Tegethoff Jana, Bischoff Roland, Saleh Sawsan, Blagojevic Biljana, Merz Karl-Heinz, Cheng Xinlai
Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Strasse 52, D-67663 Kaiserslautern, Germany.
Molecules. 2017 Sep 13;22(9):1546. doi: 10.3390/molecules22091546.
Indirubin is an active component of the herbal ingredient 'Danggui Longhui wan', which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs) in interference with AMPK and LKB1, the cellular metabolic sensors. In this study, we screened the effect of meisoindigo on a panel of 300 protein kinases and found that it selectively inhibited Stat3-associated tyrosine kinases and further confirmed its activity in cell based assays. To gain a deeper insight into the structure-activity relationship we produced 7 bromo-derivatives exhausting the accessible positions on the bisindole backbone except for in the 4-position due to the space limitation. We compared their anti-proliferative effects on tumor cells. We found that 6-bromomeisoindigo showed improved toxicity in company with increased Stat3 inhibition. Moreover, we detected that 6-bromomeisoindigo induced apoptosis of 95% of CD133+ pancreatic cancer cells. Considering that CD133 is a common marker highly expressed in a range of CSCs, our results imply the potential application of 6-bromomeisoindigo for the treatment of CSCs in different types of cancers.
靛玉红是中药成分“当归龙荟丸”的一种活性成分，在中国曾用于治疗炎症和慢性粒细胞白血病。最近的研究表明，其衍生物甲基异靛蓝（也称为美索靛蓝）优先靶向癌症干细胞（CSCs），干扰细胞代谢传感器AMPK和LKB1。在本研究中，我们筛选了美索靛蓝对一组300种蛋白激酶的作用，发现它选择性抑制与Stat3相关的酪氨酸激酶，并在细胞实验中进一步证实了其活性。为了更深入了解构效关系，由于空间限制，我们制备了7种溴代衍生物，穷尽了双吲哚骨架上除4位以外的可修饰位置。我们比较了它们对肿瘤细胞的抗增殖作用。我们发现6-溴美索靛蓝在增强对Stat3抑制作用的同时，毒性有所提高。此外，我们检测到6-溴美索靛蓝可诱导95%的CD133+胰腺癌细胞凋亡。鉴于CD133是在一系列癌症干细胞中高表达的常见标志物，我们的结果表明6-溴美索靛蓝在治疗不同类型癌症的癌症干细胞方面具有潜在应用价值。
