Zhang Qian, Fu Ying, Zhao Yufan, Cui Shanshan, Wang Jing, Liu Fengxi, Yuan Yuan, Galons Hervé, Yu Peng, Teng Yuou
China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology Tianjin 300457 China
UCTBS, INSERM U1022, Université Paris Descartes 4 Avenue de l'Observatoire 75006 France.
RSC Adv. 2019 Nov 11;9(63):36690-36698. doi: 10.1039/c9ra07002h.
Indole and its derivatives are widely distributed in both animals and plants. Among its array of biological activities, the anti-tumor activity of indole has garnered much attention. Furthermore, the synthesis and activity of indole derivatives, including isatin, constitute a flourishing research topic. Previously, many isatin derivatives were synthesized by our group, and 5-acetamido-1-(methoxybenzyl) isatin was screened as a candidate anti-tumor agent. In this study, we found that 5-acetamido-1-(methoxybenzyl) isatin inhibited the proliferation of several tumor cell lines, especially the human leukemia cell line K562. Morphological observation suggested that 5-acetamido-1-(methoxybenzyl) isatin induced apoptosis and caused cell cycle arrest in K562 cells. Flow cytometry revealed that 5-acetamido-1-(methoxybenzyl) isatin induced mitochondrial pathway-mediated apoptosis in K562 cells. Moreover, it downregulated Cyclin B and CDC25C and upregulated p-CDC25C and p-CDK1 (Thr14), and induced K562 cell cycle arrest in the G/M phase. Findings from wound healing as well as transwell assay determined that 5-acetamido-1-(methoxybenzyl) isatin could suppress migration and chemotaxis in HepG2 liver cancer cells. 5-Acetamido-1-(methoxybenzyl) isatin also inhibited angiogenesis of the human umbilical vein endothelial cell line HUVEC, determined a cell tube formation study. A clone formation study indicated that 5-acetamido-1-(methoxybenzyl) isatin can inhibit tumor cell proliferation and population dependence in a concentration-dependent manner. Thus, our findings support that 5-acetamido-1-(methoxybenzyl) isatin could be used as a potential antitumor candidate in future investigations.
吲哚及其衍生物广泛分布于动植物中。在其一系列生物活性中，吲哚的抗肿瘤活性备受关注。此外，包括异吲哚酮在内的吲哚衍生物的合成与活性构成了一个蓬勃发展的研究课题。此前，我们小组合成了许多异吲哚酮衍生物，并筛选出5-乙酰氨基-1-（甲氧基苄基）异吲哚酮作为候选抗肿瘤药物。在本研究中，我们发现5-乙酰氨基-1-（甲氧基苄基）异吲哚酮抑制了几种肿瘤细胞系的增殖，尤其是人白血病细胞系K562。形态学观察表明，5-乙酰氨基-1-（甲氧基苄基）异吲哚酮诱导K562细胞凋亡并导致细胞周期停滞。流式细胞术显示，5-乙酰氨基-1-（甲氧基苄基）异吲哚酮诱导K562细胞中线粒体途径介导的凋亡。此外，它下调细胞周期蛋白B和细胞分裂周期蛋白25C（CDC25C），上调磷酸化细胞分裂周期蛋白25C（p-CDC25C）和磷酸化周期蛋白依赖性激酶1（p-CDK1，苏氨酸14位点），并诱导K562细胞周期停滞于G/M期。伤口愈合实验以及Transwell实验结果表明，5-乙酰氨基-1-（甲氧基苄基）异吲哚酮可抑制肝癌细胞系HepG2的迁移和趋化性。细胞管形成实验表明，5-乙酰氨基-1-（甲氧基苄基）异吲哚酮还可抑制人脐静脉内皮细胞系HUVEC的血管生成。克隆形成实验表明，5-乙酰氨基-1-（甲氧基苄基）异吲哚酮能够以浓度依赖性方式抑制肿瘤细胞增殖和群体依赖性。因此，我们的研究结果支持5-乙酰氨基-1-（甲氧基苄基）异吲哚酮在未来研究中可作为一种潜在的抗肿瘤候选药物。
