Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells

Sung Kyun Ko, Sung Kuk Kim, Andrew Share, Vincent M. Lynch, Jinhong Park, Wan Namkung, Wim Van Rossom, Nathalie Busschaert, Philip A. Gale, Jonathan L. Sessler, Injae Shin

Research output: Contribution to journalArticlepeer-review

213 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)885-892
Number of pages8
JournalNature chemistry
Volume6
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

Bibliographical note

Funding Information:
This work was supported by the National Creative Research Initiative (grant no. 2010-0018272 to I.S.) program in Korea, as well as by the Office of Basic Energy Sciences, US Department of Energy (grant no. DE-FG02-01ER15186 to J.L.S.). P.A.G. thanks the Engineering and Physical Sciences Research Council for a postdoctoral fellowship (N.B.) (EP/J009687/1). W.VR. and P.A.G. thank the European Union for a Marie Curie Career Integration grant. A part of this work was carried out with support from the Chemical Biology Research Center in Korea Research Institute of Bioscience and Biotechnology.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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