Park Sang-Hyun, Hwang Inhong, McNaughton Daniel A, Kinross Airlie J, Howe Ethan N W, He Qing, Xiong Shenglun, Kilde Martin Drøhse, Lynch Vincent M, Gale Philip A, Sessler Jonathan L, Shin Injae
Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
These authors contributed equally.
Chem. 2021 Dec 9;7(12):3325-3339. doi: 10.1016/j.chempr.2021.08.018. Epub 2021 Sep 14.
A number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here, we show that three hemispherand-strapped calix[4]pyrrole-based ion-pair receptors act as efficient Na/K exchangers in the presence of Cl in liposomal models and promote Na influx and K efflux (Na/K exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. This study provides support for the notion that synthetic receptors, which perturb cellular cation homeostasis, may provide new small molecules with potentially useful apoptotic activity.
为了基础研究和生物医学应用，已经开发了许多人工阳离子离子载体（或转运体）。然而，它们的作用机制以及细胞内阳离子浓度变化与诱导细胞死亡之间的假定相关性仍知之甚少。在这里，我们表明，在脂质体模型中，三种基于半球形束缚杯[4]吡咯的离子对受体在有Cl存在的情况下作为有效的Na/K交换剂起作用，并促进癌细胞中的Na内流和K外流（Na/K交换）以诱导凋亡。机制研究表明，这些阳离子交换剂通过扰乱细胞内阳离子稳态在癌细胞中诱导内质网（ER）应激，促进活性氧的产生，并最终增强线粒体介导的凋亡。然而，它们既不诱导渗透应激也不影响自噬。这项研究为这样一种观点提供了支持，即扰乱细胞阳离子稳态的合成受体可能提供具有潜在有用凋亡活性的新小分子。
