School of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
Ruhr-Universität Bochum, Anorganische Chemie I, Universitätsstraße 150, 44801 Bochum, Germany.
Dalton Trans. 2022 Apr 12;51(15):5904-5912. doi: 10.1039/d2dt00788f.
Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)-NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates.
几十年来，人们一直在研究铜（II）配合物的抗癌特性，但没有一种配合物能进入先进的人体临床试验。将铜（II）配合物从研究转化为（临床前）研究的效果不佳，可归因于其在动物模型中的疗效有限，这主要与铜浸出和形态（在生物流体中）有关。在这里，我们报告了一种基于 I 型 Cu 电子传递蛋白活性部位的生物稳定铜（II）配合物。铜（II）配合物 1 由二硫代氮杂环戊烷（具有软和硬供体原子）和两个双氯芬酸单元组成，双氯芬酸是一种非甾体抗炎药（NSAID）。广泛的生物物理和电化学研究表明，1 在溶液中的固态结构得以保留，并且可以在不浸出铜或发生形态（在存在细胞还原剂的情况下）的情况下进入铜（I）和铜（II）氧化态。细胞研究表明，1 以微摩尔浓度杀死大量乳腺癌细胞和高度耐药的乳腺癌干细胞（CSC），并且对一组非癌细胞的毒性明显降低。临床相关球体研究表明，1 能够以类似于金标准抗 CSC 药物萨利霉素的程度抑制富含 CSC 的乳腺球体形成。机制研究表明，1 通过升高细胞内活性氧（ROS）并抑制环氧化酶-2（COX-2）活性来引发乳腺癌 CSC 死亡。前者导致应激途径（JNK 和 p38）的激活，最终导致 caspase 依赖性细胞凋亡。这项研究强化了铜（II）-NSAID 配合物的治疗潜力，并提供了一种受生物启发的方法来开发稳定的、产生 ROS 的基于铜的抗 CSC 药物候选物。
