Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family

• Published in: Redox biology Vol. 37; p. 101705
• Main Authors: Peruzzo, Roberta, Mattarei, Andrea, Azzolini, Michele, Becker-Flegler, Katrin Anne, Romio, Matteo, Rigoni, Giovanni, Carrer, Andrea, Biasutto, Lucia, Parrasia, Sofia, Kadow, Stephanie, Managò, Antonella, Urbani, Andrea, Rossa, Andrea, Semenzato, Gianpietro, Soriano, Maria Eugenia, Trentin, Livio, Ahmad, Syed, Edwards, Michael, Gulbins, Erich, Paradisi, Cristina, Zoratti, Mario, Leanza, Luigi, Szabò, Ildikò
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2020; Elsevier
• Subjects: Animals; Cell Line, Tumor; Complex I; Dissection; Humans; Kv1.3 potassium channel; Kv1.3 Potassium Channel - antagonists & inhibitors; Kv1.3 Potassium Channel - genetics; Medicin och hälsovetenskap; Melanoma; Mice, Inbred C57BL; Mitochondria; Psoralenic compounds; Reactive Oxygen Species; Research Paper; Psoralenic compounds; Mitochondria; Reactive oxygen species; Complex I; Kv1.3 potassium channel; Melanoma
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101705

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. [Display omitted] •The mitochondrial channel mitoKv1.3 is a promising pharmacological target.•MitoKv1.3 interacts with Complex I of the respiratory chain.•Psoralenic inhibitors of Kv1.3 facilitate the diversion of e− from complex I to O2.•A novel psoralenic Kv1.3 inhibitor with increased solubility reduces melanoma volume.