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Targeting ion channels in malignancy

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Published: 14 Aug 2019
By Niamh McKerr

The Hallmarks of Cancer 

In January 2000, Hanahan and Weinberg simplified the complex intricacies of cancer into six common traits observed during malignant transformation, termed The Hallmarks of Cancer. This was further developed with two new hallmarks and specific enabling characteristics in an update published in 2011 The Hallmarks of Cancer: the next generation. Ion channels have been linked to many of these underlying principles due to their roles in cellular homeostasis which has resulted in renewed interest in targeting ion channels as a cancer therapeutic strategy.  

Therapeutically, ion channels are the second largest targetable group of membrane proteins in drug discovery after G protein-coupled receptors (GPCRs). Therapeutic inhibition of specific ion channels in the cardiovascular, neurological and pain management settings has been successful for many years. As the toxicity profiles, adverse effects and mode of delivery of ion channel targeting drugs has been studied in other contexts, it may be foreseeable for ion channel drugs to be tested and be repurposed for other pathophysiological areas, such as cancer.  

What are ion channels and what role do they play in cancer? 

Ion channels are a diverse group of proteins spanning cellular membranes and are expressed extensively across all human cells. They are a gateway for ions between organelles, the cytosol and extracellular environment and regulate fundamental cellular processes such as muscle contraction, action potential generation, cell volume regulation and hormone secretion.

Due to their critical role in maintaining cellular homeostasis, ion channel mutations and subsequent dysfunction results in debilitating conditions, sometimes referred to as ‘channelopathies’. This includes cystic fibrosis, QT syndromes and forms of epilepsy. Evidence of changes in ion channel expression and dysfunction in malignancy has led some researchers to suggest that in the cancer setting, oncochannels may contribute to cancer growth and metastasis. Oncochannels may be:  

  1.  absent in a cancer and giving cancer cells an advantage 
  2.  overexpressed 
  3.  have aberrant function and any of these could help the cancer to proliferate, invade, metastasise etc  

When genomic alterations occur during malignant transformation of cells, ion channels are often dysregulated in expression and function alongside other signalling pathways. Oncogenes and tumour suppressor genes result in overactivity and/or limited control of these pathways, respectively, causing cells to become detrimentally rewired, fuelling cell growth and tumour formation. The stage at which specific ion channels become dysregulated during carcinogenesis will likely differ across different cancer types and probably occurs as a consequence rather than a cause.  


Regulation of cellular growth by ion channels 

In normal physiology, ion channels can facilitate cellular proliferation by regulating cell volume (Na+/H+ exchange and Na+,K+,2Cl- co-transport) and controlling membrane potential (voltage-gated sodium and potassium channels, Na+-K+ ATPase). During normal cell cycle progression, cells display hyperpolarised resting membrane potentials (RMP) during the G1 and mitosis phase which becomes depolarised during S and G2 phases. Quiescent cells (muscle, neurons) tend to have a significantly more negative RMP than rapidly proliferating (4 cell embryo, proliferating fibroblast) cells so it is interesting that studies have shown cancer cell types often exhibit a depolarised resting membrane potential. Due to the changes in ion channel expression and activity in malignancy, it may be predictable that proliferation has been shown to be fuelled by overexpression and increased activity of these proteins


Ion channel inhibition can reduce migration and invasion of cancer cells 

Cells require motility for purposes such as wound healing and immune defence. Ion channels facilitate this through regulating cell volume, modulating cellular pH and altering membrane potential. During cancer progression, cells adopt characteristics to invade neighbouring tissues and migrate outside the region of the original tissue site. Many cells undergo a process called epithelial-to-mesenchymal transition (EMT) where they lose their polarity and cell adhesion properties, becoming morphologically elongated and mobile. Ion channels have been shown to both contribute to EMT induction and become altered during EMT.   

Voltage-gated sodium channels (VGSC) have been implicated in cancer cell invasion in breast, lung and prostate cancer cells. Using a Matrigel invasion assay, an in vitro study performed in highly invasive non-small cell lung carcinoma (H460) cells showed that the VGSC blocker, tetrodotoxin (TTX) reduced invasion by approximately 50% in H460 cells. Furthermore, the activation of VGSC using veratridine significantly increased invasion. Interestingly, overexpression of NaV1.7 showed increased invasion in other non-small cell lung carcinoma (NSCLC) cell lines which could then be inhibited upon TTX treatment.  

The calcium-permeable Transient Receptor Potential Melastatin-2 (TRPM2) ion channel is increasingly becoming recognised as a potential therapeutic target in cancer due to its increased expression across many cancers. Upon shRNA-mediated knockdown of TRMP2 in severe combined immunodeficient mice, a significant reduction of gastric tumour volume was detected with increased expression of epithelial markers and reduced mesenchymal marker expression.   


Lessons from repurposing calcium channel blockers as a potential cancer therapy 

Calcium signalling is a critical cellular pathway where Ca2+ acts as a secondary messenger to numerous physiological processes and cell signalling pathways facilitating activities such as muscle contraction, exocytosis, proliferation and apoptosis. It is well understood that in neoplastic cells, calcium signalling becomes rewired with changes detected in calcium channels, transporters, pumps and even the nature of the Ca2+ signal itself.  

Increased expression of voltage-gated calcium channel (VGCC) genes has been associated with numerous cancer types in various studies, even being considered in the top 1% of highly overexpressed genes in some cases. As a result, inhibition of calcium channels has been investigated with favourable therapeutic effects being shown in cases of breast, colorectal and prostate cancers. Numerous epidemiology studies have investigated the association of calcium channel blockers and the risk of developing multiple cancer types which have come to conflicting conclusions. Further refinement of these studies with patient and molecular stratification may highlight any benefits of these drugs


Can ion channel blockers put a break on tumour angiogenesis pathways? 

As malignant progression proceeds, angiogenesis is often induced by cancer cells to obtain a plentiful supply of oxygen and nutrients for proliferation whilst forming an avenue for cells to spread to other organs resulting in metastases. Tumour cells aid this process through release of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) in response to oncogenic signalling pathways and hypoxic conditions. Amoroso et al (2015) showed both in vitro and in vivo, that antagonists of the P2X7 cationic receptor channel can reduce VEGF release, the number of blood vessels and overall tumour volume in neuroblastoma tumour cells.  

Similarly, in another recent study, the effect of mefloquine and 4-aminopyridine (4-AP), a chloride and potassium channel blocker respectively, were investigated using three angiogenic models (in vitro, in vivo and in ovo). Both drugs significantly reduced proliferation of endothelial cells, the number of blood vessels formed and number of branching points per blood vessel.  

 

Pitfalls and progress in targeting ion channels for cancer therapy 

Despite success of ion channel modulators in the treatment of other pathophysiological settings, these drugs have not been employed in the treatment of cancer yet. Considerable in vitro evidence is available suggesting that they may be advantages in cancer combination therapies however, further in vivo and mechanistic studies are required.  

One major issue that may arise using ion channel inhibitors is tumour targeting. As specific ion channels are ubiquitously expressed in different tissue types, there is potential risk of systemic side effects such as cardiac arrhythmia. However, the presence of ion channel splice variants and their association with modulatory subunits could allow for specific drug design to inhibit tumour-specific channels. Alternatively, design of alternative drug delivery systems may facilitate localised targeting e.g. intravesical instillation of bacillus Calmette-Guérin treatment for non-muscle invasive bladder cancer. 

Numerous suggestions on how to target ion channels have arisen, including using drugs that bind the channel in specific conformational states (open/closed), development of more specific blockers and usage of monoclonal antibodies. Only recently has a polyclonal antibody, BIL010t (Biosceptre, Cambridge, UK) targeting non-functional (nfP2X7), a variant of the purinergic P2X7 ion channel, began Phase I trials for treatment of basal cell carcinoma. Previously, issues have arisen in the design of these antibodies due to the short, highly-conserved extracellular regions of the membrane-spanning proteins. 

Despite the extensive evidence of ion channels and their participation in malignant progression, ion channels remain a largely unexploited group of proteins in cancer therapy. Further work is required to establish the underlying biology of ion channel expression and function within carcinogenesis, the effects of ion channel modulators and the potential side effects that may arise upon patient treatment. 

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Published: 14 Aug 2019
By Niamh McKerr

About the author

Niamh McKerr 


Niamh graduated in 2013 with a BSc (Hons) Biomedical Sciences from Queen’s University Belfast. After her undergraduate degree, she worked for three years in the animal pharmaceutical industry at Norbrook Laboratories in Newry. Niamh is now in her final year of a PhD at Queen’s with Professors Karen McCloskey and Ian Mills, which focuses on ion channels in prostate cancer. She became a Society member in 2017 and presented a poster abstract at Pharmacology 2017.

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