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Busschaert, Nathalie,Park, Seong-Hyun,Baek, Kyung-Hwa,Choi, Yoon Pyo,Park, Jinhong,Howe, Ethan N. W.,Hiscock, Jennifer R.,Karagiannidis, Louise E.,Marques, Igor,Fé,lix, Ví,tor,Namkung, Wan Nature Publishing Group 2017 Nature chemistry Vol.9 No.7
<P>Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.</P>
Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells
Ko, Sung-Kyun,Kim, Sung Kuk,Share, Andrew,Lynch, Vincent M.,Park, Jinhong,Namkung, Wan,Van Rossom, Wim,Busschaert, Nathalie,Gale, Philip A.,Sessler, Jonathan L.,Shin, Injae Nature Publishing Group 2014 Nature chemistry Vol.6 No.10
Anion transporters based on small molecules have received attention as therapeutic agents because of their potential to disrupt cellular ion homeostasis. However, a direct correlation between a change in cellular chloride anion concentration and cytotoxicity has not been established for synthetic ion carriers. Here we show that two pyridine diamide-strapped calix[4]pyrroles induce coupled chloride anion and sodium cation transport in both liposomal models and cells, and promote cell death by increasing intracellular chloride and sodium ion concentrations. Removing either ion from the extracellular media or blocking natural sodium channels with amiloride prevents this effect. Cell experiments show that the ion transporters induce the sodium chloride influx, which leads to an increased concentration of reactive oxygen species, release of cytochrome c from the mitochondria and apoptosis via caspase activation. However, they do not activate the caspase-independent apoptotic pathway associated with the apoptosis-inducing factor. Ion transporters, therefore, represent an attractive approach for regulating cellular processes that are normally controlled tightly by homeostasis.