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The Emerging Role of Ion Channels in Brain Cancer: Mechanisms...
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The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 22713

Special Issue Editor

Prof. Dr. Terrance G. Johns

E-Mail Website
Guest Editor
Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA 6008, Australia
Interests: glioma; EGFR; antibody therapeutics; ion channels; pediatric brain cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ion channels are membrane proteins that allow the selective passage of single or multiple ion species. The human genome encodes over 300 ion channels that can be activated by a host of extracellular or intracellular molecules or by changes in electrical potential across the cell membrane. Importantly, ion channels are critical mediators of neural growth and plasticity. As exemplified by several recent high-profile publications (see commentary in Nature: 573, 499–501, 2019), there is a rapidly growing appreciation of the role of ion channels in the growth and invasion of both pediatric and adult brain cancers. Given that there are many ion channel drugs already approved for clinical use, repurposing these drugs for brain cancer treatment may be an effective therapeutic approach.

In this Special Issue, we will publish reviews and original research that provide new insights into the role of ion channels in adult and pediatric brain cancer and how they can be targeted therapeutically. Papers exploring the role of ion channels in brain cancer plasticity and neuronal interaction will be particularly welcome.

Prof. Dr. Terrance G. Johns
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • high grade glioma
  • glioblastoma
  • ion channels
  • pediatric brain cancer
  • cellular plasticity
  • drug repurposing
  • neurons

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Published Papers (5 papers)

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Research

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20 pages, 3137 KiB  
Article
Pharmacological Inhibition of Membrane Signaling Mechanisms Reduces the Invasiveness of U87-MG and U251-MG Glioblastoma Cells In Vitro
by Alanah Varricchio, Sidra Khan, Zoe K. Price, Rohan A. Davis, Sunita A. Ramesh and Andrea J. Yool
Cancers 2023, 15(4), 1027; https://doi.org/10.3390/cancers15041027 - 6 Feb 2023
Cited by 11 | Viewed by 3805
Abstract
Impairing the motility of glioblastoma multiforme (GBM) cells is a compelling goal for new approaches to manage this highly invasive and rapidly lethal human brain cancer. Work here characterized an array of pharmacological inhibitors of membrane ion and water channels, alone and in [...] Read more.
Impairing the motility of glioblastoma multiforme (GBM) cells is a compelling goal for new approaches to manage this highly invasive and rapidly lethal human brain cancer. Work here characterized an array of pharmacological inhibitors of membrane ion and water channels, alone and in combination, as tools for restraining glioblastoma spread in human GBM cell lines U87-MG and U251-MG. Aquaporins, AMPA glutamate receptors, and ion channel classes (shown to be upregulated in human GBM at the transcript level and linked to mechanisms of motility in other cell types) were selected as pharmacological targets for analyses. Effective compounds reduced the transwell invasiveness of U87-MG and U251-MG glioblastoma cells by 20–80% as compared with controls, without cytotoxicity. The compounds and doses used were: AqB013 (14 μM); nifedipine (25 µM); amiloride (10 µM); apamin (10 µM); 4-aminopyridine (250 µM); and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 30 µM). Invasiveness was quantified in vitro across transwell filter chambers layered with extracellular matrix. Co-application of each of the ion channel agents with the water channel inhibitor AqB013 augmented the inhibition of invasion (20 to 50% greater than either agent alone). The motility impairment achieved by co-application of pharmacological agents differed between the GBM proneural-like subtype U87-MG and classical-like subtype U251-MG, showing patterns consistent with relative levels of target channel expression (Human Protein Atlas database). In addition, two compounds, xanthurenic acid and caelestine C (from the Davis Open Access Natural Product-based Library, Griffith University QLD), were discovered to block invasion at micromolar doses in both GBM lines (IC50 values from 0.03 to 1 µM), without cytotoxicity, as measured by full mitochondrial activity under conditions matching those in transwell assays and by normal growth in spheroid assays. Mechanisms of action of these agents based on published work are likely to involve modulation of glutamatergic receptor signaling. Treating glioblastoma by the concurrent inhibition of multiple channel targets could be a powerful approach for slowing invasive cell spread without cytotoxic side effects, potentially enhancing the effectiveness of clinical interventions focused on eradicating primary tumors. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)
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Review

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23 pages, 3095 KiB  
Review
Aquaporins and Ion Channels as Dual Targets in the Design of Novel Glioblastoma Therapeutics to Limit Invasiveness
by Alanah Varricchio and Andrea J. Yool
Cancers 2023, 15(3), 849; https://doi.org/10.3390/cancers15030849 - 30 Jan 2023
Cited by 4 | Viewed by 4106
Abstract
Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. [...] Read more.
Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. Transcriptomic analyses of GBM biopsies reveal clusters of membrane signaling proteins that in combination serve as robust prognostic indicators, including aquaporins and ion channels, which are upregulated in GBM and implicated in enhanced glioblastoma motility. Accumulating evidence supports our proposal that the concurrent pharmacological targeting of selected subclasses of aquaporins and ion channels could impede glioblastoma invasiveness by impairing key cellular motility pathways. Optimal sets of channels to be selected as targets for combined therapies could be tailored to the GBM cancer subtype, taking advantage of differences in patterns of expression between channels that are characteristic of GBM subtypes, as well as distinguishing them from non-cancerous brain cells such as neurons and glia. Focusing agents on a unique channel fingerprint in GBM would further allow combined agents to be administered at near threshold doses, potentially reducing off-target toxicity. Adjunct therapies which confine GBM tumors to their primary sites during clinical treatments would offer profound advantages for treatment efficacy. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)
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29 pages, 808 KiB  
Review
Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?
by Brittany Dewdney, Lauren Ursich, Emily V. Fletcher and Terrance G. Johns
Cancers 2022, 14(23), 5932; https://doi.org/10.3390/cancers14235932 - 30 Nov 2022
Cited by 2 | Viewed by 4042
Abstract
Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most [...] Read more.
Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)
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23 pages, 1538 KiB  
Review
Potassium Ion Channels in Malignant Central Nervous System Cancers
by Yasmin Boyle, Terrance G. Johns and Emily V. Fletcher
Cancers 2022, 14(19), 4767; https://doi.org/10.3390/cancers14194767 - 29 Sep 2022
Cited by 7 | Viewed by 3730
Abstract
Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. [...] Read more.
Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)
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25 pages, 4271 KiB  
Review
Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma
by Ruth M. Urbantat, Peter Vajkoczy and Susan Brandenburg
Cancers 2021, 13(12), 2983; https://doi.org/10.3390/cancers13122983 - 15 Jun 2021
Cited by 51 | Viewed by 6165
Abstract
With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment [...] Read more.
With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)
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