title: Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells.
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.
authors.affiliation: 1] Department of Chemistry, Yonsei University, Seoul 120-749, Korea [2] Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongwon-gun, Chungbuk 363-883, Korea [3].
authors.forename: Sung-Kyun
authors.initials: SK
authors.lastname: Ko
authors.affiliation: 1] Department of Chemistry &Biochemistry, University of Texas at Austin, Austin, Texas 78712-1224, USA [2].
authors.forename: Sung Kuk
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Chemistry &Biochemistry, University of Texas at Austin, Austin, Texas 78712-1224, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Share
authors.affiliation: Department of Chemistry &Biochemistry, University of Texas at Austin, Austin, Texas 78712-1224, USA.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Lynch
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 406-840, Korea.
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Rossom
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busschaert
authors.affiliation: 1] Chemistry, University of Southampton, Southampton SO17 1BJ, UK [2] Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Philip A
authors.identifier: 0000000197514910
authors.initials: PA
authors.lastname: Gale
authors.affiliation: 1] Department of Chemistry, Yonsei University, Seoul 120-749, Korea [2] Department of Chemistry &Biochemistry, University of Texas at Austin, Austin, Texas 78712-1224, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Sessler
authors.affiliation: Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
authors.forename: Injae
authors.initials: I
authors.lastname: Shin
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D047250:Calixarenes / Q000737:chemistry / Q000378:metabolism; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002712:Chlorides / Q000737:chemistry / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D003958:Diamide / Q000737:chemistry; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport; D008081:Liposomes / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D054852:Small Molecule Libraries / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D027321:Anion Transport Proteins; D002712:Chlorides; D008081:Liposomes; D011166:Porphyrins; D011725:Pyridines; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C469811:calix(4)pyrrole; D003958:Diamide; D047250:Calixarenes; D045304:Cytochromes c; D020169:Caspases; C023666:pyridine