Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family.
Complex I
Kv1.3 potassium channel
Melanoma
Mitochondria
Psoralenic compounds
Reactive oxygen species
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
17
06
2020
revised:
14
08
2020
accepted:
25
08
2020
pubmed:
3
10
2020
medline:
22
6
2021
entrez:
2
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33007503
pii: S2213-2317(20)30910-1
doi: 10.1016/j.redox.2020.101705
pmc: PMC7527709
pii:
doi:
Substances chimiques
Kv1.3 Potassium Channel
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101705Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020. Published by Elsevier B.V.
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