Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, 150081, PR China.
Liver Disease Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200120, PR China.
Biomed Pharmacother. 2020 Aug;128:110244. doi: 10.1016/j.biopha.2020.110244. Epub 2020 May 25.
Emodin is a promising anti-cancer reagent. To improve the physicochemical and anti-cancer property, we modified its structure and get a derivative called emodin succinyl ester (ESE). Here, we investigated the effect of ESE on the suppression of hepatocellular carcinoma (HCC) and the underlying mechanism. Our results showed that ESE strongly inhibited HCC cell proliferation and migration in vitro. Further study revealed that ESE treatment decreased transcription level and protein expression of androgen receptor (AR) and enhancer of zeste homolog 2 (EZH2), two key factors interacting to promote aggressive HCC development. Conversely, overexpression of AR attenuated the inhibitory effect of ESE on EZH2 expression, and vice versa. Importantly, overexpression of AR or EZH2 could counteract ESE-suppressed cell proliferation and migration. The association of ESE-targeted AR and EZH2 with the suppression of tumorigenicity was further confirmed in xenograft and diethylnitrosamine (DEN)-induced HCC mouse models. These findings validate the therapeutic effect of ESE on HCC aggression by targeting the interaction of AR and EZH2, suggesting ESE may be a potent drug in the clinical treatment of HCC.
大黄素是一种很有前途的抗癌试剂。为了改善其理化性质和抗癌性能，我们对其结构进行了修饰，得到了一种叫做大黄素琥珀酸酯（ESE）的衍生物。在这里，我们研究了 ESE 对抑制肝细胞癌（HCC）的作用及其潜在机制。我们的结果表明，ESE 能强烈抑制 HCC 细胞在体外的增殖和迁移。进一步的研究表明，ESE 处理降低了雄激素受体（AR）和增强子的 zeste 同源物 2（EZH2）的转录水平和蛋白表达，这两个关键因子相互作用促进了侵袭性 HCC 的发展。相反，AR 的过表达减弱了 ESE 对 EZH2 表达的抑制作用，反之亦然。重要的是，AR 或 EZH2 的过表达可以抵消 ESE 抑制细胞增殖和迁移的作用。ESE 靶向 AR 和 EZH2 与抑制肿瘤发生的相关性在异种移植和二乙基亚硝胺（DEN）诱导的 HCC 小鼠模型中进一步得到了证实。这些发现验证了 ESE 通过靶向 AR 和 EZH2 的相互作用对 HCC 侵袭性的治疗作用，表明 ESE 可能是 HCC 临床治疗的一种有效药物。
