Grummt and Dr. Renata Voit from the German Cancer Research Center (DKFZ) for their assistance in performing the immunoblot and the kinase assays as well as for the DAAD scholarship A/01/05883. The authors are grateful to ME Avila Aguirre, M Medina-Jiménez and A Espinoza-Sánchez for their technical assistance. This research was supported by the PAPITT-UNAM IN209010-2 , the CONACYT 52175 and the DAAD .
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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 50-100 mg/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.
AB - 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 50-100 mg/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.
KW - Antiproliferative effect
KW - Coumarin
KW - Cyclin D1
KW - Daphnetin
KW - Esculetin
KW - Estrogenicity
UR - http://www.scopus.com/inward/record.url?scp=80052072002&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2011.06.024
DO - 10.1016/j.ejphar.2011.06.024
M3 - Artículo
SN - 0014-2999
VL - 668
SP - 35
EP - 41
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -