Department of Natural Products Chemistry, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Department of Natural Products Chemistry, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Xiamen Institute for Food and Drug Quality Control, Xiamen 3161012, People's Republic of China.
Chem Biol Interact. 2018 Jun 1;289:1-8. doi: 10.1016/j.cbi.2018.04.014. Epub 2018 Apr 24.
Hepatocellular carcinoma (HCC) is a primary malignant tumor with very poor prognosis. To search for more effective compounds for HCC treatment, two new pairs of flavan enantiomers, daphnegiranol C/C (1a/1b) and daphnegiranol D/D (2a/2b), were isolated from the stem bark and roots of Daphne giraldii by using chiral chromatography. MTT assay was applied to evaluate their cytotoxicity against three hepatocarcinoma cell lines (Hep3B, MHCC97H, HepG2) as well as a normal liver cell line L02. The results showed that these compounds preferred to inhibit the growth of Hep3B cells (p53 null). Among them, 2a/2b (the IC value was 4.87 and 3.35 μM, respectively) exhibited a stronger cytotoxic effect than sorafenib (IC = 6.59 μM) in Hep3B cells. A further study demonstrated that 2a/2b could induce apoptotic cell death with an increase in reactive oxygen species (ROS) in Hep3B cells. In addition, the IC values of 2a/2b in HepG2 and MHCC97H cells (both harbored p53 gene) were more than 10-folds greater when compared with Hep3B cells, indicating that 2a/2b selectively exhibited cytotoxicity in p53-null hepatocarcinoma cells. Moreover, inhibition of p53 increased the inhibitory effect in p53-wild hepatocarcinoma cells, as well as apoptotic cells and ROS generation. Taken together, flavan enantiomers 2a/2b selectively induced apoptosis in Hep3B cells because of p53 deficiency.
肝细胞癌 (HCC) 是一种预后极差的原发性恶性肿瘤。为了寻找更有效的 HCC 治疗化合物，从瑞香科芫花属植物芫花的茎皮和根部分离得到了两对新的黄烷对映体，即达芙尼醇 C/C（1a/1b）和达芙尼醇 D/D（2a/2b）。采用手性色谱法对其进行了分离。MTT 法评价了它们对三种肝癌细胞系（Hep3B、MHCC97H、HepG2）以及正常肝细胞系 L02 的细胞毒性。结果表明，这些化合物优先抑制 Hep3B 细胞（p53 缺失）的生长。其中，2a/2b（IC 值分别为 4.87 和 3.35 μM）在 Hep3B 细胞中的细胞毒性作用强于索拉非尼（IC = 6.59 μM）。进一步研究表明，2a/2b 可诱导 Hep3B 细胞发生凋亡性细胞死亡，并增加活性氧（ROS）。此外，与 Hep3B 细胞相比，2a/2b 在 HepG2 和 MHCC97H 细胞（均携带 p53 基因）中的 IC 值增加了 10 倍以上，表明 2a/2b 对 p53 缺失的肝癌细胞具有选择性细胞毒性。此外，抑制 p53 增加了 p53 野生型肝癌细胞的抑制作用以及凋亡细胞和 ROS 的产生。总之，黄烷对映体 2a/2b 选择性地诱导 Hep3B 细胞凋亡是由于 p53 缺失。
