Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
J Enzyme Inhib Med Chem. 2013 Aug;28(4):695-703. doi: 10.3109/14756366.2012.672414. Epub 2012 Apr 3.
Inhibition of the local formation of estrogens seems to be an attractive strategy for pharmacological intervention in hormone-dependent disorders. The direct antiproliferative properties of ten nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitors were investigated on human cancer cell lines of gynecological origin. The mechanism of the antiproliferative action was approximated by cell cycle analysis, fluorescent microscopy, BrdU assay, determination of caspase-3 activity and quantification of the expression of cell cycle regulators at mRNA level. Treatment of HeLa cells with some of the compounds resulted in a concentration-dependent inhibition of the G1-S transition and an increase in the apoptotic population. The most effective agents increased the expression of tumor suppressors p21 and p53, while CDK2 and Rb were down-regulated. The reported anticancer actions of the tested compounds are independent of the 17β-HSD1-inhibiting capacity. These results indicate that it is possible to combine direct antiproliferative activity and 17β-HSD1 inhibition resulting in novel agents with dual mode of action.
抑制雌激素的局部形成似乎是一种有吸引力的策略，可用于对激素依赖性疾病进行药物干预。研究了 10 种非甾体 17β-羟甾类脱氢酶 1（17β-HSD1）抑制剂对妇科来源的人类癌细胞系的直接抗增殖特性。通过细胞周期分析、荧光显微镜、BrdU 测定、半胱天冬酶-3 活性测定和细胞周期调节剂 mRNA 水平表达的定量来近似抗增殖作用的机制。用一些化合物处理 HeLa 细胞导致 G1-S 期转变的浓度依赖性抑制和凋亡群体的增加。最有效的试剂增加了肿瘤抑制剂 p21 和 p53 的表达，而 CDK2 和 Rb 则下调。所测试化合物的报道抗癌作用与 17β-HSD1 抑制能力无关。这些结果表明，将直接的抗增殖活性与 17β-HSD1 抑制相结合是有可能的，从而产生具有双重作用模式的新型试剂。
