title: Direct Pharmacological Targeting of a Mitochondrial Ion Channel Selectively Kills Tumor Cells In Vivo.
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.
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Leanza
authors.affiliation: Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Romio
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
authors.affiliation: Department of Biomedical Sciences, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Managò
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Venturini
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Arnold-Heller-Strasse 3 (Haus 17), 24105 Kiel, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Zaccagnino
authors.affiliation: Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Carraretto
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kadow
authors.affiliation: Department of Biomedical Sciences, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Martini
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Severin
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Peruzzo
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Arnold-Heller-Strasse 3 (Haus 17), 24105 Kiel, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Arnold-Heller-Strasse 3 (Haus 17), 24105 Kiel, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Visentin
authors.affiliation: Department of Medicine, Hematology and Immunological Branch, University of Padova, and Venetian Institute for Molecular Medicine (VIMM), via G. Orus 2, 35129 Padova, Italy.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.affiliation: Institute for Experimental Cancer Research, Medical Faculty, CAU, Kiel, and Department of Surgery, UKSH, Campus Kiel, Arnold-Heller-Strasse 3 (Haus 17), 24105 Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Department of Biomedical Sciences, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA. Electronic address: erich.gulbins@uni-due.de.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy. Electronic address: cristina.paradisi@unipd.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy; CNR Institute of Neuroscience, viale G. Colombo 3, 35121 Padova, Italy. Electronic address: ildi@civ.bio.unipd.it.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Szabo
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology; D016022:Case-Control Studies; D003374:Coumarins / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D051664:Kv1.3 Potassium Channel; D009943:Organophosphorus Compounds; C000620661:PAPTP compound; C000620712:PCARBTP compound; D026902:Potassium Channel Blockers
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