Department of Chemistry, Indian Institute of Science Education and Research Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, Maharashtra, India.
Department of Biology, Indian Institute of Science Education and Research Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, Maharashtra, India.
Angew Chem Int Ed Engl. 2020 May 11;59(20):7944-7952. doi: 10.1002/anie.202000961. Epub 2020 Mar 12.
Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance. In this study, we describe a novel 2,4-nitrobenzenesulfonyl (DNS) protected 2-hydroxyisophthalamide system that exploits GSH for its activation into free 2-hydroxyisophthalamide forming supramolecular M /Cl channels. Better permeation of the DNS protected compound into MCF-7 cells compared to the free 2-hydroxyisophthalamide and GSH-activatable ion transport resulted in higher cytotoxicity, which was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway. The GSH-activatable transport-mediated cell death was further validated in rat insulinoma cells (INS-1E); wherein the intracellular GSH levels showed a direct correlation to the resulting cytotoxicity. Lastly, the active compound was found to restrict the growth and proliferation of 3D spheroids of MCF-7 cells with efficiency similar to that of the anticancer drug doxorubicin.
癌细胞利用升高的谷胱甘肽 (GSH) 水平作为内在防御线来逃避细胞凋亡并产生耐药性。在这项研究中，我们描述了一种新颖的 2,4-硝基苯磺酰基 (DNS) 保护的 2-羟基邻苯二甲酰胺系统，该系统利用 GSH 将其激活成游离的 2-羟基邻苯二甲酰胺，形成超分子 M/Cl 通道。与游离的 2-羟基邻苯二甲酰胺和 GSH 激活的离子转运相比，DNS 保护的化合物更好地渗透到 MCF-7 细胞中，导致更高的细胞毒性，这与氧化应激的增加有关，进一步降低了细胞内 GSH 水平并改变了线粒体膜通透性，导致内在凋亡途径的诱导。GSH 激活的转运介导的细胞死亡在大鼠胰岛素瘤细胞 (INS-1E) 中进一步得到验证；其中，细胞内 GSH 水平与产生的细胞毒性直接相关。最后，发现活性化合物能够有效地抑制 MCF-7 细胞的 3D 球体生长和增殖，其效率与抗癌药物阿霉素相似。
