Kv1.3: a multifunctional channel with many pathological implications

Serrano-Albarrás, Antonio; Estadella, Irene; Cirera-Rocosa, Sergi; Navarro-Pérez, María; Felipe, Antônio

doi:10.1080/14728222.2017.1420170

Cited by 40 publications

(76 citation statements)

References 22 publications

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“…The role of Kv1.3 channels in the immune responses to tumors may be more complex, dependant dynamically on disease stage ( 191 ). On the one hand, tumor infiltration may involve downregulation of the channel ( 192 ).…”

Section: Potential Novel Immunotherapy Co-targetsmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a “backbone,” we cover a range of emerging (“second-generation”) therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic “gene circuits.” A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.

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Section: Potential Novel Immunotherapy Co-targetsmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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“…Refs. [ [40] , [18] , [37] ]). In leukocytes, where the repertoire of K + channels is limited, Kv1.3 fine-tunes the activation and proliferation of these cells and regulates the immune response [ 3 , 5 ], making Kv1.3 a good pharmacological target for autoimmune and chronic inflammatory diseases [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…In leukocytes, where the repertoire of K + channels is limited, Kv1.3 fine-tunes the activation and proliferation of these cells and regulates the immune response [ 3 , 5 ], making Kv1.3 a good pharmacological target for autoimmune and chronic inflammatory diseases [ 6 ]. Moreover, Kv1.3 has been related to non-insulin-dependent type II diabetes mellitus, obesity and cancer, since it regulates insulin sensitivity, cell proliferation and apoptosis [ 2 ]. In particular, in the context of cancer and autoimmune diseases a drug acting on the plasmamembrane Kv1.3 is expected to exert beneficial effects by reducing proliferation of the pathological cells (see e.g.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Moreover, Kv1.3 channel was also discovered in the cis-Golgi apparatus membrane in rat cancer astrocytoma C6 cells as well as in non-cancerous CTX TNA2 astrocyte cell line and in rat primary astrocytes (7). Activity of Kv1.3 channel plays an important role in cell proliferation and apoptosis (3, 5, 8–14). The channel activity is inhibited by many chemically unrelated compounds: heavy-metal cations, small-molecule organic compounds and venom-isolated oligopeptides (3, 8–14).…”

Section: Introductionmentioning

confidence: 99%

Voltage-Gated Potassium Channel Kv1.3 as a Target in Therapy of Cancer

et al. 2019

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Voltage-gated potassium channel Kv1.3 is an integral membrane protein, which is selectively permeable for potassium ions and is activated upon a change of membrane potential. Channel activation enables transportation of potassium ions down their electrochemical gradient. Kv1.3 channel is expressed in many cell types, both normal and cancer. Activity of the channel plays an important role in cell proliferation and apoptosis. Inhibition of Kv1.3 channel may be beneficial in therapy of several diseases including some cancer disorders. This review focuses on Kv1.3 channel as a new potentially attractive molecular target in cancer therapy. In the first part, changes in the channel expression in selected cancer disorders are described. Then, the role of the channel activity in cancer cell proliferation and apoptosis is presented. Finally, it is shown that some low molecular weight organic inhibitors of the channel including selected biologically active plant-derived polycyclic compounds may selectively induce apoptosis of Kv1.3-expressing cancer cells while sparing normal cells and healthy organs. These compounds may be promising candidates for putative application in therapy of some cancer disorders, such as melanoma, pancreatic ductal adenocarcinoma (PDAC), or B-type chronic lymphocytic leukemia (B-CLL).

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Kv1.3: a multifunctional channel with many pathological implications

Cited by 40 publications

References 22 publications

Immuno-Oncology: Emerging Targets and Combination Therapies

Immuno-Oncology: Emerging Targets and Combination Therapies

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

Voltage-Gated Potassium Channel Kv1.3 as a Target in Therapy of Cancer

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