Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family
Roberta Peruzzo,
Andrea Mattarei,
Michele Azzolini,
Katrin Anne Becker-Flegler,
Matteo Romio,
Giovanni Rigoni,
Andrea Carrer,
Lucia Biasutto,
Sofia Parrasia,
Stephanie Kadow,
Antonella Managò,
Andrea Urbani,
Andrea Rossa,
Gianpietro Semenzato,
Maria Eugenia Soriano,
Livio Trentin,
Syed Ahmad,
Michael Edwards,
Erich Gulbins,
Cristina Paradisi,
Mario Zoratti,
Luigi Leanza,
Ildikò Szabò
Affiliations
Roberta Peruzzo
Department of Biology, University of Padua, Italy
Andrea Mattarei
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Italy
Michele Azzolini
Department of Biomedical Sciences, University of Padua, Italy
Katrin Anne Becker-Flegler
Department of Molecular Biology, University of Duisburg-Essen, Germany
Matteo Romio
Department of Chemical Sciences, University of Padua, Italy
Giovanni Rigoni
Department of Biology, University of Padua, Italy
Andrea Carrer
Department of Biology, University of Padua, Italy; Department of Biomedical Sciences, University of Padua, Italy
Lucia Biasutto
Department of Biomedical Sciences, University of Padua, Italy; CNR Institute of Neuroscience, Padua, Italy
Sofia Parrasia
Department of Biomedical Sciences, University of Padua, Italy
Stephanie Kadow
Department of Molecular Biology, University of Duisburg-Essen, Germany
Antonella Managò
Department of Biology, University of Padua, Italy
Andrea Urbani
Department of Biology, University of Padua, Italy; Department of Biomedical Sciences, University of Padua, Italy
Andrea Rossa
Department of Chemical Sciences, University of Padua, Italy
Gianpietro Semenzato
Department of Medicine, University of Padua, Italy
Maria Eugenia Soriano
Department of Biology, University of Padua, Italy
Livio Trentin
Department of Medicine, University of Padua, Italy
Syed Ahmad
Department of Surgery, Medical School, University of Cincinnati, USA
Michael Edwards
Department of Surgery, Medical School, University of Cincinnati, USA
Erich Gulbins
Department of Molecular Biology, University of Duisburg-Essen, Germany
Cristina Paradisi
Department of Chemical Sciences, University of Padua, Italy
Mario Zoratti
Department of Biomedical Sciences, University of Padua, Italy; CNR Institute of Neuroscience, Padua, Italy
Luigi Leanza
Department of Biology, University of Padua, Italy
Ildikò Szabò
Department of Biology, University of Padua, Italy; CNR Institute of Neuroscience, Padua, Italy; Corresponding author.
The potassium channel Kv1.3, involved in several important pathologies, is the target of a family of psoralen-based drugs whose mechanism of action is not fully understood. Here we provide evidence for a physical interaction of the mitochondria-located Kv1.3 (mtKv1.3) and Complex I of the respiratory chain and show that this proximity underlies the death-inducing ability of psoralenic Kv1.3 inhibitors. The effects of PAP-1-MHEG (PAP-1, a Kv1.3 inhibitor, with six monomeric ethylene glycol units attached to the phenyl ring of PAP-1), a more soluble novel derivative of PAP-1 and of its various portions on mitochondrial physiology indicate that the psoralenic moiety of PAP-1 bound to mtKv1.3 facilitates the diversion of electrons from Complex I to molecular oxygen. The resulting massive production of toxic Reactive Oxygen Species leads to death of cancer cells expressing Kv1.3. In vivo, PAP-1-MHEG significantly decreased melanoma volume. In summary, PAP-1-MHEG offers insights into the mechanisms of cytotoxicity of this family of compounds and may represent a valuable clinical tool.
