Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Coyoacán, Mexico.
Eur J Pharmacol. 2011 Oct 1;668(1-2):35-41. doi: 10.1016/j.ejphar.2011.06.024. Epub 2011 Jul 3.
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.
七叶苷（6,7-二羟香豆素）和瑞香素（7,8-二羟香豆素）是民间药物中植物的次生代谢产物。这些化合物在几种肿瘤细胞系中表现出很强的抗增殖活性，并被提议作为潜在的抗癌剂。然而，迄今为止，这些两种化合物的雌激素潜力尚未报道。本研究比较了 esculetin 和瑞香素对 MCF-7 雌激素反应性人癌细胞系的细胞增殖和细胞周期进程的抑制作用。还评估了这两种化合物的体内和体外雌激素活性。Esculetin 在 72 小时暴露后抑制细胞增殖（IC50=193±6.6μM），而瑞香素在 24 小时暴露时表现出抑制作用（72 小时，IC50=73±4.1μM）。这两种作用均显示细胞周期蛋白 D1 基因表达的变化。在非雌激素条件下（E-screening 测定），Esculetin 对 MCF-7 细胞的增殖产生了双相反应；在 10（-8）-10（-6）M 浓度下，浓度诱导增殖作用，EC50=4.07×10（-9）M（E2=2.91×10（-12）M）；在较高浓度（10（-5）-10（-4）M）下，细胞增殖受到抑制。E2 时的相对增殖效应为 52%（E2=100），相对增殖效力为 0.072（E2=100）。此外，Esculetin 在体内试验中显示出在 50-100mg/kg 剂量下的雌激素作用；E2 时的相对子宫增重效应为 37%，相对子宫增重效力为 0.003。相比之下，瑞香素在体外或体内模型中均未诱导雌激素作用。Esculetin 的低雌激素活性可能在绝经后治疗中有用，但不能作为雌激素依赖性肿瘤的安全抗肿瘤剂。瑞香素对 MCF-7 细胞的抗增殖选择性表明，瑞香素也是一种有前途的抗肿瘤剂，也作用于雌激素依赖性肿瘤。
