Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/115520
Title: Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo
Authors: Leanza, Luigi 
Romio, Matteo 
Becker, Katrin Anne
Azzolini, Michele
Trentin, Livio 
Managò, Antonella 
Venturini, Elisa
Zaccagnino, Angela
Mattarei, Andrea 
Carraretto, Luca 
Urbani, Andrea 
Kadow, Stephanie
Biasutto, Lucia 
Martini, Veronica
Severin, Filippo 
Peruzzo, Roberta 
Trimarco, Valentina 
Egberts, Jan-Hendrik
Hauser, Charlotte
Visentin, Andrea 
Semenzato, Gianpietro 
Kalthoff, Holger
Zoratti, Mario 
Gulbins, Erich
Paradisi, Cristina 
Szabo, Ildiko
Keywords: ROS-induced apoptosis;bioenergetics;chronic lymphocytic leukemia;ion channels and cancer;mitochondrial metabolism;mitochondrial potassium channels;mitochondriotropic inhibitors;orthotopic melanoma model;pancreatic ductal adenocarcinoma;pharmacokinetics
Keywords Plus: KV1.3 POTASSIUM CHANNEL;CHRONIC LYMPHOCYTIC-LEUKEMIA;BAX-INDUCED APOPTOSIS;PERMEABILITY TRANSITION;CANCER-THERAPY;AUTOIMMUNE-DISEASES;T-LYMPHOCYTES;ROS RELEASE;COMPLEX-I;MECHANISMS
Mesh headings: Antineoplastic Agents;Kv1.3 Potassium Channel;Leukemia, Lymphocytic, Chronic, B-Cell;Potassium Channel Blockers
Secondary Mesh headings: Aged;Animals;Carcinoma, Pancreatic Ductal;Case-Control Studies;Coumarins;Drug Stability;Female;Humans;Male;Melanoma;Mice, Inbred C57BL;Middle Aged;Mitochondria;Molecular Targeted Therapy;Organophosphorus Compounds;Pancreatic Neoplasms
Issue Date: 2017
Publisher: CELL PRESS
Journal: Cancer cell 
Abstract: 
The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.
URI: http://hdl.handle.net/20.500.12857/115520
ISSN: 15356108
DOI: 10.1016/j.ccell.2017.03.003
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