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

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.