Determinants of Ion-Transporter Cancer Cell Death

Recently, we showed that synthetic anion transporters DSC4P-1 and SA-3 had activity related to cancer cell death. They were found to increase intracellular chloride and sodium ion concentrations. They were also found to induce apoptosis (DSC4P-1) and both induce apoptosis and inhibit autophagy (SA-3). However, determinants underlying these phenomenological findings were not elucidated. The absence of mechanistic understanding has limited the development of yet-improved systems. Here, we show that three synthetic anion transporters, DSC4P-1, SA-3, and 8FC4P, induce osmotic stress in cells by increasing intracellular ion concentrations. This triggers the generation of reactive oxygen species via a sequential process and promotes caspase-dependent apoptosis. In addition, two of the transporters, SA-3 and 8FC4P, induce autophagy by increasing the cytosolic calcium ion concentration promoted by osmotic stress. However, they eventually inhibit the autophagy process as a result of their ability to disrupt lysosome function through a transporter-mediated decrease in a lysosomal chloride ion concentration and an increase in the lysosomal pH. New approaches to treating cancer remain at the forefront of necessity in spite of considerable clinical progress. Among the attractive strategies currently being explored at the early stages of drug discovery is the use of ion transporters that can disrupt the normal ion balance across cell membranes. Recently, a number of synthetic ion transporters have been described. Several with so-called drug-like properties have been shown to enhance chloride fluxes and to induce apoptosis, a process also known as programed cell death. Select agents also show promise for inhibiting autophagy, a key cellular degradation process that is critical to maintaining a healthy cellular environment. Understanding how synthetic ion transporters affect these two cellular processes may prove critical to elucidating their mode of action. The present study thus serves to highlight the potential of ion transporters as possible drug leads and underscore the complexities associated with their mode of action. Park et al. show that three synthetic ion transporters, SA-3, 8FC4P, and DSC4P-1, promote apoptosis by increasing intracellular sodium and chloride concentrations in cells and consequently inducing osmotic stress. In addition, two of the transporters, SA-3 and 8FC4P, induce autophagy by increasing the cytosolic calcium ion concentration promoted by osmotic stress. However, they eventually inhibit the autophagy process because of their ability to disrupt lysosome function through a transporter-mediated decrease in lysosomal chloride ion concentration and an increase in the lysosomal pH.