Nat. Chem. 10.1038/nchem.2021

The maintenance of ion homeostasis is crucial to ensure cell viability. Disrupting this balance through increased ion flux into cells triggers programed cell death, a process known as apoptosis. Prodigiosin is a natural product that promotes cancer cell death by allowing the influx of HCl into cells across what are normally impermeable membranes. Many groups have synthesized similar ion transporters, but few have been successful in mimicking the biological effects of prodigiosin. Ko et al. synthesized pyridine diamide–strapped calixpyrroles, which transport chloride and sodium ions across lipophilic membranes. Using ion-specific fluorescent probes, the authors observed an increase in the intracellular levels of chloride and sodium in mammalian cells when the small-molecule transporter was present. These cell lines exhibited reduced cellular viability features consistent with caspase-mediated apoptosis, including increased reactive oxygen species, mitochondrial cytochrome c release and activation of caspases. The authors verified the requirement of sodium and chloride for promoting apoptosis. For instance, they showed that the frequency of cell death decreased when the transporter was added to cells cultured in a chloride- or sodium-free medium. Finally, the authors found that sodium chloride influx and ROS production occurred earlier than the first indication of cell death, confirming that the influx of ions into cells promotes apoptosis.