Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Venturini, Elisa; Leanza, Luigi; Azzolini, Michele; Kadow, Stephanie; Mattarei, Andrea; Weller, Michael; Tabatabai, Ghazaleh; Edwards, Michael J.; Zoratti, Mario; Paradisi, Cristina; Szabó, Ildikò; Gulbins, Erich; Becker, Katrin Anne

doi:10.1159/000480643

Cited by 43 publications

(38 citation statements)

References 59 publications

(72 reference statements)

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“… Channel Tumour Drug References Cav3.2 GSC Mibefradil [ 92 ] Cav1.1, Cav1.2, Cav1.3, Cav1.4 Rat Derived GBM GBM mouse models GBM cell lines Pimozide Fluspirilene [ 107 , 108 , 109 ] Nav1.1 and Nav1.2. Human GBM Valporate Levetiracetam [ 110 , 111 , 112 ] Nav1.4 and Nav1.5 GBM cell line Riluzole [ 113 , 114 ] Kv1.4 GBM cell line Tamoxifen [ 115 ] Kv1.3 Human and mouse GBM biopsies Clofazimine [ 116 , 117 ] EAG1 Glioma Imipramine [ 118 , 119 ] …”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

“…Kv1.3 voltage gated potassium channel is expressed in the mitochondria of both mouse and human models; treatment with novel Kv1.3 inhibitors PAPTP and PCARBTP both induce cell death in glioma cell lines [ 117 ]. Similarly, clofazimine an antimycobacterial indicated in the treatment for leprosy, exhibited inhibitory effects [ 117 ].…”

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

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Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

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Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

Section: Ion Channel Inhibitors As Therapeutic Targetsmentioning

confidence: 99%

Ion Channels as Therapeutic Targets in High Grade Gliomas

Griffin

Khan

Basu

et al. 2020

Cancers

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“…To minimize the possibility of interference with the pharmacological activity, one may resort to prodrugs in which the mitochondria‐targeting portion is shed, hopefully after performing its task. In some such studies, the strategy has relied on the incorporation, into the linker portion of the molecule, of a hydrolyzable bond system such as a carbamate group ( Leanza et al ., ; Peruzzo et al ., ; Teixeira et al ., ; Venturini et al ., ; Mattarei et al ., ). Insurance that the regeneration of the active principle takes place only, or mostly, at mitochondria may be a desirable feature.…”

Section: Successfully Applied Strategies For In Vivo Subcellular Targmentioning

confidence: 97%

Pharmacological modulation of mitochondrial ion channels

Leanza

Checchetto

Biasutto

et al. 2019

British J Pharmacology

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The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…In prostate cancer cells, VGKC expressions are linked to the increased metastatic potential 93 . Furthermore, inhibition of K v 1.3 VGKC has been shown to induce apoptosis of glioblas-toma cells in vitro 94 .…”

Section: E Glioblastoma Electrotaxis Is Mediated By Voltage-gated Iomentioning

confidence: 99%

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

Tsai

IJspeert

Shen

2020

Preprint

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Transformed astrocytes in the most aggressive form cause glioblastoma, the most common cancer in central nervous system with high mortality. The physiological electric field by neuronal local field potentials and tissue polarity may guide the infiltration of glioblastoma cells through the electrotaxis process. However, microenvironments with multiplex gradients are difficult to create. In this work, we have developed a hybrid microfluidic platform to study glioblastoma electrotaxis in controlled microenvironments with high throughput quantitative analysis by a machine learning-powered single cell tracking software. By equalizing the hydrostatic pressure difference between inlets and outlets of the microchannel, uniform single cells can be seeded reliably inside the microdevice. The electrotaxis of two glioblastoma models, T98G and U-251MG, require optimal laminin-containing extracellular matrix and exhibits opposite directional and electro-alignment tendencies. Calcium signaling is a key contributor in glioblastoma pathophysiology but its role in glioblastoma electrotaxis is still an open question. Anodal T98G electrotaxis and cathodal U-251MG electrotaxis require the presence of extracellular calcium cations. U-251MG electrotaxis is dependent on the P/Q-type voltage-gated calcium channel (VGCC) and T98G is dependent on the R-type VGCC. U-251MG and T98G electrotaxis are also mediated by A-type (rapidly inactivating) voltage-gated potassium channels and acidsensing sodium channels. The involvement of multiple ion channels suggests that the glioblastoma electrotaxis is complex and patient-specific ion channel expression can be critical to develop personalized therapeutics to fight against cancer metastasis. The hybrid microfluidic design and machine learning-powered single cell analysis provide a simple and flexible platform for quantitative investigation of complicated biological systems.

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Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

Cited by 43 publications

References 59 publications

Ion Channels as Therapeutic Targets in High Grade Gliomas

Ion Channels as Therapeutic Targets in High Grade Gliomas

Pharmacological modulation of mitochondrial ion channels

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

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