德国埃尔朗根-纽伦堡大学Andriy Mokhir课题组的一项最新研究开发出一种针对癌细胞内质网的自由氧放大分子。该项研究成果发表在2021年3月3日出版的《德国应用化学》上。

蛋白质的折叠和输出以及未折叠蛋白质的水解在癌细胞的内质网（ER）中失衡，从而导致所谓的ER应激。进一步增强这种作用的分子可开发成抗癌药物，包括临床批准的蛋白酶体抑制剂硼替佐米和卡非佐米。但是，这些药物会影响正常细胞，因为正常细胞也强烈依赖于内质网功能，导致活性氧（ROS）累积和其他副作用。

在该研究中，团队为这个问题提出了一个解决方案。课题组人员开发出了仅在肿瘤细胞中活性氧含量升高时才激活的ER靶向前药。这些化合物是胆酸与N-烷基氨基二茂铁基前药的共价化合物。研究人员证实了它们在癌细胞内质网中的累积，以及它们的抗癌效果和癌细胞特异性。这些前药可诱导ER应激，降低线粒体膜电位，产生线粒体ROS，通过坏死导致细胞死亡。该课题组人员还证明了新的前药可在Nemeth‐Kellner淋巴瘤小鼠模型体内被激活。

附：英文原文

Title: An endoplasmic reticulum – specific pro‐amplifier of reactive oxygen species in cancer cells

Author: Andriy Mokhir, Honggui Xu, Margot Schikora, Miroslav Sisa, Steffen Daum, Christina Janko, Christoph Alexiou, Rostyslav Bilyy, Insa Klemt, Leopold Sellner, Wenjie Gong, Michael Schmitt, Galyna Bila

Issue&Volume: 2021-03-03

Abstract: Folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in endoplasmic reticulum (ER) of cancer cells leading to so called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading e.g. to accumulation of reactive oxygen species (ROS) and other side effects. Herein we suggested a solution for this problem. In particular, we developed ER‐targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N‐alkylaminoferrocene‐based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth‐Kellner lymphoma murine model.

DOI: 10.1002/anie.202100054

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202100054