Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China; College of Medical Sciences, Ningde Normal University, Ningde 352100, China.
Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
Biochem Pharmacol. 2020 Jan;171:113680. doi: 10.1016/j.bcp.2019.113680. Epub 2019 Oct 25.
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron, showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo. It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis, the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo. In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，往往具有耐药性。从卷柏中分离得到的新型二氢黄酮类抗癌药二氢芹菜素（DLF）具有较强的抗 CRC 活性，但尚未见报道。本研究在体外和体内研究了 DLF 的作用及其可能的抗 CRC 机制。MTT 检测、透射电镜、流式细胞术和倒置荧光显微镜观察结果表明，DLF 显著抑制 HT29 和 HCT116 细胞活力，诱导 G2/M 期阻滞、细胞凋亡、线粒体膜电位（Δψm）丧失、ROS 生成和细胞内 Ca2+增加。Western blot 和 qPCR 检测结果进一步证实，DLF 通过激活 Caspase-依赖性凋亡，抑制 CRC 细胞中 PI3K/AKT/mTOR 和 Ras/MEK/Erk 信号通路。同时，DLF 在体内显著抑制肿瘤生长，而不引起明显的副作用，其作用机制可能与 Caspase-9 和 Caspase-3 蛋白的激活以及 ki67 和 CD34 蛋白的减少有关。综上所述，这些结果表明 DLF 通过 ER 应激和线粒体途径诱导 ROS 介导的细胞周期阻滞和凋亡，同时抑制 PI3K/AKT/mTOR 和 Ras/MEK/Erk 信号级联。因此，DLF 可能是 CRC 的一种潜在治疗药物。
